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Sample records for rat ventral tegmental

  1. Sources of input to the rostromedial tegmental nucleus, ventral tegmental area, and lateral habenula compared: A study in rat.

    PubMed

    Yetnikoff, Leora; Cheng, Anita Y; Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S

    2015-11-01

    Profound inhibitory control exerted on midbrain dopaminergic neurons by the lateral habenula (LHb), which has mainly excitatory outputs, is mediated by the GABAergic rostromedial tegmental nucleus (RMTg), which strongly innervates dopaminergic neurons in the ventral midbrain. Early reports indicated that the afferent connections of the RMTg, excepting its very strong LHb inputs, do not differ appreciably from those of the ventral tegmental area (VTA). Presumably, however, the RMTg contributes more to behavioral synthesis than to simply invert the valence of the excitatory signal coming from the LHb. Therefore, the present study was done to directly compare the inputs to the RMTg and VTA and, in deference to its substantial involvement with this circuitry, the LHb was also included in the comparison. Data indicated that, while the afferents of the RMTg, VTA, and LHb do originate within the same large pool of central nervous system (CNS) structures, each is also related to structures that project more strongly to it than to the others. The VTA gets robust input from ventral striatopallidum and extended amygdala, whereas RMTg biased inputs arise in structures with a more direct impact on motor function, such as deep layers of the contralateral superior colliculus, deep cerebellar and several brainstem nuclei, and, via a relay in the LHb, the entopeduncular nucleus. Input from the ventral pallidal-lateral preoptic-lateral hypothalamus continuum is strong in the RMTg and VTA and dominant in the LHb. Axon collateralization was also investigated, providing additional insights into the organization of the circuitry of this important triad of structures. PMID:25940654

  2. Protracted Maturation of Forebrain Afferent Connections of the Ventral Tegmental Area in the Rat

    PubMed Central

    Yetnikoff, Leora; Reichard, Rhett A.; Schwartz, Zachary M.; Parsely, Kenneth P.; Zahm, Daniel S.

    2014-01-01

    The mesocorticolimbic dopamine system has long attracted the interest of researchers concerned with the unique gamut of behavioral and mental health vulnerabilities associated with adolescence. Accordingly, the development of the mesocorticolimbic system has been studied extensively, but almost exclusively with regard to dopaminergic output, particularly in the nucleus accumbens and medial prefrontal cortex. To the contrary, the ontogeny of inputs to the ventral tegmental area (VTA), the source of mesocorticolimbic dopamine, has been neglected. This is not a trivial oversight, as the activity of VTA neurons, which reflects their capacity to transmit information about salient events, is sensitively modulated by inputs. Here, we assessed the development of VTA afferent connections using the β subunit of cholera toxin (Ctβ) as a retrograde axonal tracer in adolescent (postnatal day 39) and early adult (8–9-week-old) rats. After intra-VTA injections of Ctβ, adolescent and early adult animals exhibited qualitatively similar distributions of retrogradely labeled neurons in the sense that VTA-projecting neurons were present at all of the same rostrocaudal levels in all of the same structures in both age groups. However, quantitation of retrogradely labeled neurons revealed that adolescent brains, compared with early adult brains, had significantly fewer VTA-projecting neurons preferentially within an interconnected network of cortical and striatopallidal forebrain structures. These findings provide a novel perspective on the development of the mesocorticolimbic dopamine system and may have important implications for age-dependent specificity in the function of this system, particularly with regard to adolescent impulsivity and mental health vulnerabilities. PMID:23983069

  3. Presynaptic dopamine D2-like receptors inhibit excitatory transmission onto rat ventral tegmental dopaminergic neurones

    PubMed Central

    Koga, Eiko; Momiyama, Toshihiko

    2000-01-01

    The effects of dopamine (DA) on non-NMDA glutamatergic transmission onto dopaminergic neurones in the ventral tegmental area (VTA) were examined in rat midbrain slices using the whole-cell patch-clamp technique. EPSCs in dopaminergic neurones evoked by focal stimulation within the VTA were reversibly blocked by 5 μm CNQX in the presence of bicuculline (20 μm), strychnine (0.5 μm) and D-amino-5-phosphonopentanoic acid (D-AP5, 25 μm). Bath application of DA reduced the amplitude of EPSCs up to 65.1 ± 9.52% in a concentration-dependent manner between 0.3–1000 μm (IC50, 16.0 μm) without affecting the holding current at −60 mV measured using a Cs+-filled electrode. The effect of DA on evoked EPSCs was mimicked by the D2-like receptor agonist quinpirole but not by the D1-like receptor agonist SKF 81297, and was antagonized by the D2-like receptor antagonist sulpiride (KB, 0.96 μm), but not by the D1-like receptor antagonist SCH 23390 (KB, 228.6 μm). Dopamine (30 μm) reduced the mean frequency of spontaneous miniature EPSCs (mEPSCs) without affecting their mean amplitude, and the DA-induced effect on the mEPSCs was dependent on the external Ca2+ concentration. These results suggest that afferent glutamatergic fibres which terminate on VTA dopaminergic neurones possess presynaptic D2-like receptors, activation of which inhibits glutamate release by reducing Ca2+ influx. PMID:10673553

  4. Affective Analgesia following Muscarinic Activation of the Ventral Tegmental Area in Rats

    PubMed Central

    Kender, Robert G.; Harte, Steven E.; Munn, Elizabeth M.; Borszcz, George S.

    2009-01-01

    Cholinergic stimulation of dopamine neurons in the ventral tegmental area (VTA) underlies activation of the brain reward circuitry. Activation of this circuit is proposed to preferentially suppress the affective reaction to noxious stimulation. Vocalization afterdischarges (VADs) are a validated model of the affective response of rats to noxious tailshock. The antinociceptive action of the acetylcholine agonist carbachol microinjected into the VTA on VAD threshold was compared to its effect on the thresholds of other tailshock-elicited responses (VDS = vocalizations during shock, and SMR = spinal motor reflexes). Whereas VADs are organized within the forebrain, VDSs and SMRs are organized at medullary and spinal levels of the neuraxis, respectively. Carbachol (1 μg, 2 μg, and 4 μg) injected into VTA produced dose-dependent increases in VAD and VDS thresholds, although increases in VAD threshold were significantly greater than increases in VDS threshold. Administration of carbachol into VTA failed to elevate SMR threshold. Elevations in vocalization thresholds produced by intra-VTA carbachol were reversed in a dose-dependent manner by local administration of the muscarinic receptor antagonist atropine sulfate (30 μg and 60 μg). These results provide the first demonstration of the involvement of the VTA in muscarinic-induced suppression of pain affect. Perspective Cholinergic activation of the brain reward circuit produced a preferential suppression of rats’ affective reaction to noxious stimulation. The neurobiology that relates reinforcement to suppression of pain affect may provide insights into new treatments for pain and its associated affective disorders. PMID:18387853

  5. Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area

    PubMed Central

    Valdés, José L.; McNaughton, Bruce L.

    2015-01-01

    In a rest period immediately after a task, neurons in the hippocampus, neocortex, and striatum exhibit spatiotemporal correlation patterns resembling those observed during the task. This reactivation has been proposed as a neurophysiological substrate for memory consolidation. We provide new evidence that rodent ventral tegmental area (VTA) neurons are selective for different types of food stimuli and that stimulus-sensitive neurons strongly reactivate during the rest period following a task that involved those stimuli. Reactivation occurred primarily during slow wave sleep and during quiet awakeness. In these experiments, VTA reactivation patterns were uncompressed and occurred at the firing rate level, rather than on a spike-to-spike basis. Mildly aversive stimuli were reactivated more often than positive ones. The VTA is a pivotal structure involved in the perception and prediction of reward and stimulus salience and is a key neuromodulatory system involved in synaptic plasticity. These results suggest new ways in which dopaminergic signals could contribute to the biophysical mechanisms of selective, system-wide, memory consolidation, and reconsolidation during sleep. PMID:26108957

  6. Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area.

    PubMed

    Valdés, José L; McNaughton, Bruce L; Fellous, Jean-Marc

    2015-08-01

    In a rest period immediately after a task, neurons in the hippocampus, neocortex, and striatum exhibit spatiotemporal correlation patterns resembling those observed during the task. This reactivation has been proposed as a neurophysiological substrate for memory consolidation. We provide new evidence that rodent ventral tegmental area (VTA) neurons are selective for different types of food stimuli and that stimulus-sensitive neurons strongly reactivate during the rest period following a task that involved those stimuli. Reactivation occurred primarily during slow wave sleep and during quiet awakeness. In these experiments, VTA reactivation patterns were uncompressed and occurred at the firing rate level, rather than on a spike-to-spike basis. Mildly aversive stimuli were reactivated more often than positive ones. The VTA is a pivotal structure involved in the perception and prediction of reward and stimulus salience and is a key neuromodulatory system involved in synaptic plasticity. These results suggest new ways in which dopaminergic signals could contribute to the biophysical mechanisms of selective, system-wide, memory consolidation, and reconsolidation during sleep. PMID:26108957

  7. Multiple Personalities in the Ventral Tegmental Area

    PubMed Central

    Borgkvist, Anders; Mrejeru, Ana; Sulzer, David

    2016-01-01

    A small number of ventral tegmental area dopamine neurons engage in numerous and apparently contradictory functions—how can this be? A clue is provided by Lammel and colleagues in this issue of Neuron: some VTA dopamine neurons display synaptic plasticity in response to cocaine, and others in response to pain, and these populations are distinguished by their axonal projections and Ih. PMID:21658574

  8. Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

    PubMed

    Li, Ai-Ling; Sibi, Jiny E; Yang, Xiaofei; Chiao, Jung-Chih; Peng, Yuan Bo

    2016-06-01

    Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas. PMID:26821313

  9. Oxytocin injected into the hippocampal ventral subiculum induces penile erection in male rats by increasing glutamatergic neurotransmission in the ventral tegmental area.

    PubMed

    Succu, Salvatora; Sanna, Fabrizio; Argiolas, Antonio; Melis, Maria Rosaria

    2011-01-01

    Oxytocin (100 ng) injected unilaterally into the ventral subiculum of the hippocampus induces penile erection episodes, which started 30 min after treatment and were abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (2 μg), an oxytocin receptor antagonist, into the ventral subiculum. Oxytocin-induced penile erection occurred 15 min after the increase of the concentration of extracellular dopamine in the dialysate obtained from either the nucleus accumbens or the prelimbic medial prefrontal cortex, which was also abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin. An increase in extracellular glutamic acid concentration was also observed in the same dialysate obtained from the ventral tegmental area, but not from the prelimbic medial prefrontal cortex or the nucleus accumbens in which dopamine concentration was measured, 15 min after the injection of oxytocin into the ventral subiculum. This effect was also abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin into the ventral subiculum. These results confirm previous findings showing that ventral subiculum oxytocin-induced penile erection is mediated by an increase of glutamic acid neurotransmission in the ventral tegmental area. This in turn increases mesolimbic and mesocortical dopaminergic activity, releasing dopamine in the nucleus accumbens and in the prelimbic medial prefrontal cortex. These results are in line with previous studies supporting the hypothesis that the ventral subiculum participates in a complex neural circuit controlling not only penile erection and copulation, but also sexual motivation, arousal and rewarding. PMID:21496460

  10. Taurine activates excitatory non-synaptic glycine receptors on dopamine neurones in ventral tegmental area of young rats

    PubMed Central

    Wang, Fushun; Xiao, Cheng; Ye, Jiang Hong

    2005-01-01

    The physiological and pharmacological properties of taurine-induced responses were investigated in dopaminergic (DA) neurones from the ventral tegmental area (VTA) of young rats aged 1–13 postnatal days, either in acute brain slices or acutely dissociated neurones. When whole-cell responses were recorded from current-clamped neurones using the gramicidin-perforated technique, the application of taurine (0.01–30 mm) accelerated firings and induced membrane depolarization. In voltage-clamped neurones, taurine induced a current which was antagonized by strychnine and by picrotoxin, but not by bicuculline. In addition, taurine-induced current showed complete cross-desensitization with glycine-activated currents but not with γ-aminobutyric acid (GABA)-activated currents. Thus, taurine is a full agonist of the glycine receptors (GlyRs) in the VTA. Further studies found that taurine acted mainly on non-synaptic GlyRs. The application of 20 μm bicuculline abolished the spontaneous inhibitory post-synaptic currents (IPSCs) in 40/45 neurones, and 93% of the evoked IPSCs. The addition of 1 μm strychnine completely eliminated the remaining IPSCs. These results suggest that GABAergic IPSCs predominate, and that functional glycinergic synapses are present in a subset of the VTA neurones. The application of 1 μm strychnine alone induced an outward current, suggesting that these neurones were exposed to tonically released taurine/glycine. In conclusion, by activating non-synaptic GlyRs, taurine may act as an excitatory extra-synaptic neurotransmitter in the VTA during early development. PMID:15817633

  11. Mechanism of the cardiovascular effects of the GABAA receptors of the ventral tegmental area of the rat brain.

    PubMed

    Yeganeh, Fahimeh; Ranjbar, Afsaneh; Hatam, Masoumeh; Nasimi, Ali

    2015-07-23

    The ventral tegmental area (VTA) contains GABA terminals involved in the regulation of the cardiovascular system. Previously, we demonstrated that blocking GABAA but not GABAB receptors produced a pressor response accompanied by marked bradycardia. This study was performed to find the possible mechanisms involved in these responses by blocking ganglionic nicotinic receptors, peripheral muscarinic receptors or peripheral V1 vasopressin receptors. Experiments were performed on urethane anesthetized male Wistar rats. Drugs were microinjected unilaterally into the VTA (100 nl). The average changes in mean arterial pressure (MAP) and heart rate (HR) were compared between pre- and post-treatment using paired t-test. Injection of bicuculline methiodide (BMI), a GABAA antagonist, into the VTA caused a significant increase in MAP and a decrease in HR. Administration (i.v.) of the nicotinic receptor blocker, hexamethonium, enhanced the pressor response but abolished the bradycardic response to BMI, which ruled out involvement of the sympathetic nervous system. Blockade of the peripheral muscarinic receptors by homatropine (i.v.) abolished the bradycardic effect of BMI, but had no effect on the pressor response, indicating that bradycardia was produced by the parasympathetic outflow to the heart. Both the pressor and bradycardic responses to BMI were blocked by V1 receptor antagonist (i.v.), indicating that administration of BMI in the VTA disinhibited the release of vasopressin into the circulation. In conclusion, we demonstrated that GABAergic mechanism of the VTA exerts a tonic inhibition on vasopressin release through activation of GABAA receptors. The sympathetic system is not involved in the decrease of blood pressure by GABA of the VTA. PMID:26079327

  12. Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats

    PubMed Central

    Dardou, David; Chassain, Carine; Durif, Franck

    2015-01-01

    The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating. PMID:25610366

  13. Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats.

    PubMed

    Dardou, David; Chassain, Carine; Durif, Franck

    2014-01-01

    The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating. PMID:25610366

  14. Comparison between the pharmacology of dopamine receptors mediating the inhibition of cell firing in rat brain slices through the substantia nigra pars compacta and ventral tegmental area.

    PubMed Central

    Bowery, B.; Rothwell, L. A.; Seabrook, G. R.

    1994-01-01

    1. Electrophysiological recordings were made from presumed dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of rat brain slices. The ability of selective dopamine receptor agonists to hyperpolarize neurones and inhibit cell firing, as well as the ability of dopamine receptor antagonists to block responses to quinpirole were compared. 2. Six dopamine receptor agonists were examined for their ability to hyperpolarize neurones within the substantia nigra pars compacta. Of these, the most potent ligand tested was naxagolide with an EC50 value of 20 nM and estimated maximum of 10 mV. The rank order of agonist potency was naxagolide > quinpirole > apomorphine > dopamine. 3. Quinpirole was more potent at inhibiting cell firing in the substantia nigra pars compacta (pIC50 = 7.65 +/ 0.06, n = 35) than in the ventral tegmental area (pIC50 = 7.24 +/- 0.06, n = 32; P < 0.01, Student's t test). 7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), a putative D3 selective agonist, had a comparable potency to quinpirole in both the ventral tegmental area (pIC50 = 7.39 +/- 0.26, n = 4), and substantia nigra pars compacta (pIC50 = 7.71 +/- 0.20; n = 4). 4. The inhibition of cell firing by quinpirole was antagonized by haloperidol, S(-)-sulpiride, clozapine, and ritanserin. S(-)-sulpiride and haloperidol had the highest estimated affinities in the substantia nigra, with pA2 values of 8.97 (slope = 0.85) and 8.20 (slope = 2.09) respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7921615

  15. Optogenetic Activation of the Excitatory Neurons Expressing CaMKIIα in the Ventral Tegmental Area Upregulates the Locomotor Activity of Free Behaving Rats

    PubMed Central

    Guo, Songchao; Chen, Sicong; Zhang, Qiaosheng; Wang, Yueming; Xu, Kedi; Zheng, Xiaoxiang

    2014-01-01

    The ventral tegmental area (VTA) plays an important role in motivation and motor activity of mammals. Previous studies have reported that electrical stimulations of the VTA's neuronal projections were able to upregulate the locomotor activity of behaving rats. However, which types of neurons in the VTA that take part in the activation remain elusive. In this paper we employed optogenetic technique to selectively activate the excitatory neurons expressing CaMKIIα in the VTA region and induced a higher locomotor activity for free behaving rats. Further behavioral studies indicated that reward learning mediated in the enhancement of the rat locomotor activity. Finally the immunohistochemistry studies explored that the excitatory neurons under the optogenetic activation in VTA were partly dopaminergic that may participate as a vital role in the optogenetic activation of the locomotor activity. In total, our study provided an optogenetic approach to selectively upregulate the locomotor activity of free behaving rats, thus facilitating both neuroscience researches and neural engineering such as animal robotics in the future. PMID:24711999

  16. Role of pregnane xenobiotic receptor in the midbrain ventral tegmental area for estradiol- and 3α,5α-THP-facilitated lordosis of female rats

    PubMed Central

    Frye, C.A.; Koonce, C.J.; Walf, A.A.

    2014-01-01

    Rationale Progesterone and its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17β-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3α,5α-THP, is required for successful reproductive behavior. Objectives A question of interest is the role of pregnane xenobiotic receptor (PXR), a nuclear receptor that regulates enzymes needed for the production of 3α,5α-THP, for estradiol-mediated lordosis. The hypothesis tested was that if PXR is involved in estradiol-mediated biosynthesis of 3α,5α-THP and reproductive behavior, knocking down expression of PXR in the VTA of estradiol-primed, but not vehicle-primed, rats should decrease lordosis and midbrain 3α,5α-THP; effects may be attenuated by 3α,5α-THP administered to the VTA. Methods Ovariectomized rats were administered subcutaneous injections of oil vehicle or estradiol. Rats were then administered PXR antisense oligonucleotides (PXR AS-ODNs; which are expected to locally knock down expression of PXR), or control (saline), infusions to the VTA. Rats were administered 3α,5α-THP or vehicle via infusions to the VTA. Reproductive behavior (paced mating task) of rats was determined in addition to exploratory (open field), affective (elevated plus maze), pro-social (social interaction task) behavior. Results Reproductive behavior (i.e. increased lordosis) was enhanced with estradiol-priming and infusions of 3α,5α-THP to the VTA. Infusions of PXR AS-ODNs to the VTA attenuated responses in estradiol-, but not vehicle-, primed rats, compared to control infusions. Conclusions PXR may be involved in a neuroregulatory response involving biosynthesis of 3α,5α-THP in the midbrain VTA of estradiol-primed rats. PMID:24435323

  17. Effect of Transient Inactivation of Ventral Tegmental Area on the Expression and Acquisition of Nicotine-Induced Conditioned Place Preference in Rats

    PubMed Central

    Chalabi-Yani, Durna; Sahraei, Hedayat; Meftahi, Gholam Hossein; Hosseini, Seydeh Bentolhuda; Sadeghi-Gharajehdaghi, Sara; Ali Beig, Hengameh; Bourbour, Zahra; Ranjabaran, Mina

    2015-01-01

    Background: Nicotine can activate dopaminergic neurons within the ventral tegmental area (VTA). However, there is no evidence about complete inhibition of VTA on nicotine reinforcement. Methods: in the present study, we used conditioned-place preference (CPP) method to study the effect of transient inhibition of left and/or right side of the VTA by lidocaine on nicotine reward properties. Male Wistar rats seven days after recovery from surgery and cannulation were conditioned to nicotine (1.5 mg/kg) in an unbiased designed CPP apparatus. Five min before each nicotine injection in conditioning phase, lidocaine (2%) was administered either uni- or bi-laterally into the VTA (0.5µl/rat). Results: results revealed that lidocaine administration into the left but not right side of the VTA reduced nicotine CPP significantly. The reduction was potentiated when lidocaine injected in to both sides of the VTA. In addition, the number of compartment crossing was reduced when lidocaine injected in both side of VTA as well as left side. On the other hand, rearing was reduced when lidocaine injected to the right but not left side of VTA. At last, sniffing was reduced only in the group in which received lidocaine in both side of VTA. Sniffing and rearing increased in the group in which received lidocaine in right side. Conclusion: It is concluded that the right and left side of VTA play different role in nicotine-induced activity and reward. PMID:26210948

  18. Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate

    PubMed Central

    Harrison, Ian F.; Anis, Hiba K.; Dexter, David T.

    2016-01-01

    Parkinson’s disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection. PMID:26742637

  19. Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate.

    PubMed

    Harrison, Ian F; Anis, Hiba K; Dexter, David T

    2016-02-12

    Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection. PMID:26742637

  20. Intra-ventral tegmental area HIV-1 Tat1–86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats

    PubMed Central

    Zhu, Jun; Midde, Narasimha M.; Gomez, Adrian M.; Sun, Wei-Lun; Harrod, Steven B.

    2015-01-01

    Cigarette smoking prevalence in the HIV-positive individuals is profoundly higher than that in the HIV-negative individuals. We have demonstrated that HIV-1 transgenic rats exhibit attenuated nicotine-mediated locomotor activity, altered cAMP response element binding protein (CREB) and extracellular regulated kinase (ERK1/2) signaling in the mesocorticolimbic regions. This study investigated the role of HIV-1 transactivator of transcription (Tat) protein in the alterations of nicotine-mediated behavior and the signaling pathway observed in the HIV-1 transgenic rats. Rats received bilateral microinjection of recombinant Tat1–86 (25 μg/side) or vehicle directed at ventral tegmental area (VTA) followed by locomotor testing in response to 13 daily intravenous injections of nicotine (0.05 mg/kg, freebase, once/day) or saline. Further, we examined the phosphorylated levels of CREB (pCREB) and ERK1/2 (pERK1/2) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and VTA. Tat diminished baseline activity in saline control rats, and attenuated nicotine-induced behavioral sensitization. Following repeated saline injection, the basal levels of pERK1 in the NAc and VTA and pERK2 in VTA were lower in the vehicle control group, relative to the Tat group. After repeated nicotine injection, pERK1 in NAc and VTA and pERK2 in VTA were increased in the vehicle group, but not in the Tat group. Moreover, repeated nicotine injections decreased pCREB in the PFC and VTA in the Tat group but not in the vehicle group. Thus, these findings indicate that the direct injection of Tat at the VTA may mediate CREB and ERK activity in response to nicotine-induced locomotor activity. PMID:26150803

  1. Social defeat stress-induced sensitization and escalated cocaine self-administration: The role of ERK signaling in the rat ventral tegmental area

    PubMed Central

    Yap, Jasmine J.; Chartoff, Elena H.; Holly, Elizabeth N.; Potter, David N.; Carlezon, William A.; Miczek, Klaus A.

    2015-01-01

    Rationale Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK). Objective The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress. Materials and methods Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 μg/side) or vehicle (20% DMSO) into the ventral tegmental area (VTA) prior to each of 4 defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access “binge” (0.3 mg/kg/infusion). Results We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge. Conclusions These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking. PMID:25373870

  2. Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat.

    PubMed

    Wang, Junshi; Bastle, Ryan M; Bass, Caroline E; Hammer, Ronald P; Neisewander, Janet L; Nikulina, Ella M

    2016-10-01

    Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake. PMID:27154426

  3. Characterization of Cognitive Deficits in Rats Overexpressing Human Alpha-Synuclein in the Ventral Tegmental Area and Medial Septum Using Recombinant Adeno-Associated Viral Vectors

    PubMed Central

    Hall, Hélène; Jewett, Michael; Landeck, Natalie; Nilsson, Nathalie; Schagerlöf, Ulrika; Leanza, Giampiero; Kirik, Deniz

    2013-01-01

    Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration. PMID:23705016

  4. Targeting of serotonin 1A receptors to dopaminergic neurons within the parabrachial subdivision of the ventral tegmental area in rat brain.

    PubMed

    Doherty, M D; Pickel, V M

    2001-05-01

    Serotonin (5-hydroxytryptamine [5-HT]) modulates dopamine-related cognitive functions and motor activity through activation of selective receptor subtypes including 5-HT1A. Potential targets for these 5-HT1A-mediated actions of 5-HT include mesocortical and mesolimbic dopaminergic neurons having partially segregated distribution in the parabrachial and paranigral subdivisions of the ventral tegmental area (VTA), respectively. We therefore examined the ultrastructural immunocytochemical localization of the 5-HT1A receptor in the parabrachial (VTApb) and paranigral (VTApn) subdivisions of rat VTA, to determine 1) the functional sites for receptor activation, and 2) the cellular associations between this receptor and dopaminergic neurons identified by their tyrosine hydroxylase (TH) content. In each region, 5-HT1A immunoreactivity was mainly observed in somatodendritic profiles, but it was also present in small unmyelinated axons and in a few axon terminals and glia, suggesting a role for 5-HT1A receptors in presynaptic and glial functions, as well as postsynaptic neuronal activation, in VTA. In somatodendritic profiles, 5-HT1A gold particles were mainly localized to tubulovesicles presumed to be smooth endoplasmic reticulum. In addition, however, in distal dendrites receiving multiple inputs the receptor was targeted to selective postsynaptic junctions, or more randomly distributed on nonsynaptic portions of the plasma membrane. Of the 5-HT1A-labeled dendrites, 64% in VTApb and 44% in VTApn contained TH. These findings suggest a reserve of cytoplasmic 5-HT1A receptors that are mobilized to functional postsynaptic sites on the plasma membrane by afferent input to distal dendrites in the VTA. They also indicate that 5-HT1A activation may affect a larger population of dopaminergic neurons in VTApb compared with VTApn, thus having a potentially greater impact on cognitive functions modulated by mesocortical dopaminergic neurons. PMID:11298363

  5. Area-specific analysis of the distribution of hypothalamic neurons projecting to the rat ventral tegmental area, with special reference to the GABAergic and glutamatergic efferents

    PubMed Central

    Kalló, Imre; Molnár, Csilla S.; Szöke, Sarolta; Fekete, Csaba; Hrabovszky, Erik; Liposits, Zsolt

    2015-01-01

    The ventral tegmental area (VTA) is a main regulator of reward and integrates a wide scale of hormonal and neuronal information. Feeding-, energy expenditure-, stress, adaptation- and reproduction-related hypothalamic signals are processed in the VTA and influence the reward processes. However, the neuroanatomical origin and chemical phenotype of neurons mediating these signals to the VTA have not been fully characterized. In this study we have systematically mapped hypothalamic neurons that project to the VTA using the retrograde tracer Choleratoxin B subunit (CTB) and analyzed their putative gamma-aminobutyric acid (GABA) and/or glutamate character with in situ hybridization in male rats. 23.93 ± 3.91% of hypothalamic neurons projecting to the VTA was found in preoptic and 76.27 ± 4.88% in anterior, tuberal and mammillary hypothalamic regions. Nearly half of the retrogradely-labeled neurons in the preoptic, and more than one third in the anterior, tuberal and mammillary hypothalamus appeared in medially located regions. The analyses of vesicular glutamate transporter 2 (VGLUT2) and glutamate decarboxylase 65 (GAD65) mRNA expression revealed both amino acid markers in different subsets of retrogradely-labeled hypothalamic neurons, typically with the predominance of the glutamatergic marker VGLUT2. About one tenth of CTB-IR neurons were GAD65-positive even in hypothalamic nuclei expressing primarily VGLUT2. Some regions were populated mostly by GAD65 mRNA-containing retrogradely-labeled neurons. These included the perifornical part of the lateral hypothalamus where 58.63 ± 19.04% of CTB-IR neurons were GABAergic. These results indicate that both the medial and lateral nuclear compartments of the hypothalamus provide substantial input to the VTA. Furthermore, colocalization studies revealed that these projections not only use glutamate but also GABA for neurotransmission. These GABAergic afferents may underlie important inhibitory mechanism to fine-tune the

  6. Activation of D2 autoreceptors alters cocaine-induced locomotion and slows down local field oscillations in the rat ventral tegmental area.

    PubMed

    Koulchitsky, Stanislav; Delairesse, Charlotte; Beeken, Thom; Monteforte, Alexandre; Dethier, Julie; Quertemont, Etienne; Findeisen, Rolf; Bullinger, Eric; Seutin, Vincent

    2016-09-01

    Psychoactive substances affecting the dopaminergic system induce locomotor activation and, in high doses, stereotypies. Network mechanisms underlying the shift from an active goal-directed behavior to a "seemingly purposeless" stereotypic locomotion remain unclear. In the present study we sought to determine the relationships between the behavioral effects of dopaminergic drugs and their effects on local field potentials (LFPs), which were telemetrically recorded within the ventral tegmental area (VTA) of freely moving rats. We used the D2/D3 agonist quinpirole in a low, autoreceptor-selective (0.1 mg/kg, i.p.) and in a high (0.5 mg/kg, i.p.) dose, and a moderate dose of cocaine (10 mg/kg, i.p.). In the control group, power spectrum analysis revealed a prominent peak of LFP power in the theta frequency range during active exploration. Cocaine alone stimulated locomotion, but had no significant effect on the peak of the LFP power. In contrast, co-administration of low dose quinpirole with cocaine markedly altered the pattern of locomotion, from goal-directed exploratory behavior to recurrent motion resembling locomotor stereotypy. This behavioral effect was accompanied by a shift of the dominant theta power toward a significantly lower (by ∼15%) frequency. High dose quinpirole also provoked an increased locomotor activity with signs of behavioral stereotypies, and also induced a shift of the dominant oscillation frequency toward the lower range. These results demonstrate a correlation between the LFP oscillation frequency within the VTA and a qualitative aspect of locomotor behavior, perhaps due to a variable level of coherence of this region with its input or output areas. PMID:27130904

  7. Area-specific analysis of the distribution of hypothalamic neurons projecting to the rat ventral tegmental area, with special reference to the GABAergic and glutamatergic efferents.

    PubMed

    Kalló, Imre; Molnár, Csilla S; Szöke, Sarolta; Fekete, Csaba; Hrabovszky, Erik; Liposits, Zsolt

    2015-01-01

    The ventral tegmental area (VTA) is a main regulator of reward and integrates a wide scale of hormonal and neuronal information. Feeding-, energy expenditure-, stress, adaptation- and reproduction-related hypothalamic signals are processed in the VTA and influence the reward processes. However, the neuroanatomical origin and chemical phenotype of neurons mediating these signals to the VTA have not been fully characterized. In this study we have systematically mapped hypothalamic neurons that project to the VTA using the retrograde tracer Choleratoxin B subunit (CTB) and analyzed their putative gamma-aminobutyric acid (GABA) and/or glutamate character with in situ hybridization in male rats. 23.93 ± 3.91% of hypothalamic neurons projecting to the VTA was found in preoptic and 76.27 ± 4.88% in anterior, tuberal and mammillary hypothalamic regions. Nearly half of the retrogradely-labeled neurons in the preoptic, and more than one third in the anterior, tuberal and mammillary hypothalamus appeared in medially located regions. The analyses of vesicular glutamate transporter 2 (VGLUT2) and glutamate decarboxylase 65 (GAD65) mRNA expression revealed both amino acid markers in different subsets of retrogradely-labeled hypothalamic neurons, typically with the predominance of the glutamatergic marker VGLUT2. About one tenth of CTB-IR neurons were GAD65-positive even in hypothalamic nuclei expressing primarily VGLUT2. Some regions were populated mostly by GAD65 mRNA-containing retrogradely-labeled neurons. These included the perifornical part of the lateral hypothalamus where 58.63 ± 19.04% of CTB-IR neurons were GABAergic. These results indicate that both the medial and lateral nuclear compartments of the hypothalamus provide substantial input to the VTA. Furthermore, colocalization studies revealed that these projections not only use glutamate but also GABA for neurotransmission. These GABAergic afferents may underlie important inhibitory mechanism to fine-tune the

  8. Oxytocin induces penile erection when injected into the ventral tegmental area of male rats: role of nitric oxide and cyclic GMP.

    PubMed

    Succu, Salvatora; Sanna, Fabrizio; Cocco, Cristina; Melis, Tiziana; Boi, Antonio; Ferri, Gian-Luca; Argiolas, Antonio; Melis, Maria Rosaria

    2008-08-01

    Oxytocin (80 ng) injected into the caudal mesencephalic ventral tegmental area (VTA) of male rats induces penile erection. Such an effect occurs together with an increase in nitric oxide (NO) production, as measured by the augmented concentration of NO(2)(-) and NO(3)(-) found in the dialysate obtained from this brain area by means of intracerebral microdialysis. Both effects are abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), an oxytocin receptor antagonist, by S-methyl-l-thiocitrulline acetate (20 microg), a neuronal NO synthase inhibitor, or by omega-conotoxin GVIA (50 ng), a N-type Ca(2+) channel blocker, all injected into the VTA 15 min before oxytocin. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (40 microg), a guanylate cyclase inhibitor, given into the VTA 15 min before oxytocin, abolishes penile erection, but not the increase in NO production, while haemoglobin (40 microg), a NO scavenger, injected immediately before oxytocin reduces the increase in NO production, but not penile erection. 8-Bromo-cyclic guanosine monophosphate (0.5-10 microg) microinjected into the VTA induces penile erection with an inverted U-shaped dose-response curve; the maximal effective dose being 3 microg. Immunohistochemistry reveals that in the caudal VTA oxytocin-containing axons/fibres (originating from the paraventricular nucleus of the hypothalamus) contact cell bodies of mesolimbic dopaminergic (tyrosine hydroxylase-positive) neurons containing both NO synthase and guanylate cyclase. These results suggest that oxytocin injected into the VTA induces penile erection by activating NO synthase in the cell bodies of mesolimbic dopaminergic neurons. NO in turn activates guanylate cyclase present in these neurons, thereby increasing cyclic GMP concentration. PMID:18671741

  9. Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

    PubMed

    Sotomayor-Zárate, Ramón; Abarca, Jorge; Araya, Katherine A; Renard, Georgina M; Andrés, María E; Gysling, Katia

    2015-11-01

    A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20μM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10μM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100μM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems. PMID:26318765

  10. Glutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration.

    PubMed

    Ghasemzadeh, M Behnam; Vasudevan, Preethi; Giles, Chad; Purgianto, Anthony; Seubert, Chad; Mantsch, John R

    2011-09-21

    Glutamate signaling in prefrontal cortex and ventral tegmental area plays an important role in the molecular and behavioral plasticity associated with addiction to drugs of abuse. The current study investigated the expression and postsynaptic density redistribution of glutamate receptors and synaptic scaffolding proteins in dorsomedial and ventromedial prefrontal cortex and ventral tegmental area after cocaine self-administration. After 14 days of extended-access (6h/day) cocaine self-administration, rats were exposed to one of three withdrawal regimen for 10 days. Animals either stayed in home cages (Home), returned to self-administration boxes with the levers withdrawn (Box), or underwent extinction training (Extinction). Extinction training was associated with significant glutamatergic plasticity. In dorsomedial prefrontal cortex of the Extinction group, there was an increase in postsynaptic density GluR1, PSD95, and actin proteins; while postsynaptic density mGluR5 protein decreased and there was no change in NMDAR1, Homer1b/c, or PICK1 proteins. These changes were not observed in ventromedial prefrontal cortex or ventral tegmental area. In ventral tegmental area, Extinction training reversed the decreased postsynaptic density NMDAR1 protein in the Home and Box withdrawal groups. These data suggest that extinction of drug seeking is associated with selective glutamatergic plasticity in prefrontal cortex and ventral tegmental area that include modulation of receptor trafficking to postsynaptic density. PMID:21855055

  11. Pyramidal Neurons in Rat Prefrontal Cortex Projecting to Ventral Tegmental Area and Dorsal Raphe Nucleus Express 5-HT2A Receptors

    PubMed Central

    Vázquez-Borsetti, Pablo; Cortés, Roser

    2009-01-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotics modulate cortico-limbic circuits mainly through subcortical D2 receptor blockade, whereas second generation (atypical) antipsychotics preferentially target cortical 5-HT receptors. Anatomical and functional evidence supports a PFC-based control of the brainstem monoaminergic nuclei. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of PFC pyramidal neurons projecting to the dorsal raphe (DR) and/or ventral tegmental area (VTA) express 5-HT2A receptors. Cholera-toxin B application into the DR and the VTA retrogradely labeled projection neurons in the medial PFC (mPFC) and in orbitofrontal cortex (OFC). In situ hybridization of 5-HT2A receptor mRNA in the same tissue sections labeled a large neuronal population in mPFC and OFC. The percentage of DR-projecting neurons expressing 5-HT2A receptor mRNA was ∼60% in mPFC and ∼75% in OFC (n = 3). Equivalent values for VTA-projecting neurons were ∼55% in both mPFC and ventral OFC. Thus, 5-HT2A receptor activation/blockade in PFC may have downstream effects on dopaminergic and serotonergic systems via direct descending pathways. Atypical antipsychotics may distally modulate monoaminergic cells through PFC 5-HT2A receptor blockade, presumably decreasing the activity of neurons receiving direct cortical inputs. PMID:19029064

  12. Cognitive Neurostimulation: Learning to Volitionally Sustain Ventral Tegmental Area Activation.

    PubMed

    MacInnes, Jeff J; Dickerson, Kathryn C; Chen, Nan-kuei; Adcock, R Alison

    2016-03-16

    Activation of the ventral tegmental area (VTA) and mesolimbic networks is essential to motivation, performance, and learning. Humans routinely attempt to motivate themselves, with unclear efficacy or impact on VTA networks. Using fMRI, we found untrained participants' motivational strategies failed to consistently activate VTA. After real-time VTA neurofeedback training, however, participants volitionally induced VTA activation without external aids, relative to baseline, Pre-test, and control groups. VTA self-activation was accompanied by increased mesolimbic network connectivity. Among two comparison groups (no neurofeedback, false neurofeedback) and an alternate neurofeedback group (nucleus accumbens), none sustained activation in target regions of interest nor increased VTA functional connectivity. The results comprise two novel demonstrations: learning and generalization after VTA neurofeedback training and the ability to sustain VTA activation without external reward or reward cues. These findings suggest theoretical alignment of ideas about motivation and midbrain physiology and the potential for generalizable interventions to improve performance and learning. PMID:26948894

  13. Leptin/LepRb in the Ventral Tegmental Area Mediates Anxiety-Related Behaviors

    PubMed Central

    Liu, Jing; Guo, Ming

    2016-01-01

    Background: Leptin, an adipose-derived hormone, has been implicated in emotional regulation. We have previously shown that systemic administration of leptin produces anxiolytic-like effects and deletion of the leptin receptor, LepRb, in midbrain dopamine neurons leads to an anxiogenic phenotype. This study investigated whether activation or deletion of LepRb in the ventral tegmental area of adult mice is capable of inducing anxiolytic and anxiogenic effects, respectively. Methods: Mice were cannulated in the ventral tegmental area and received bilateral intra-ventral tegmental area infusions of leptin or the JAK2/STAT3 inhibitor AG490. Anxiety-like behaviors were assessed using the elevated plus-maze, light-dark box, and novelty suppressed feeding tests. Deletion of LepRb in the ventral tegmental area was achieved by bilateral injection of AAV-Cre into the ventral tegmental area of adult Leprflox/flox mice. Anxiety-related behaviors were evaluated 3 weeks after viral injection. Results: Intra-ventral tegmental area infusions of leptin reduced anxiety-like behaviors, as indicated by increased percent open-arm time and open-arm entries in the elevated plus-maze test, increased time spent in the light side and decreased latency to enter the light side of the light-dark box, and decreased latency to feed in the novelty suppressed feeding test. Blockade of JAK2/STAT3 signaling in the ventral tegmental area by AG490 attenuated the anxiolytic effect produced by systemic administration of leptin. Leprflox/flox mice injected with AAV-Cre into the ventral tegmental area showed decreased leptin-induced STAT3 phosphorylation and enhanced anxiety-like behaviors in the elevated plus-maze test and the novelty suppressed feeding test. Conclusions: These findings suggest that leptin-LepRb signaling in the ventral tegmental area plays an important role in the regulation of anxiety-related behaviors. PMID:26438799

  14. Morphine-induced apoptosis in the ventral tegmental area and hippocampus after the development but not extinction of reward-related behaviors in rats.

    PubMed

    Razavi, Yasaman; Alamdary, Shabnam Zeighamy; Katebi, Seyedeh-Najmeh; Khodagholi, Fariba; Haghparast, Abbas

    2014-03-01

    Some data suggest that morphine induces apoptosis in neurons, while other evidences show that morphine could have protective effects against cell death. In this study, we suggested that there is a parallel role of morphine in reward circuitry and apoptosis processing. Therefore, we investigated the effect of morphine on modifications of apoptotic factors in the ventral tegmental area (VTA) and hippocampus (HPC) which are involved in the reward circuitry after the acquisition and extinction periods of conditioned place preference (CPP). In behavioral experiments, different doses of morphine (0.5, 5, and 10 mg/kg) and saline were examined in the CPP paradigm. Conditioning score and locomotor activity were recorded by Ethovision software after acquisition on the post-conditioning day, and days 4 and 8 of extinction periods. In order to investigate the molecular mechanisms in each group, we then dissected the brains and measured the expression of apoptotic factors in the VTA and HPC by western blotting analysis. All of the morphine-treated groups showed an increase of apoptotic factors in these regions during acquisition but not in extinction period. In the HPC, morphine significantly increased the ratio of Bax/Bcl-2, caspases-3, and PARP by the lowest dose (0.5 mg/kg), but, in the VTA, a considerable increase was seen in the dose of 5 mg/kg; promotion of apoptotic factors in the HPC and VTA insinuates that morphine can affect the molecular mechanisms that interfere with apoptosis through different receptors. Our findings suggest that a specific opioid receptor involves in modification of apoptotic factors expression in these areas. It seems that the reduction of cell death in response to high dose of morphine in the VTA and HPC may be due to activation of low affinity opioid receptors which are involved in neuroprotective features of morphine. PMID:24281942

  15. Intravenous prenatal nicotine exposure increases orexin expression in the lateral hypothalamus and orexin innervation of the ventral tegmental area in adult male rats

    PubMed Central

    Morgan, Amanda J.; Harrod, Steven B.; Lacy, Ryan T.; Stanley, Emily M.; Fadel, Jim R.

    2013-01-01

    BACKGROUND Approximately 18% of pregnant women continue to smoke tobacco cigarettes throughout pregnancy. Offspring exposed to tobacco smoke in utero exhibit a higher incidence of drug use in later stages of development relative to non-exposed children. Animal models indicate that prenatal nicotine (PN) exposure alone alters the development of the mesocorticolimbic dopamine (DA) system, which, in part, organizes motivated behavior and reward. The orexin/hypocretin neuropeptide system, which originates in the lateral hypothalamus (LH), projects to key areas of the mesocorticolimbic DA pathway. Previous research suggests that orexin exerts a major influence on motivation and reward. METHODS The present experiments determined if intravenous (IV) PN exposure alters (1) the expression of orexin neurons and melanin-concentrating hormone (MCH; positive control) in the LH; and (2) orexin projections from the LH onto DA neurons in the ventral tegmental area (VTA). Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline 3×/day during gestational days 8–21. Tissues from adult male offspring (~130 days) were examined using immunohistochemistry. RESULTS Relative to controls, offspring of IV PN exposure showed (1) increased numbers of orexin neurons in the LH, and no changes in the expression of MCH; and (2) increased orexin appositions on DA cells in the VTA. CONCLUSION The findings indicate that the influence of PN exposure is enduring, and suggests that the PN-induced modification of orexin expression on mesolimbic circuitry may contribute to the reported changes in motivated behaviors related to food and drug reward observed in offspring prenatally exposed to nicotine. PMID:23664126

  16. Ventral Tegmental Area Afferents and Drug-Dependent Behaviors

    PubMed Central

    Oliva, Idaira; Wanat, Matthew J.

    2016-01-01

    Drug-related behaviors in both humans and rodents are commonly thought to arise from aberrant learning processes. Preclinical studies demonstrate that the acquisition and expression of many drug-dependent behaviors involves the ventral tegmental area (VTA), a midbrain structure comprised of dopamine, GABA, and glutamate neurons. Drug experience alters the excitatory and inhibitory synaptic input onto VTA dopamine neurons, suggesting a critical role for VTA afferents in mediating the effects of drugs. In this review, we present evidence implicating the VTA in drug-related behaviors, highlight the diversity of neuronal populations in the VTA, and discuss the behavioral effects of selectively manipulating VTA afferents. Future experiments are needed to determine which VTA afferents and what neuronal populations in the VTA mediate specific drug-dependent behaviors. Further studies are also necessary for identifying the afferent-specific synaptic alterations onto dopamine and non-dopamine neurons in the VTA following drug administration. The identification of neural circuits and adaptations involved with drug-dependent behaviors can highlight potential neural targets for pharmacological and deep brain stimulation interventions to treat substance abuse disorders. PMID:27014097

  17. Haloperidol treatment downregulates DCC expression in the ventral tegmental area.

    PubMed

    Grant, Alanna; Manitt, Colleen; Flores, Cecilia

    2014-07-11

    A core feature in the pathophysiology of schizophrenia is abnormal development and function of mesocorticolimbic dopamine (DA) circuitry. We have previously shown that variations in the function of the netrin-1 receptor, deleted in colorectal cancer (DCC), result in changes to the development, organization and ongoing plasticity of DA circuitry. In rodents, repeated exposure to the indirect DA-agonist, amphetamine upregulates DCC expression in the ventral tegmental area (VTA), but not in DA terminal regions. This elevation in DCC expression is associated with increased vulnerability to developing and maintaining sensitized mesolimbic DA function. Antipsychotic medications remain the best treatment option for managing the symptoms in schizophrenia. The peak effects of these medications are gradual, suggesting that a therapeutic component of antipsychotic treatment involves structural reorganization. Here we assessed whether repeated exposure to typical and atypical antipsychotics could also regulate DCC. Adult mice were orally administered haloperidol, clozapine, or risperidone via their drinking water for 4 weeks. Levels of DCC were measured by Western blot analysis of tissue punches of the VTA, medial prefrontal cortex, nucleus accumbens, and dorsal striatum. Haloperidol decreased DCC levels by approximately 50% in the VTA, but not in DA targets. Furthermore, haloperidol did not alter UNC-5 homologue levels, another family of netrin-1 receptors, confirming that its effects target DCC-mediated netrin-1 signaling specifically. The atypical antipsychotics did not alter DCC expression. These results suggest that typical antipsychotics induce selective functional reorganization in the VTA via DCC-mediated netrin-1 signaling. PMID:24861518

  18. Multiplexed neurochemical signaling by neurons of the ventral tegmental area.

    PubMed

    Barker, David J; Root, David H; Zhang, Shiliang; Morales, Marisela

    2016-04-01

    The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. PMID:26763116

  19. Persistent Adaptations in Afferents to Ventral Tegmental Dopamine Neurons after Opiate Withdrawal

    PubMed Central

    Kaufling, Jennifer

    2015-01-01

    Protracted opiate withdrawal is accompanied by altered responsiveness of midbrain dopaminergic (DA) neurons, including a loss of DA cell response to morphine, and by behavioral alterations, including affective disorders. GABAergic neurons in the tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, are important for behavioral responses to opiates. We investigated the tVTA–VTA circuit in rats after chronic morphine exposure to determine whether tVTA neurons participate in the loss of opiate-induced disinhibition of VTA DA neurons observed during protracted withdrawal. In vivo recording revealed that VTA DA neurons, but not tVTA GABAergic neurons, are tolerant to morphine after 2 weeks of withdrawal. Optogenetic stimulation of tVTA neurons inhibited VTA DA neurons similarly in opiate-naive and long-term withdrawn rats. However, tVTA inactivation increased VTA DA activity in opiate-naive rats, but not in withdrawn rats, resembling the opiate tolerance effect in DA cells. Thus, although inhibitory control of DA neurons by tVTA is maintained during protracted withdrawal, the capacity for disinhibitory control is impaired. In addition, morphine withdrawal reduced both tVTA neural activity and tonic glutamatergic input to VTA DA neurons. We propose that these changes in glutamate and GABA inputs underlie the apparent tolerance of VTA DA neurons to opiates after chronic exposure. These alterations in the tVTA–VTA DA circuit could be an important factor in opiate tolerance and addiction. Moreover, the capacity of the tVTA to inhibit, but not disinhibit, DA cells after chronic opiate exposure may contribute to long-term negative affective states during withdrawal. SIGNIFICANCE STATEMENT Dopaminergic (DA) cells of the ventral tegmental area (VTA) are the origin of a brain reward system and are critically involved in drug abuse. Morphine has long been known to affect VTA DA cells via GABAergic interneurons. Recently, GABAergic neurons

  20. Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

    PubMed Central

    Johnston, Caitlin E.; Herschel, Daniel; Lasek, Amy W.; Hammer, Ronald P.; Nikulina, Ella M.

    2014-01-01

    Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse. PMID:25446676

  1. Corticotropin-releasing factor type-2 receptor and corticotropin-releasing factor-binding protein coexist in rat ventral tegmental area nerve terminals originated in the lateral hypothalamic area.

    PubMed

    Slater, Paula G; Noches, Veronica; Gysling, Katia

    2016-01-01

    There is significant functional evidence showing that corticotropin-releasing factor type-2 receptor (CRF2R) and corticotropin-releasing factor-binding protein (CRF-BP) regulate glutamatergic synapses onto ventral tegmental area (VTA) dopaminergic neurons. It has been shown that CRF requires CRF-BP to potentiate N-methyl-D-aspartate receptors in dopaminergic neurons through CRF2R, and that increases glutamate release in cocaine-treated rats through the activation of CRF2R only by agonists with high affinity to CRF-BP. Furthermore, this CRF-mediated increase in VTA glutamate is responsible for stress-induced relapse to cocaine-seeking behaviour. However, there is a lack of anatomical evidence to explain the mechanisms of CRF actions in VTA. Thus, it was studied whether CRF2R and CRF-BP are expressed in VTA nerve terminals, using a synaptosomal preparation devoid of postsynaptic elements. The current results show that both proteins are co-expressed in glutamatergic and γ-aminobutyric acid (GABA)ergic VTA synaptosomes. A main glutamatergic input to the VTA that has been associated to addictive behaviour is originated in the lateral hypothalamic area (LHA). Thus, this study was focused in the LHA-VTA input using orexin as a marker of this input. The results show that CRF2R and CRF-BP mRNA and protein are expressed in the LHA, and that both proteins are present in orexin-positive VTA synaptosomes. The results showing that CRF2R and CRF-BP are expressed in the LHA-VTA input give anatomical support to suggest that this input plays a role in stress-induced relapse to cocaine-seeking behaviour. PMID:26503565

  2. Role of the Ventral Tegmental Area in Methamphetamine Extinction: AMPA Receptor-Mediated Neuroplasticity

    ERIC Educational Resources Information Center

    Chen Han-Ting; Chen, Jin-Chung

    2015-01-01

    The molecular mechanisms underlying drug extinction remain largely unknown, although a role for medial prefrontal cortex (mPFC) glutamate neurons has been suggested. Considering that the mPFC sends glutamate efferents to the ventral tegmental area (VTA), we tested whether the VTA is involved in methamphetamine (METH) extinction via conditioned…

  3. Ventral Tegmental Area and Substantia Nigra Neural Correlates of Spatial Learning

    ERIC Educational Resources Information Center

    Martig, Adria K.; Mizumori, Sheri J. Y.

    2011-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) may provide modulatory signals that, respectively, influence hippocampal (HPC)- and striatal-dependent memory. Electrophysiological studies investigating neural correlates of learning and memory of dopamine (DA) neurons during classical conditioning tasks have found DA…

  4. Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

    PubMed Central

    de Jong, Johannes W; Roelofs, Theresia J M; Mol, Frédérique M U; Hillen, Anne E J; Meijboom, Katharina E; Luijendijk, Mieneke C M; van der Eerden, Harrie A M; Garner, Keith M; Vanderschuren, Louk J M J; Adan, Roger A H

    2015-01-01

    Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior. PMID:25735756

  5. Neuropeptide Y system in accumbens shell mediates ethanol self-administration in posterior ventral tegmental area.

    PubMed

    Borkar, Chandrashekhar D; Upadhya, Manoj A; Shelkar, Gajanan P; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2016-07-01

    Although modulatory effects of neuropeptide Y (NPY) on ethanol consumption are well established, its role in ethanol reward, in the framework of mesolimbic dopaminergic system, has not been studied. We investigated the influence of nucleus accumbens shell (AcbSh) NPYergic system on ethanol self-administration in posterior ventral tegmental area (p-VTA) using intracranial self-administration paradigm. Rats were stereotaxically implanted with cannulae targeted unilaterally at the right p-VTA and trained to self-administer ethanol (200 mg%) in standard two-lever (active/inactive) operant chamber, an animal model with high predictive validity to test the rewarding mechanisms. Over a period of 7 days, these rats showed a significant increase in the number of lever presses for ethanol self-administration suggesting reinforcement. While intra-AcbSh NPY (1 or 2 ng/rat) or [Leu(31) , Pro(34) ]-NPY (0.5 or 1 ng/rat) dose-dependently increased ethanol self-administration, BIBP3226 (0.4 or 0.8 ng/rat) produced opposite effect. The rats conditioned to self-administer ethanol showed significant increase in the population of NPY-immunoreactive cells and fibres in the AcbSh, central nucleus of amygdala (CeA), hypothalamic arcuate nucleus (ARC) and lateral part of bed nucleus of stria terminalis as compared with that in the naïve rats. Neuronal tracing studies showed that NPY innervations in the AcbSh may derive from the neurons of ARC and CeA. As NPY and dopamine systems in reward areas are known to interact, we suggest that NPY inputs from ARC and CeA may play an important role in modulation of the dopaminergic system in the AcbSh and consequently influence the ethanol induced reward and addiction. PMID:25929272

  6. Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats.

    PubMed

    Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A; McBride, William J

    2016-10-01

    Repeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the 'EtOH' than 'Water' groups (e.g., 150 mg% EtOH: to ∼ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the 'Water' than 'EtOH' groups (e.g., 200 μM sulpiride: to ∼ 190-240 vs 150-160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the 'Water' (to ∼ 150-180% and 180-230% of baseline, respectively) but not the 'EtOH' groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA. PMID:27260326

  7. Blockade of GABA(A) receptors within the extended amygdala attenuates D(2) regulation of alcohol-motivated behaviors in the ventral tegmental area of alcohol-preferring (P) rats.

    PubMed

    Eiler, William J A; June, Harry L

    2007-06-01

    The dopamine (DA) mesolimbic pathway, which originates from DA cell bodies within the ventral tegmental area (VTA), has been shown by various studies to play a role in the mediation of various drugs of abuse including alcohol (EtOH). It has been suggested that the VTA's control of EtOH reward is mediated in part by the D2 receptors within the VTA. These receptors may be under the regulation of reciprocal GABAergic inputs from forebrain components of the mesolimbic path such as the nucleus accumbens (NAcc), a classic EtOH reward substrate, and the bed nucleus of the stria terminalis, a substrate recently implicated in EtOH reinforcement, forming a self-regulating feedback loop. To test this hypothesis, D2 regulation of EtOH self-administration (SA) was evaluated by the microinfusion of the D2 antagonist eticlopride into the VTA of P rats, which produced profound reductions in EtOH SA in the highest (20.0 and 40.0microg) doses tested in both BST/VTA and NAcc/VTA implanted P rats. To determine the role of GABA in the mediation of EtOH SA, a 32.0ng dose the non-selective GABA antagonist SR 95531 was microinfused into the BST producing no effect on responding for EtOH and into the NAcc which lead to a reduction in EtOH responding. Finally, the hypothesis that GABA innervation of the VTA from the mesolimbic forebrain may influence EtOH SA was examined by the simultaneous infusion of eticlopride (40.0microg) into the VTA and SR 95531 (32.0ng) into either the BST or NAcc. This combination infusion completely attenuated the reduction in EtOH SA observed with the 40.0microg dose of eticlopride alone in both groups of animals. These results suggest that while the D2 receptors within the VTA regulate EtOH-motivated behaviors, this is modulated by GABAergic input from the mesolimbic forebrain, specifically from the BST and NAcc. PMID:17451754

  8. Nicotine reinforcement is reduced by cannabinoid CB1 receptor blockade in the ventral tegmental area.

    PubMed

    Simonnet, Amelie; Cador, Martine; Caille, Stephanie

    2013-11-01

    Cannabinoid type 1 (CB1) receptors control the motivational properties and reinforcing effects of nicotine. Indeed, peripheral administration of a CB1 receptor antagonist dramatically decreases both nicotine taking and seeking. However, the neural substrates through which the cannabinoid CB1 receptors regulate the voluntary intake of nicotine remain to be elucidated. In the present study, we sought to determine whether central injections of a CB1 receptor antagonist delivered either into the ventral tegmental area (VTA) or the nucleus accumbens (NAC) may alter nicotine intravenous self-administration (IVSA). Rats were first trained to self-administer nicotine (30 μg/kg/0.1 ml). The effect of central infusions of the CB1 antagonist AM 251 (0, 1 and 10 μg/0.5 μl/side) on nicotine-taking behavior was then tested. Intra-VTA infusions of AM 251 dose dependently reduced IVSA with a significant decrease for the dose 10 μg/0.5 μl/side. Moreover, operant responding for water was unaltered by intra-VTA AM 251 at the same dose. Surprisingly, intra-NAC delivery of AM 251 did not alter nicotine behavior at all. These data suggest that in rats chronically exposed to nicotine IVSA, the cannabinoid CB1 receptors located in the VTA rather than in the NAC specifically control nicotine reinforcement and, subsequently, nicotine-taking behavior. PMID:22784230

  9. Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

    PubMed Central

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

    2015-01-01

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

  10. Programmed acute electrical stimulation of ventral tegmental area alleviates depressive-like behavior.

    PubMed

    Friedman, Alexander; Frankel, Michael; Flaumenhaft, Yakov; Merenlender, Avia; Pinhasov, Albert; Feder, Yuval; Taler, Michal; Gil-Ad, Irit; Abeles, Moshe; Yadid, Gal

    2009-03-01

    Depressive disorders affect approximately 5% of the population in any given year. Antidepressants may require several weeks to produce their clinical effects. Despite progress being made in this area there is still room and a need to explore additional therapeutic modes to increase treatment effectiveness and responsiveness. Herein, we examined a new method for intervention in depressive states based on deep brain stimulation of the ventral tegmental area (VTA) as a source of incentive motivation and hedonia, in comparison to chemical antidepressants. The pattern of stimulation was fashioned to mimic the firing pattern of VTA neurons in the normal rat. Behavioral manifestations of depression were then monitored weekly using a battery of behavioral tests. The results suggest that treatment with programmed acute electrical stimulation of the VTA substantially alleviates depressive behavior, as compared to chemical antidepressants or electroconvulsive therapy, both in onset time and longitudinal effect. These results were also highly correlated with increases in brain-derived neurotrophic factor mRNA levels in the prefrontal cortex. PMID:18843267

  11. Voltage-sensitive dye imaging of primary motor cortex activity produced by ventral tegmental area stimulation.

    PubMed

    Kunori, Nobuo; Kajiwara, Riichi; Takashima, Ichiro

    2014-06-25

    The primary motor cortex (M1) receives dopaminergic projections from the ventral tegmental area (VTA) through the mesocortical dopamine pathway. However, few studies have focused on changes in M1 neuronal activity caused by VTA activation. To address this issue, we used voltage-sensitive dye imaging (VSD) to reveal the spatiotemporal dynamics of M1 activity induced by single-pulse stimulation of VTA in anesthetized rats. VSD imaging showed that brief electrical stimulation of unilateral VTA elicited a short-latency excitatory-inhibitory sequence of neuronal activity not only in the ipsilateral but also in the contralateral M1. The contralateral M1 response was not affected by pharmacological blockade of ipsilateral M1 activity, but it was completely abolished by corpus callosum transection. Although the VTA-evoked neuronal activity extended throughout the entire M1, we found the most prominent activity in the forelimb area of M1. The 6-OHDA-lesioned VTA failed to evoke M1 activity. Furthermore, both excitatory and inhibitory intact VTA-induced activity was entirely extinguished by blocking glutamate receptors in the target M1. When intracortical microstimulation of M1 was paired with VTA stimulation, the evoked forelimb muscle activity was facilitated or inhibited, depending on the interval between the two stimuli. These findings suggest that VTA neurons directly modulate the excitability of M1 neurons via fast glutamate signaling and, consequently, may control the last cortical stage of motor command processing. PMID:24966388

  12. D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine.

    PubMed

    Betts, Jill F; Schweimer, Judith V; Burnham, Katherine E; Burnet, Philip W J; Sharp, Trevor; Harrison, Paul J

    2014-01-01

    D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study. PMID:24822045

  13. Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area.

    PubMed

    Sarti, Federica; Borgland, Stephanie L; Kharazia, Viktor N; Bonci, Antonello

    2007-08-01

    Growing evidence indicates that the expression of synaptic plasticity in the central nervous system results in dendritic reorganization and spine remodeling. Although long-term potentiation of glutamatergic synapses after cocaine exposure in the ventral tegmental area (VTA) has been proposed as a cellular mechanism underlying addictive behaviors, the relationship between long-term potentiation and dendritic remodeling induced by cocaine on the dopaminergic neurons of the VTA has not been demonstrated. Here we report that rat VTA cells classified as type I and II showed distinct morphological responses to cocaine, as a single cocaine exposure significantly increased dendritic spine density in type I but not in type II cells. Further, only type I cells had a significant increase in the AMPA receptor:NMDA receptor ratio after a single cocaine exposure. Taken together, our data provide evidence that increased spine density and synaptic plasticity are coexpressed within the same VTA neuronal population and that only type I neurons are structurally and synaptically modified by cocaine. PMID:17686047

  14. Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia

    PubMed Central

    Solt, Ken; Van Dort, Christa J.; Chemali, Jessica J.; Taylor, Norman E.; Kenny, Jonathan D.; Brown, Emery N.

    2014-01-01

    BACKGROUND Methylphenidate or a D1 dopamine receptor agonist induce reanimation (active emergence) from general anesthesia. We tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. METHODS In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (SN, n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120μA. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. RESULTS To maintain loss of righting, the dose of isoflurane was 0.9% ± 0.1 vol%, and the target plasma dose of propofol was 4.4 μg/ml ± 1.1 μg/ml (mean ± SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from δ (<4 Hz) to θ (4–8 Hz). In all rats with SN electrodes, stimulation did not elicit an arousal response or significant electroencephalogram changes. CONCLUSIONS Electrical stimulation of the VTA, but not the SN, induces reanimation during general anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA, but not SN, neurons induces reanimation from general anesthesia. PMID:24398816

  15. General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

    PubMed

    Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

    2012-03-14

    Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen

  16. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test

    PubMed Central

    Addy, N.A.; Nunes, E.J.; Wickham, R.J.

    2015-01-01

    Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125 mg/kg, intra-cranial; 1 or 2 μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24 μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST. PMID:25865152

  17. Intra-ventral tegmental area microinjections of urotensin II modulate the effects of cocaine

    PubMed Central

    Mueller, L E; Kausch, M A; Markovic, T; MacLaren, D A A; Dietz, D M; Park, J; Clark, S D

    2014-01-01

    Although the peptide urotensin II (UII) has well studied direct actions on the cardiovascular system, the UII receptor (UIIR) is expressed by neurons of the hindbrain. Specifically, the UIIR is expressed by the cholinergic neurons of the laterodorsal tegmentum (LDTg) and the pedunculopontine tegmentum (PPTg). These neurons send axons to the ventral tegmental area (VTA), for which the PPTg and LDTg are the sole source of acetylcholine. Therefore, it was hypothesized that UIIR activation within the VTA would modulate reward-related behaviors, such as cocaine-induced drug seeking. Intra-VTA microinjections of UII at high concentrations (1 nmole) established conditioned place preference (CPP), but also blocked cocaine-mediated CPP (10 mg/kg). When rats received systemic sub-effectual doses of cocaine (7.5mg/kg) with intra-VTA injections of 1 or 10 pmole of UII CPP was formed. Furthermore, the second endogenous ligand for the UIIR, urotensin II-related peptide, had the same effect at the 10 pmole dose. The effects of low doses of UII were blocked by pretreatment with the UIIR antagonist SB657510. Furthermore, it was found that intra-VTA UII (10 pmole) further increased cocaine-mediated (7.5 mg/kg) rises in electrically evoked dopamine in the nucleus accumbens. Our study has found that activation of VTA-resident UIIR produces observable behavioral changes in rats, and that UIIR is able to modulate the effects of cocaine. In addition, it was found that UIIR activation within the VTA can potentiate cocaine-mediated neurochemical effects. Therefore, the coincident activation of the UII-system and cocaine administration may increase the liability for drug taking behavior. PMID:25264578

  18. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test.

    PubMed

    Addy, N A; Nunes, E J; Wickham, R J

    2015-07-15

    Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125mg/kg, intra-cranial; 1 or 2μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST. PMID:25865152

  19. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress.

    PubMed

    Iñiguez, Sergio D; Vialou, Vincent; Warren, Brandon L; Cao, Jun-Li; Alcantara, Lyonna F; Davis, Lindsey C; Manojlovic, Zarko; Neve, Rachael L; Russo, Scott J; Han, Ming-Hu; Nestler, Eric J; Bolaños-Guzmán, Carlos A

    2010-06-01

    Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors. PMID:20519540

  20. Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

    PubMed Central

    van der Plasse, G; van Zessen, R; Luijendijk, M C M; Erkan, H; Stuber, G D; Ramakers, G M J; Adan, R A H

    2015-01-01

    Background/objectives: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. Subjects/methods: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. Results: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). Conclusions: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling. PMID:26183405

  1. Leptin reduces hyperactivity in an animal model for anorexia nervosa via the ventral tegmental area.

    PubMed

    Verhagen, Linda A W; Luijendijk, Mieneke C M; Adan, Roger A H

    2011-03-01

    Hyperactivity in anorexia nervosa (AN) is associated with low plasma leptin levels and negatively impacts on disease outcome. Using an animal model that mimics features of AN including food-restriction induced hyperlocomotion, we demonstrate that central leptin injections in the lateral ventricle and local injections of leptin into the ventral tegmental area (VTA) suppress running wheel activity. The results support that falling levels of leptin, that accompany caloric restriction, result in increased activity levels because of decreased leptin signaling in the VTA, part of the mesolimbic reward system. PMID:21190812

  2. Self-administration of ethanol, cocaine, or nicotine does not decrease the soma size of ventral tegmental area dopamine neurons.

    PubMed

    Mazei-Robison, Michelle S; Appasani, Raghu; Edwards, Scott; Wee, Sunmee; Taylor, Seth R; Picciotto, Marina R; Koob, George F; Nestler, Eric J

    2014-01-01

    Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent. PMID:24755634

  3. Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway

    PubMed Central

    Gigante, Eduardo D.; Benaliouad, Faiza; Zamora-Olivencia, Veronica; Wise, Roy A.

    2016-01-01

    Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates. PMID:27387668

  4. Timing and expectation of reward: a neuro-computational model of the afferents to the ventral tegmental area

    PubMed Central

    Vitay, Julien; Hamker, Fred H.

    2014-01-01

    Neural activity in dopaminergic areas such as the ventral tegmental area is influenced by timing processes, in particular by the temporal expectation of rewards during Pavlovian conditioning. Receipt of a reward at the expected time allows to compute reward-prediction errors which can drive learning in motor or cognitive structures. Reciprocally, dopamine plays an important role in the timing of external events. Several models of the dopaminergic system exist, but the substrate of temporal learning is rather unclear. In this article, we propose a neuro-computational model of the afferent network to the ventral tegmental area, including the lateral hypothalamus, the pedunculopontine nucleus, the amygdala, the ventromedial prefrontal cortex, the ventral basal ganglia (including the nucleus accumbens and the ventral pallidum), as well as the lateral habenula and the rostromedial tegmental nucleus. Based on a plausible connectivity and realistic learning rules, this neuro-computational model reproduces several experimental observations, such as the progressive cancelation of dopaminergic bursts at reward delivery, the appearance of bursts at the onset of reward-predicting cues or the influence of reward magnitude on activity in the amygdala and ventral tegmental area. While associative learning occurs primarily in the amygdala, learning of the temporal relationship between the cue and the associated reward is implemented as a dopamine-modulated coincidence detection mechanism in the nucleus accumbens. PMID:24550821

  5. The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta

    PubMed Central

    Jhou, Thomas C.; Geisler, Stefanie; Marinelli, Michela; DeGarmo, Beth A.; Zahm, Daniel S.

    2011-01-01

    Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responding to aversive stimuli. We now designate the region containing them as the mesopontine rostromedial tegmental nucleus (RMTg) and report herein on its neuroanatomy. Dense mu opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD 67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic-lateral hypothalamic continuum and midline-intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe and the locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures. PMID:19235216

  6. Sensory effects of intravenous cocaine on dopamine and non-dopamine ventral tegmental area neurons

    PubMed Central

    Brown, P. Leon; Kiyatkin, Eugene A.

    2008-01-01

    Intravenous (iv) cocaine mimics salient somato-sensory stimuli in their ability to induce rapid physiological effects, which appear to involve its action on peripherally located neural elements and fast neural transmission via somato-sensory pathways. To further clarify this mechanism, single-unit recording with fine glass electrodes was used in awake rats to examine responses of ventral tegmental area (VTA) neurons, both presumed dopamine (DA) and non-DA, to iv cocaine and tail-press, a typical somato-sensory stimulus. To exclude the contribution of DA mechanisms to the observed neuronal responses to sensory stimuli and cocaine, recordings were conducted during full DA receptor blockade (SCH23390+eticloptide). Iv cocaine (0.25 mg/kg delivered over 10 s) induces significant excitations of ~63% of long-spike (presumed DA) and ~70% of short-spike (presumed non-DA) VTA neurons. In both subgroups, neuronal excitations occurred with short latencies (4–8 s), peaked at 10–20 s (30–40% increase over baseline) and disappeared at 30–40 s after the injection onset. Most long- (67%) and short-spike (89%) VTA neurons also showed phasic responses to tail-press (5-s). All responsive long-spike cells were excited by tail-press; excitations were very rapid (peak at 1 s) and strong (100% rate increase over baseline) but brief (2–3 s). In contrast, both excitations (60%) and inhibitions (29%) were seen in short-spike cells. These responses were also rapid and transient, but excitations of short-spike units were more prolonged and sustained (10–15 s) than in long-spike cells. These data suggest that in awake animals iv cocaine, like somato-sensory stimuli, rapidly and transiently excites VTA neurons of different subtypes. Therefore, along with direct action on specific brain substrates, central effects of cocaine may occur via indirect mechanism, involving peripheral neural elements, visceral sensory nerves and rapid neural transmission. Via this mechanism, cocaine, like

  7. Inactivation of the Ventral Tegmental Area Abolished the General Excitatory Influence of Pavlovian Cues on Instrumental Performance

    ERIC Educational Resources Information Center

    Murschall, Anja; Hauber, Wolfgang

    2006-01-01

    Pavlovian stimuli can markedly elevate instrumental responding, an effect known as Pavlovian-instrumental transfer (PIT). As the role of the ventral tegmental area (VTA) in PIT is yet unknown, we examined the effects of transient VTA inactivation by direct microinjections of a mixture of the GABA[subscript A] and GABA[subscript B] receptor…

  8. Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.

    PubMed

    Chen, Nicola A; Ganella, Despina E; Bathgate, Ross A D; Chen, Alon; Lawrence, Andrew J; Kim, Jee Hyun

    2016-09-01

    The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory. PMID:27397862

  9. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons

    PubMed Central

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Wang, Huikun; de Jesus Aceves Buendia, Jose; Hoffman, Alexander F.; Lupica, Carl R.; Seal, Rebecca P.; Morales, Marisela

    2014-01-01

    Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibers of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibers have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release innucleus accumbens. Activation also reinforces instrumental behavior and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR—one of the most sensitive reward sites in the brain—to VTA dopaminergic neurons. PMID:25388237

  10. Role of Acetylcholine Transmission in Nucleus Accumbens and Ventral Tegmental Area in Heroin-Seeking Induced by Conditioned Cues

    PubMed Central

    Zhou, Wenhua; Liu, Huifen; Zhang, Fuqiang; Tang, Suien; Zhu, Huaqiang; Lai, Miaojun; Kalivas, Peter W.

    2007-01-01

    The involvement of cholinergic transmission in heroin self-administration and the reinstatement of heroin-seeking was examined in rats trained to nose-poke for intravenous heroin. Systemic treatment with physostigmine, an inhibitor of acetylcholinesterase, modestly reduced the acquisition and rate of heroin self-administration, and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine. Following 10–14 days of self-administration, rats were left in the home environment for 14 days. Subsequently, rats were evaluated for extinction of nose-pokes during the first hour after being returned to the self-administration apparatus. One hr later a conditioned stimulus (house light, light in the nose-poke hole, sound of the infusion pump) was presented to initiate cue-induced reinstatement. Physostigmine produced a dose-dependent inhibition of cue-induced reinstatement, but only the dose of 0.5 mg/kg significantly decreased nose-poke responding in the extinction test. Chronic treatment with physostigmine (0.1 mg/kg) did not impair performance during acquisition of heroin self-administration. However, during a subsequent reinstatement test conducted in the absence of physostigmine pretreatment, heroin seeking was significantly below that of rats chronically pretreated with saline. To evaluate brain regions mediating the effects of systemic drug treatment on reinstatement, physostigmine was microinjected into the nucleus accumbens (NAc) or ventral tegmental area (VTA). Microinjection of physostigmine into the NAc prior to presenting conditioned cues inhibited the reinstatement of heroin-seeking, without affecting extinction responding. In contrast, microinjection of physostigmine into the VTA augmented the reinstatement induced by conditioned cues and extinction responding. Inactivation of either NAc or VTA by microinjecting tetrodotoxin blocked both extinction responding and cue-induced reinstatement. These data demonstrate

  11. The ventral tegmental area modulates intracortical microstimulation (ICMS)-evoked M1 activity in a time-dependent manner.

    PubMed

    Kunori, Nobuo; Kajiwara, Riichi; Takashima, Ichiro

    2016-03-11

    Intracortical microstimulation (ICMS)-evoked neural activity combined with ventral tegmental area (VTA) stimulation was studied in rat primary motor cortex (M1). We used voltage-sensitive dye (VSD) imaging to analyze the spatiotemporal dynamics of M1 activity following VTA-M1 paired stimulation. VTA stimulation was preceded by M1 ICMS at inter-stimulus intervals (ISIs) of 15-350ms. VSD imaging showed an excitatory-inhibitory sequence of neural activity after composing VTA stimulus- and ICMS-induced M1 neural activity. To evaluate the net ICMS M1 response, the optical response to unpaired VTA stimulation was subtracted from the VTA-M1 paired response. This revealed that the net ICMS-evoked M1 neural activity was inhibited when the ISI was 30-50ms, but highly facilitated when the ISI was 100-350ms. These results suggest that VTA modulates M1 excitability in the order of tens to hundreds of milliseconds and might directly affect the motor command generation process in the M1. PMID:26827719

  12. Neuroprotection with methylaminochroman and lazaroid of embryonic ventral mesencephalic tegmental dopaminergic neurons in cold storage.

    PubMed

    Thajeb, Peterus; Kuo, Jon-Son; Shyu, Woei-Cherng; Lin, Shinn-Zong

    2006-05-01

    Embryonic ventral mesencephalic tegmental (EVMT) neurons die off over time in cold storage at 4 degrees C in hibernation buffers (HB). Manipulation of HB conditions may improve the survival of neurons in cold storage. We examined the effect of lipid peroxidation inhibitors, a methylaminochroman (U83836E) and a lazaroid (U74389G) on the viability and survival of embryonic dopaminergic neurons in the co-culture system of embryonic striatal target (EST) cells and EVMT neurons that had been stored for 3 days at 4 degrees C in HB with or without U83836E or U74389G. One-way analysis of variance (ANOVA) was used for analysis of data. The density of tyrosine hydroxylase immunoreactive (THIR)-positive neurons was significantly higher in the groups stored in supplemented HB than in the control (HB alone; P < 0.001). The neuroprotective effect was concentration-dependent. We conclude that either U83836E or U74389G-conditioned HB exerted a concentration-dependent neuroprotective effect on embryonic dopaminergic neurons in cold storage for 3 days. Supplementation of U83836E and U74389G or other methylaminochromans and lazaroids in HB may be important for cold storage of donor neuronal cells. PMID:16678726

  13. Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine.

    PubMed

    Taylor, Anna M W; Castonguay, Annie; Ghogha, Atefeh; Vayssiere, Pia; Pradhan, Amynah A A; Xue, Lihua; Mehrabani, Sadaf; Wu, Juli; Levitt, Pat; Olmstead, Mary C; De Koninck, Yves; Evans, Christopher J; Cahill, Catherine M

    2016-03-01

    Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors. PMID:26202104

  14. Phasic activation of ventral tegmental neurons increases response and pattern similarity in prefrontal cortex neurons

    PubMed Central

    Iwashita, Motoko

    2014-01-01

    Dopamine is critical for higher neural processes and modifying the activity of the prefrontal cortex (PFC). However, the mechanism of dopamine contribution to the modification of neural representation is unclear. Using in vivo two-photon population Ca2+ imaging in awake mice, this study investigated how neural representation of visual input to PFC neurons is regulated by dopamine. Phasic stimulation of dopaminergic neurons in the ventral tegmental area (VTA) evoked prolonged Ca2+ transients, lasting ∼30 s in layer 2/3 neurons of the PFC, which are regulated by a dopamine D1 receptor-dependent pathway. Furthermore, only a conditioning protocol with visual sensory input applied 0.5 s before the VTA dopaminergic input could evoke enhanced Ca2+ transients and increased pattern similarity (or establish a neural representation) of PFC neurons to the same sensory input. By increasing both the level of neuronal response and pattern similarity, dopaminergic input may establish robust and reliable cortical representation. DOI: http://dx.doi.org/10.7554/eLife.02726.001 PMID:25269147

  15. Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine

    PubMed Central

    Taylor, Anna M W; Castonguay, Annie; Ghogha, Atefeh; Vayssiere, Pia; Pradhan, Amynah A A; Xue, Lihua; Mehrabani, Sadaf; Wu, Juli; Levitt, Pat; Olmstead, Mary C; De Koninck, Yves; Evans, Christopher J; Cahill, Catherine M

    2016-01-01

    Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K+Cl− co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl− extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl− gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors. PMID:26202104

  16. Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine

    PubMed Central

    Choi, Kwang Ho; Edwards, Scott; Graham, Danielle L.; Larson, Erin B.; Whisler, Kimberly N.; Simmons, Diana; Friedman, Allyson K.; Walsh, Jessica J.; Rahman, Zia; Monteggia, Lisa M.; Eisch, Amelia J.; Neve, Rachael L.; Nestler, Eric J.; Han, Ming-Hu; Self, David W.

    2011-01-01

    Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic up-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1S845 phosphorylation are associated with increased GluR1 mRNA in self-administering animals, while increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 up-regulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Over-expression of GluR1WT in rat VTA primarily infected dopamine neurons (75%), and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1WT over-expression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, over-expression of GluR1WT in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, over-expression of protein kinase A-resistant GluR1S845A in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and over-expression of GluR1WT or GluR1S845A in the adjacent substantia nigra had no effect on cocaine self-administration. Taken together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use. PMID:21613507

  17. Cyclin-Dependent Kinase 5 in the Ventral Tegmental Area Regulates Depression-Related Behaviors

    PubMed Central

    Zhong, Peng; Liu, Xiaojie; Zhang, Zhen; Hu, Ying; Liu, Sarah J.; Lezama-Ruiz, Martha; Joksimovic, Milan

    2014-01-01

    Dopamine neurons in the ventral tegmental area (VTA) govern reward and motivation and dysregulated dopaminergic transmission may account for anhedonia and other symptoms of depression. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that regulates a broad range of brain functions through phosphorylation of a myriad of substrates, including tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. We investigated whether and how Cdk5 activity in VTA dopamine neurons regulated depression-related behaviors in mice. Using the Cre/LoxP system to selectively delete Cdk5 in the VTA or in midbrain dopamine neurons in Cdk5loxP/loxP mice, we showed that Cdk5 loss of function in the VTA induced anxiety- and depressive-like behaviors that were associated with decreases in TH phosphorylation at Ser31 and Ser40 in the VTA and dopamine release in its target region, the nucleus accumbens. The decreased phosphorylation of TH at Ser31 was a direct effect of Cdk5 deletion, whereas decreased phosphorylation of TH at Ser40 was likely caused by impaired cAMP/protein kinase A (PKA) signaling, because Cdk5 deletion decreased cAMP and phosphorylated cAMP response element-binding protein (p-CREB) levels in the VTA. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, we showed that selectively increasing cAMP levels in VTA dopamine neurons increased phosphorylation of TH at Ser40 and CREB at Ser133 and reversed behavioral deficits induced by Cdk5 deletion. The results suggest that Cdk5 in the VTA regulates cAMP/PKA signaling, dopaminergic neurotransmission, and depression-related behaviors. PMID:24790206

  18. Oxytocin activation of neurons in ventral tegmental area and interfascicular nucleus of mouse midbrain.

    PubMed

    Tang, Yamei; Chen, Zhiheng; Tao, Huai; Li, Cunyan; Zhang, Xianghui; Tang, Aiguo; Liu, Yong

    2014-02-01

    Oxytocin (OT) was reported to affect cognitive and emotional behavior by action in ventral tegmental area (VTA) and other brain areas. However, it is still unclear how OT activates VTA and related midline nucleus. Here, using patch-clamp recording, we studied the effects of OT on neuron activity in VTA and interfascicular nucleus (IF). OT dose-dependently and selectively excited small neurons located in medial VTA and the majority of IF neurons but not large neurons in lateral VTA. We found the hyperpolarization-activated current (I(h)) and the membrane capacitance of OT-sensitive neuron were significantly smaller than those of OT-insensitive neurons. The action potential width of OT-sensitive neurons was about half that of OT-insensitive neurons. The OT effect was blocked by the OT receptor antagonist atosiban and WAY-267464 but not by tetrodotoxin, suggesting a direct postsynaptic activation of OT receptors. In addition, the phospholipase C (PLC) inhibitor U73122 antagonized the depolarization by OT. Both the nonselective cation channel (NSCC) antagonist SKF96365 and the Na(+)-Ca(2+) exchanger (NCX) blocker SN-6 attenuated OT effects. These results suggested that the PLC signaling pathway coupling to NSCC and NCX contributes to the OT-mediated activation of neurons in medial VTA and IF. Taken together, our results indicate OT directly acted on medial VTA and especially IF neurons to activate NSCC and NCX via PLC. The direct activation by OT of midbrain neurons may be one mechanism underlying OT effects on social behavior. PMID:24148809

  19. GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area

    PubMed Central

    Vashchinkina, Elena; Panhelainen, Anne; Aitta-aho, Teemu; Korpi, Esa R.

    2014-01-01

    GABAA receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity in the ventral tegmental area (VTA) dopamine neurons and their main target projections. Furthermore, depending whether synaptic or extrasynaptic GABAA receptor populations are activated, the behavioral outcome of repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. The VTA dopamine neurons project to forebrain centers such as the nucleus accumbens and medial prefrontal cortex, and receive afferent projections from these brain regions and especially from the extended amygdala and lateral habenula, forming the major part of the reward and aversion circuitry. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers as studied from Golgi-Cox-stained VTA dendrites. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be rigorously tested for a number of clinically important anxiolytics, sedatives and anesthetics in different parts of the circuitry. PMID

  20. Microinfusion of Bupropion Inhibits Putative GABAergic Neuronal Activity of the Ventral Tegmental Area

    PubMed Central

    Amirabadi, Sanaz; Pakdel, Firouz Ghaderi; Shahabi, Parviz; Naderi, Somayyeh; Osalou, Mostafa Ashrafi; Cankurt, Ulker

    2014-01-01

    Introduction The most common interpretation for the mechanisms of antidepression is the increase of the brain monoamine levels such as dopamine (DA). The increase of DA can reduce depression but it can also decrease the monoamine release because of autoreceptor inhibition. Although bupropion can decrease the dopamine release, there is evidence about stimulatory effects of chronic application of bupropion on ventral tegmental area (VTA) neurons. In this study, the intra-VTA acute microinfusion of bupropion on putative VTA non-Dopaminergic (VTA-nonDA) neuronal firing rates was evaluated by a single neuron recording technique. Methods Animals were divided into 7 groups (sham, and 6 bupropion-microinfused groups with 1, 10-1, 10-2, 10-3, 10-4, and 10-5 mol, 1 µl/3 min, intra-VTA). A single neuron recording technique was done according to the stereotaxic coordination. After 10 min baseline recording, ACSF or bupropion was microinfused. The recording continued to recovery period in the treated groups. The prestimulus time (PST) and interspike interval (ISI) histograms were calculated for every single unit. The assessment of the drug effect was carried out by one-way analysis of variance (ANOVA) and Post-hoc test. Results 126 non-DA neurons were separated. Bupropion could inhibit 116 neurons and 11 neurons had no significant response. Maximum inhibition was 79.1% of baseline firing rate with 44.3 min duration. The inhibitory effect of bupropion was dose-dependent. Discussion The acute inhibitory effects of bupropion on VTA-nonDA neurons can explain the fast inhibitory effects of bupropion and other antidepressants on the VTA. These data can explain some side effects of antidepressants. PMID:25337378

  1. Obesity attenuates D2 autoreceptor‐mediated inhibition of putative ventral tegmental area dopaminergic neurons

    PubMed Central

    Koyama, Susumu; Mori, Masayoshi; Kanamaru, Syohei; Sazawa, Takuya; Miyazaki, Ayano; Terai, Hiroki; Hirose, Shinichi

    2014-01-01

    Abstract The ventral tegmental area (VTA) in the midbrain is important for food reward. High‐fat containing palatable foods have reinforcing effects and accelerate obesity. We have previously reported that diet‐induced obesity selectively decreased the spontaneous activity of VTA GABA neurons, but not dopamine neurons. The spontaneous activity of VTA dopamine neurons is regulated by D2 autoreceptors. In this study, we hypothesized that obesity would affect the excitability of VTA dopamine neurons via D2 autoreceptors. To examine this hypothesis, we compared D2 receptor‐mediated responses of VTA dopamine neurons between lean and obese mice. Mice fed on a high‐fat (45%) diet and mice fed on a standard diet were used as obese and lean models, respectively. Brain slice preparations were made from these two groups. Spontaneous activity of VTA neurons was recorded by extracellular recording. Putative VTA dopamine neurons were identified by firing inhibition with a D2 receptor agonist quinpirole, and electrophysiological criteria (firing frequency <5 Hz and action potential current duration >1.2 msec). Single‐dose application of quinpirole (3−100 nmol/L) exhibited similar firing inhibition of putative VTA dopamine neurons between lean and obese mice. In stepwise application by increasing quinpirole concentrations of 3, 10, 30, and 100 nmol/L subsequently, quinpirole‐induced inhibition of firing decreased in putative VTA dopamine neurons of obese mice compared with those of lean mice. In conclusion, high‐fat diet‐induced obesity attenuated D2 receptor‐mediated inhibition of putative VTA dopamine neurons due to the acceleration of D2 receptor desensitization. PMID:24793981

  2. Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia.

    PubMed

    Rice, Matthew W; Roberts, Rosalinda C; Melendez-Ferro, Miguel; Perez-Costas, Emma

    2016-01-01

    Previous work from our laboratory showed deficits in tyrosine hydroxylase protein expression within the substantia nigra/ventral tegmental area (SN/VTA) in schizophrenia. However, little is known about the nature and specific location of these deficits within the SN/VTA. The present study had two aims: (1) test if tyrosine hydroxylase deficits could be explained as the result of neuronal loss; (2) assess if deficits in tyrosine hydroxylase are sub-region specific within the SN/VTA, and thus, could affect specific dopaminergic pathways. To achieve these objectives: (1) we obtained estimates of the number of dopaminergic neurons, total number of neurons, and their ratio in matched SN/VTA schizophrenia and control samples; (2) we performed a qualitative assessment in SN/VTA schizophrenia and control matched samples that were processed simultaneously for tyrosine hydroxylase immunohistochemistry. We did not find any significant differences in the total number of neurons, dopaminergic neurons, or their ratio. Our qualitative study of TH expression showed a conspicuous decrease in labeling of neuronal processes and cell bodies within the SN/VTA, which was sub-region specific. Dorsal diencephalic dopaminergic populations of the SN/VTA presented the most conspicuous decrease in TH labeling. These data support the existence of pathway-specific dopaminergic deficits that would affect the dopamine input to the cortex without significant neuronal loss. Interestingly, these findings support earlier reports of decreases in tyrosine hydroxylase labeling in the target areas for this dopaminergic input in the prefrontal and entorhinal cortex. Finally, our findings support that tyrosine hydroxylase deficits could contribute to the hypodopaminergic state observed in cortical areas in schizophrenia. PMID:25269834

  3. Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons.

    PubMed

    Wang, Hui-Ling; Qi, Jia; Zhang, Shiliang; Wang, Huikun; Morales, Marisela

    2015-12-01

    Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons. PMID:26631475

  4. Discrete cell gene profiling of ventral tegmental dopamine neurons after acute and chronic cocaine self-administration.

    PubMed

    Backes, Eric; Hemby, Scott E

    2003-11-01

    Chronic cocaine administration induces a number of biochemical alterations within the mesolimbic dopamine system that may mediate various aspects of the addictive process such as sensitization, craving, withdrawal, and relapse. In the present study, rats were allowed to self-administer cocaine (0.5 mg/infusion) for 1 or 20 days. Tyrosine hydroxylase immunopositive cells were microdissected from the ventral tegmental area (VTA) using laser capture microdissection, and changes in the abundances of 95 mRNAs were assessed using cDNA macroarrays. Five GABA-A receptor subunit mRNAs (alpha4, alpha6, beta2, gamma2, and delta) were down-regulated at both 1 and 20 days of cocaine self-administration. In contrast, the catalytic subunit of protein phosphatase 2A (PP2alpha), GABA-A alpha1, and Galphai2 were significantly increased at both time points. Additionally, calcium/calmodulin-dependent protein kinase IIalpha mRNA levels were increased initially followed by a slight decrease after 20 days, whereas neuronal nitric-oxide synthase mRNA levels were initially decreased but returned to near control levels by day 20. These results indicate that alterations of specific GABA-A receptor subtypes and other signal transduction transcripts seem to be specific neuroadaptations associated with cocaine self-administration. Moreover, as subunit composition determines the functional properties of GABA-A receptors, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine. PMID:12966149

  5. Reinstatement of cocaine-seeking by hypocretin (orexin) in the ventral tegmental area: Independence from the local CRF network

    PubMed Central

    Wang, Bin; You, Zhi-Bing; Wise, Roy A

    2009-01-01

    Background Hypocretin (Hcrt), an arousal- and feeding-associated peptide is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine-seeking. Each is presumed to act at least in part through actions local to the VTA. Here we examined the possibility that VTA perfusion of Hcrt reinstates cocaine-seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF. Methods Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA. Results VTA perfusion of Hcrt-1 or footshock stress reinstated cocaine-seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release. Conclusions While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine-seeking. PMID:19251246

  6. Excitatory synaptic function and plasticity is persistently altered in ventral tegmental area dopamine neurons after prenatal ethanol exposure.

    PubMed

    Hausknecht, Kathryn; Haj-Dahmane, Samir; Shen, Ying-Ling; Vezina, Paul; Dlugos, Cynthia; Shen, Roh-Yu

    2015-03-01

    Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders. PMID:25284318

  7. Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area.

    PubMed

    Arencibia-Albite, F; Paladini, C; Williams, J T; Jiménez-Rivera, C A

    2007-10-26

    Alterations in the state of excitability of midbrain dopamine (DA) neurons from the ventral tegmental area (VTA) may underlie changes in the synaptic plasticity of the mesocorticolimbic system. Here, we investigated norepinephrine's (NE) regulation of VTA DA cell excitability by modulation of the hyperpolarization-activated cation current, Ih, with whole cell recordings in rat brain slices. Current clamp recordings show that NE (40 microM) hyperpolarizes spontaneously firing VTA DA cells (11.23+/-4 mV; n=8). In a voltage clamp, NE (40 microM) induces an outward current (100+/-24 pA; n=8) at -60 mV that reverses at about the Nernst potential for potassium (-106 mV). In addition, NE (40 microM) increases the membrane cord conductance (179+/-42%; n=10) and reduces Ih amplitude (68+/-3% of control at -120 mV; n=10). The noradrenergic alpha-1 antagonist prazosin (40 microM; n=5) or the alpha-2 antagonist yohimbine (40 microM; n=5) did not block NE effects. All NE-evoked events were blocked by the D2 antagonists sulpiride (1 microM) and eticlopride (100 nM) and no significant reduction of Ih took place in the presence of the potassium channel blocker BaCl2 (300 microM). Therefore, it is concluded that NE inhibition of Ih was due to an increase in membrane conductance by a nonspecific activation of D2 receptors that induce an outward potassium current and is not a result of a second messenger system acting on h-channels. The results also suggest that Ih channels are mainly located at dendrites of VTA DA cells and, thus, their inhibition may facilitate the transition from single-spike firing to burst firing and vice versa. PMID:17884297

  8. Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine.

    PubMed

    Schmidt, Heath D; Mietlicki-Baase, Elizabeth G; Ige, Kelsey Y; Maurer, John J; Reiner, David J; Zimmer, Derek J; Van Nest, Duncan S; Guercio, Leonardo A; Wimmer, Mathieu E; Olivos, Diana R; De Jonghe, Bart C; Hayes, Matthew R

    2016-06-01

    Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food. As the neural circuits and neurobiological mechanisms underlying drug taking overlap to some degree with those regulating food intake, these findings suggest that activation of central GLP-1 receptors may also attenuate cocaine taking. Here, we show that intra-VTA administration of the GLP-1 receptor agonist exendin-4 (0.05 μg) significantly reduced cocaine, but not sucrose, self-administration in rats. We also demonstrate that cocaine taking is associated with elevated plasma corticosterone levels and that systemic infusion of cocaine activates GLP-1-expressing neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus that projects monosynaptically to the VTA. To determine the potential mechanisms by which cocaine activates NTS GLP-1-expressing neurons, we microinjected corticosterone (0.5 μg) directly into the hindbrain fourth ventricle. Intraventricular corticosterone attenuated cocaine self-administration and this effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin-(9-39) (10 μg) in the VTA. Finally, AAV-shRNA-mediated knockdown of VTA GLP-1 receptors was sufficient to augment cocaine self-administration. Taken together, these findings indicate that increased activation of NTS GLP-1-expressing neurons by corticosterone may represent a homeostatic response to cocaine taking, thereby reducing the reinforcing efficacy of cocaine. Therefore, central GLP-1 receptors may represent a novel target for cocaine addiction pharmacotherapies. PMID:26675243

  9. Sex differences in the ontogeny of CRF receptors during adolescent development in the dorsal raphe nucleus and ventral tegmental area.

    PubMed

    Lukkes, Jodi L; Norman, Kevin J; Meda, Shirisha; Andersen, Susan L

    2016-03-01

    Interactions between corticotropin-releasing factor (CRF) and monoaminergic systems originating from the dorsal raphe nucleus (DR) and ventral tegmental area (VTA) have been implicated in the etiology and pathophysiology of several stress-related neuropsychiatric disorders such as depression and substance abuse. Sub-regions within the DR and VTA give rise to specific projections that have unique roles in limbic- and reward-related behaviors. Given that these disorders typically emerge during adolescence, it is surprising that few studies have examined the age-, sex-, and region-dependent expression of CRF receptors throughout multiple stages of adolescence in these stress-relevant circuits. To determine the ontogeny of CRF receptors during adolescent development, three regions of the DR (dorsal, caudal, and ventrolateral parts) and the posterior VTA were microdissected from Sprague-Dawley male and female rats on postnatal day (P) 25, P35, P42, P56, and P90. Tissue was processed and analyzed with qRT-PCR to measure CRF1 and CRF2 receptors. The serotonin and catecholamine enzymes in the DR and VTA, tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase, respectively, were also analyzed for maturational differences. This study identified that CRF1 receptors are lower in males than females within the dorsal, ventrolateral region of the DR (DRVL), which is involved in anxiety-, stress-, and panic-related responses. Females had higher CRF2 receptors compared to males in the DRVL only. Levels of TPH2 mRNA in the DRVL were overproduced transiently in females before declining into adulthood. These fundamental studies suggest that sex differences in CRF receptors should be considered when examining stress-related neuropsychiatric disorders and their treatment. PMID:26696011

  10. ETHANOL ACTION ON DOPAMINERGIC NEURONS IN THE VENTRAL TEGMENTAL AREA: INTERACTION WITH INTRINSIC ION CHANNELS AND NEUROTRANSMITTER INPUTS

    PubMed Central

    Morikawa, Hitoshi; Morrisett, Richard A.

    2010-01-01

    The dopaminergic system originating in the midbrain ventral tegmental area (VTA) has been extensively studied over the past decades as a critical neural substrate involved in the development of alcoholism and addiction to other drugs of abuse. Accumulating evidence indicates that ethanol modulates the functional output of this system by directly affecting the firing activity of VTA dopamine neurons, whereas withdrawal from chronic ethanol exposure leads to a reduction in the functional output of these neurons. This chapter will provide an update on the mechanistic investigations of the acute ethanol action on dopamine neuron activity and the neuroadaptations/plasticities in the VTA produced by previous ethanol experience. PMID:20813245

  11. Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies.

    PubMed

    Devine, D P; Leone, P; Pocock, D; Wise, R A

    1993-09-01

    In vivo microdialysis was used to assess the involvement of ventral tegmental area (VTA) mu, delta, and kappa opioid receptors in modulation of basal extracellular ventral striatal dopamine (DA) and DA-metabolite concentrations. Independent groups of chloral hydrate-anesthetized rats were given VTA microinjections of selective opioid agonists, and extracellular ventral striatal DA and DA-metabolite concentrations were assayed using HPLC. VTA microinjections of [D-Ala2, N-Me-Phe4-Gly5-ol]-enkephalin (DAMGO; a mu agonist) and [D-Pen2, D-Pen5]-enkephalin (DDDPE; a delta agonist) each caused dose-orderly increases in ventral striatal DA and DA-metabolite concentrations. The effective concentrations of DPDPE were 100- to 1000-fold higher than the effective concentrations of DAMGO. VTA microinjections of (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-hexyl]- benzeneacetamide) methane sulfonate hydrate (U-50,488H); a kappa agonist) failed to alter ventral striatal DA concentrations at any dose tested, but subsequent systemic injections significantly decreased DA and DA-metabolite concentrations. Pretreatment with VTA microinjections of 17-cyclopropylmethyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'- indolmorphinan hydrochloride (naltrindole; a delta antagonist) (delta antagonist) antagonized VTA DPDPE-mediated increases in ventral striatal DA and DA-metabolite concentrations but failed to antagonize VTA DAMGO-mediated increases. Pretreatment with D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; a mu antagonist) antagonized VTA DAMGO-mediated increases but failed to antagonize VTA DPDPE-mediated increases. Thus both mu and delta receptor agonist appear capable of increasing ventral striatal DA and DA-metabolite concentrations through selective actions on their preferred class of opioid receptors in the VTA. The increases in ventral striatal DA and DA-metabolite concentrations that are seen after systemic treatment with kappa opioid agonists appear not to

  12. CRF neurons in the ventral tegmental area control the aversive effects of nicotine withdrawal and promote escalation of nicotine intake

    PubMed Central

    Grieder, Taryn E.; Herman, Melissa A.; Contet, Candice; Tan, Laura A.; Vargas-Perez, Hector; Cohen, Ami; Chwalek, Michal; Maal-Bared, Geith; Freiling, John; Schlosburg, Joel E; Clarke, Laura; Crawford, Elena; Koebel, Pascale; Canonigo, Vez; Sanna, Pietro; Tapper, Andrew; Roberto, Marisa; Kieffer, Brigitte L.; Sawchenko, Paul E.; Koob, George F.; van der Kooy, Derek; George, Olivier

    2014-01-01

    SUMMARY Dopaminergic neurons in the ventral tegmental area (VTA) are well known for their role in mediating the positive reinforcing effects of drugs of abuse. Here, we identify in rodents and humans a population of VTA dopamine neurons co-expressing corticotropin releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates CRF mRNA in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors, and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of CRF mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal, and limited the escalation of nicotine intake. These results link the brain reward and stress systems within the same brain region in signaling the negative motivational effects of nicotine withdrawal. PMID:25402857

  13. Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation.

    PubMed

    Nieh, Edward H; Vander Weele, Caitlin M; Matthews, Gillian A; Presbrey, Kara N; Wichmann, Romy; Leppla, Christopher A; Izadmehr, Ehsan M; Tye, Kay M

    2016-06-15

    Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience. VIDEO ABSTRACT. PMID:27238864

  14. Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections.

    PubMed

    Thompson, Lachlan; Barraud, Perrine; Andersson, Elin; Kirik, Deniz; Björklund, Anders

    2005-07-01

    Transplants of fetal ventral mesencephalic tissue are known to contain a mixture of two major dopamine (DA) neuron types: the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). Previous studies have suggested that these two DA neuron types may differ in their growth characteristics, but, because of technical limitations, it has so far been difficult to identify the two subtypes in fetal ventral mesencephalon (VM) grafts and trace their axonal projections. Here, we have made use of a transgenic mouse expressing green fluorescent protein (GFP) under the tyrosine hydroxylase promoter. The expression of the GFP reporter allowed for visualization of the grafted DA neurons and their axonal projections within the host brain. We show that the SNpc and VTA neuron subtypes in VM grafts can be identified on the basis of their morphology and location within the graft, and their expression of a G-protein-gated inwardly rectifying K+ channel subunit (Girk2) and calbindin, respectively, and also that the axonal projections of the two DA neuron types are markedly different. By retrograde axonal tracing, we show that dopaminergic innervation of the striatum is derived almost exclusively from the Girk2-positive SNpc cells, whereas the calbindin-positive VTA neurons project to the frontal cortex and probably also other forebrain areas. The results suggest the presence of axon guidance and target recognition mechanisms in the DA-denervated forebrain that can guide the growing axons to their appropriate targets and indicate that cell preparations used for cell replacement in Parkinson's disease will be therapeutically useful only if they contain cells capable of generating the correct nigral DA neuron phenotype. PMID:16000637

  15. A cytoarchitectonic and chemoarchitectonic analysis of the dopamine cell groups in the substantia nigra, ventral tegmental area, and retrorubral field in the mouse.

    PubMed

    Fu, Yuhong; Yuan, Yuan; Halliday, Glenda; Rusznák, Zoltán; Watson, Charles; Paxinos, George

    2012-04-01

    The three main dopamine cell groups of the brain are located in the substantia nigra (A9), ventral tegmental area (A10), and retrorubral field (A8). Several subdivisions of these cell groups have been identified in rats and humans but have not been well described in mice, despite the increasing use of mice in neurodegenerative models designed to selectively damage A9 dopamine neurons. The aim of this study was to determine whether typical subdivisions of these dopamine cell groups are present in mice. The dopamine neuron groups were analysed in 15 adult C57BL/6J mice by anatomically localising tyrosine hydroxylase (TH), dopamine transporter protein (DAT), calbindin, and the G-protein-activated inward rectifier potassium channel 2 (GIRK2) proteins. Measurements of the labeling intensity, neuronal morphology, and the proportion of neurons double-labeled with TH, DAT, calbindin, or GIRK2 were used to differentiate subregions. Coronal maps were prepared and reconstructed in 3D. The A8 cell group had the largest dopamine neurons. Five subregions of A9 were identified: the reticular part with few dopamine neurons, the larger dorsal and smaller ventral dopamine tiers, and the medial and lateral parts of A9. The latter has groups containing some calbindin-immunoreactive dopamine neurons. The greatest diversity of dopamine cell types was identified in the seven subregions of A10. The main dopamine cell groups in the mouse brain are similar in terms of diversity to those observed in rats and humans. These findings are relevant to models using mice to analyse the selective vulnerability of different types of dopamine neurons. PMID:21935672

  16. Increased number of TH-immunoreactive cells in the ventral tegmental area after deep brain stimulation of the anterior nucleus of the thalamus.

    PubMed

    Dela Cruz, J A D; Hescham, S; Adriaanse, B; Campos, F L; Steinbusch, H W M; Rutten, B P F; Temel, Y; Jahanshahi, A

    2015-09-01

    Dopamine (DA) has been long implicated with the processes of memory. In long-term memory, the hippocampus and ventral tegmental area (VTA) use DA to enhance long-term potentiation, while prefrontal DA D1 receptors are involved in working memory. Deep brain stimulation (DBS) of specific brain areas have been shown to affect memory impairments in animal models. Here, we tested the hypothesis that DBS could reverse memory impairments by increasing the number of dopaminergic cells in the VTA. Rats received DBS at the level of the mammillothalamic tract, the anterior nucleus of the thalamus, and entorhinal cortex before euthanasia. These regions are part of the so-called memory circuit. Brain sections were processed for c-Fos and tyrosine hydroxylase (TH) immunocytochemistry in the VTA and the substantia nigra pars compacta (SNc). c-Fos, TH and c-Fos/TH immunoreactive cells were analyzed by means of stereology and confocal microscopy. Our results showed that DBS of the anterior nucleus of the thalamus induced substantial higher numbers of TH-immunoreactive cells in the VTA, while there were no significant differences between the experimental groups in the number of TH immunoreactive cells in the SNc, c-Fos immunoreactive cells and c-Fos/TH double-labeled cells in both the SNc and VTA. Our findings suggest a phenotypic switch, or neurotransmitter respecification, of DAergic cells specifically in the VTA which may be induced by DBS in the anterior nucleus of the thalamus. PMID:25074751

  17. Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine.

    PubMed

    Schenk, S; Partridge, B

    1997-09-26

    Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-D-aspartate (NMDA) (0.6, 1.25 or 2.5 microg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs. PMID:9374190

  18. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release.

    PubMed

    Pehek, E A; Hernan, A E

    2015-04-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

  19. Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation.

    PubMed

    Moradi, Marzieh; Yazdanian, Mohamadreza; Haghparast, Abbas

    2015-10-01

    Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230-280 g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4 μg/0.3 μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4 μg/0.5 μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125 nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60 min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens. PMID:26166189

  20. Ventral Tegmental Area Neurotensin Signaling Links the Lateral Hypothalamus to Locomotor Activity and Striatal Dopamine Efflux in Male Mice

    PubMed Central

    Patterson, Christa M.; Wong, Jenny-Marie T.; Leinninger, Gina M.; Allison, Margaret B.; Mabrouk, Omar S.; Kasper, Chelsea L.; Gonzalez, Ian E.; Mackenzie, Alexander; Jones, Justin C.

    2015-01-01

    Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA-derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function. PMID:25734363

  1. DAMGO depresses inhibitory synaptic transmission via different downstream pathways of μ opioid receptors in ventral tegmental area and periaqueductal gray.

    PubMed

    Zhang, W; Yang, H L; Song, J J; Chen, M; Dong, Y; Lai, B; Yu, Y G; Ma, L; Zheng, P

    2015-08-20

    Opioid-induced rewarding and motorstimulant effects are mediated by an increased activity of the ventral tegmental area (VTA) dopamine (DA) neurons. The excitatory mechanism of opioids on VTA-DA neurons has been proposed to be due to the depression of GABAergic synaptic transmission in VTA-DA neurons. However, how opioids depress GABAergic synaptic transmission in VTA-DA neurons remain to be studied. In the present study, we explored the mechanism of the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on GABAergic synaptic transmission in VTA-DA neurons using multiple approaches and techniques. Our results showed that (1) DAMGO inhibits GABAergic inputs in VTA-DA neurons at presynaptic sites; (2) effect of DAMGO on GABAergic inputs in VTA-DA neurons is inhibited by potassium channel blocker 4-aminopyridine (4-AP) and Gi protein inhibitor N-ethylmaleimide (NEM); (3) phospholipase A2 (PLA2) does not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons, but mediates it in the periaqueductal gray (PAG); (4) multiple downstream signaling molecules of μ receptors do not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons. These results suggest that DAMGO depresses inhibitory synaptic transmission via μ receptor-Gi protein-Kv channel pathway in VTA-DA neurons, but via μ receptor-PLA2 pathway in PAG neurons. PMID:26047721

  2. Loss of D2 Dopamine Receptor Function Modulates Cocaine-Induced Glutamatergic Synaptic Potentiation in the Ventral Tegmental Area

    PubMed Central

    Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello

    2013-01-01

    Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons. PMID:23884939

  3. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area.

    PubMed

    Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello; Whistler, Jennifer L

    2013-07-24

    Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons. PMID:23884939

  4. Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons

    PubMed Central

    Mazei-Robison, M.S.; Koo, J.W.; Friedman, A.; Lansink, C.S.; Robison, A.J.; Vinish, M.; Krishnan, V.; Kim, S.; Siuta, M.A.; Galli, M. A.; Niswender, K.D.; Appasani, R.; Horvath, M.C.; Neve, R.L.; Worley, P.F.; Snyder, S.H.; Hurd, Y.L.; Cheer, J.F.; Han, M.H.; Russo, S.J.; Nestler, E.J.

    2011-01-01

    SUMMARY While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knock-out of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse. PMID:22196333

  5. Morphofunctional alterations in ventral tegmental area dopamine neurons in acute and prolonged opiates withdrawal. A computational perspective.

    PubMed

    Enrico, P; Migliore, M; Spiga, S; Mulas, G; Caboni, F; Diana, M

    2016-05-13

    Dopamine (DA) neurons of the ventral tegmental area (VTA) play a key role in the neurobiological basis of goal-directed behaviors and addiction. Morphine (MOR) withdrawal induces acute and long-term changes in the morphology and physiology of VTA DA cells, but the mechanisms underlying these modifications are poorly understood. Because of their predictive value, computational models are a powerful tool in neurobiological research, and are often used to gain further insights and deeper understanding on the molecular and physiological mechanisms underlying the development of various psychiatric disorders. Here we present a biophysical model of a DA VTA neuron based on 3D morphological reconstruction and electrophysiological data, showing how opiates withdrawal-driven morphological and electrophysiological changes could affect the firing rate and discharge pattern. The model findings suggest how and to what extent a change in the balance of GABA/GLU inputs can take into account the experimentally observed hypofunction of VTA DA neurons during acute and prolonged withdrawal, whereas morphological changes may play a role in the increased excitability of VTA DA cell to opiate administration observed during opiate withdrawal. PMID:26899424

  6. Efferent projections of the retrorubral nucleus to the substantia nigra and ventral tegmental area in cats as shown by anterograde tracing.

    PubMed

    Arts, M P; Groenewegen, H J; Veening, J G; Cools, A R

    1996-01-01

    The aim of the present study was to determine whether the retrorubral nucleus projects to the dopaminergic nuclei in the ventral midbrain of the cat. For this purpose, injections of biotinylated dextran-amine or Phaseolus vulgaris-leucoagglutinin were placed into the retrorubral nucleus under stereotaxic guidance. The tracers were visualized by means of (immuno) histochemical procedures. In addition, tyrosine hydroxylase immunohistochemistry was used to evaluate the location of the injection sites and the distribution of the anterogradely labeled fibers. Both tracers reveal the same topography of labeled fibers in the ventral mesencephalon. Labeled fibers with varicosities were found ipsilaterally in the substantia nigra pars compacta, the substantia nigra pars lateralis, the ventral tegmental area and, contralaterally, in the substantia nigra pars compacta, the ventral tegmental area, and the retrorubral nucleus. A considerable number of labeled axons with varicosities were observed to be wrapped around the dendrites and perikarya of tyrosine hydroxylase-positive neurons in these areas. The present results are discussed in view of the possible role of the A8 dopaminergic cell group in the coordination of A9 nigrostriatal and A10 mesolimbic systems, as well as in the progressive pathology seen in patients suffering from Parkinson's disease. PMID:8736584

  7. Long-range projection neurons of the mouse ventral tegmental area: a single-cell axon tracing analysis

    PubMed Central

    Aransay, Ana; Rodríguez-López, Claudia; García-Amado, María; Clascá, Francisco; Prensa, Lucía

    2015-01-01

    Pathways arising from the ventral tegmental area (VTA) release dopamine and other neurotransmitters during the expectation and achievement of reward, and are regarded as central links of the brain networks that create drive, pleasure, and addiction. While the global pattern of VTA projections is well-known, the actual axonal wiring of individual VTA neurons had never been investigated. Here, we labeled and analyzed the axons of 30 VTA single neurons by means of single-cell transfection with the Sindbis-pal-eGFP vector in mice. These observations were complemented with those obtained by labeling the axons of small populations of VTA cells with iontophoretic microdeposits of biotinylated dextran amine. In the single-cell labeling experiments, each entire axonal tree was reconstructed from serial sections, the length of terminal axonal arbors was estimated by stereology, and the dopaminergic phenotype was tested by double-labeling for tyrosine hydroxylase immunofluorescence. We observed two main, markedly different VTA cell morphologies: neurons with a single main axon targeting only forebrain structures (FPN cells), and neurons with multibranched axons targeting both the forebrain and the brainstem (F + BSPN cells). Dopaminergic phenotype was observed in FPN cells. Moreover, four “subtypes” could be distinguished among the FPN cells based on their projection targets: (1) “Mesocorticolimbic” FPN projecting to both neocortex and basal forebrain; (2) “Mesocortical” FPN innervating the neocortex almost exclusively; (3) “Mesolimbic” FPN projecting to the basal forebrain, accumbens and caudateputamen; and (4) “Mesostriatal” FPN targeting only the caudateputamen. While the F + BSPN cells were scattered within VTA, the mesolimbic neurons were abundant in the paranigral nucleus. The observed diversity in wiring architectures is consistent with the notion that different VTA cell subpopulations modulate the activity of specific sets of prosencephalic and

  8. Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area.

    PubMed

    Shumake, Jason; Ilango, Anton; Scheich, Henning; Wetzel, Wolfram; Ohl, Frank W

    2010-04-28

    Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LHb lesions. We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning. PMID:20427648

  9. Involvement of ventral tegmental area ionotropic glutamate receptors in the expression of ethanol-induced conditioned place preference.

    PubMed

    Pina, Melanie M; Cunningham, Christopher L

    2016-10-15

    The ventral tegmental area (VTA) is a well-established neural substrate of reward-related processes. Activity within this structure is increased by the primary and conditioned rewarding effects of abused drugs and its engagement is heavily reliant on excitatory input from structures upstream. In the case of drug seeking, it is thought that exposure to drug-associated cues engages glutamatergic VTA afferents that signal directly to dopamine cells, thereby triggering this behavior. It is unclear, however, whether glutamate input to VTA is directly involved in ethanol-associated cue seeking. Here, the role of intra-VTA ionotropic glutamate receptor (iGluR) signaling in ethanol-cue seeking was evaluated in DBA/2J mice using an ethanol conditioned place preference (CPP) procedure. Intra-VTA iGluRs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)/kainate and N-methyl-d-aspartate (NMDAR) were blocked during ethanol CPP expression by co-infusion of antagonist drugs 6,7-dinitroquinoxaline-2,3-dione (DNQX; AMPA/kainate) and d-(-)-2-Amino-5-phosphonopentanoic acid (AP5; NMDA). Compared to aCSF, bilateral infusion of low (1 DNQX+100 AP5ng/side) and high (5 DNQX+500 AP5ng/side) doses of the AMPAR and NMDAR antagonist cocktail into VTA blocked ethanol CPP expression. This effect was site specific, as DNQX/AP5 infusion proximal to VTA did not significantly impact CPP expression. An increase in activity was found at the high but not low dose of DNQX/AP5. These findings demonstrate that activation of iGluRs within the VTA is necessary for ethanol-associated cue seeking, as measured by CPP. PMID:27378337

  10. Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: A molecular, cellular and behavioral analysis

    PubMed Central

    Gillies, G.E.; Virdee, K.; McArthur, S.; Dalley, J.W.

    2014-01-01

    The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. This may be driven by sex differences in the hormonal environment during adulthood (‘activational’ effects) and development (perinatal and/or pubertal ‘organizational’ effects), as well as genetic factors, especially the SRY gene on the Y chromosome in males, which is expressed in a sub-population of adult midbrain dopaminergic neurons. Stress and stress hormones, especially glucocorticoids, are important factors which interact with the VTA dopaminergic systems in order to achieve behavioral adaptation and enable the individual to cope with environmental change. Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and

  11. Nicotinic Acetylcholine Receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons

    PubMed Central

    Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J. Michael; Tapper, Andrew R.

    2013-01-01

    Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild-type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100 mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the α6 nAChR subunit (α6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre-application of the α6 subtype-selective nAChR antagonist, α-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices. Finally, pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse. PMID:23811312

  12. Sex Differences and Effects of Prenatal Exposure to Excess Testosterone on Ventral Tegmental Area Dopamine Neurons in Adult Sheep

    PubMed Central

    Brown, Erinna C. Z.; Steadman, Casey J.; Lee, Theresa M.; Padmanabhan, Vasantha; Lehman, Michael N.; Coolen, Lique M.

    2015-01-01

    Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesized to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep with higher numbers of tyrosine hydroxylase (TH)-immunoreactive cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30–90 or 60–90 resulted in increased numbers of VTA TH- immunoreactive cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T-treated ewes, which was primarily accounted for by greater numbers of TH-immunoreactive cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T-treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH as well as the protein levels with dopamine cells. Sex differences were also noted in numbers of TH-immunoreactive cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH-immunoreactive cells in the substantia nigra, suggesting that this sex difference is organized independently from prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T. PMID:25784297

  13. Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

    PubMed

    Cha, Jiook; Carlson, Joshua M; Dedora, Daniel J; Greenberg, Tsafrir; Proudfit, Greg H; Mujica-Parodi, Lilianne R

    2014-04-23

    The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety. PMID:24760845

  14. Glucocorticoid receptors in the prefrontal cortex regulate dopamine efflux to stress via descending glutamatergic feedback to the ventral tegmental area.

    PubMed

    Butts, Kelly A; Phillips, Anthony G

    2013-09-01

    Enhanced dopamine (DA) efflux in the medial prefrontal cortex (mPFC) is a well-documented response to acute stress. We have previously shown that glucocorticoid receptors in the mPFC regulate stress-evoked DA efflux but the underlying mechanism is unknown. DA neurons in the ventral tegmental area (VTA) receive excitatory input from and send reciprocal projections to the mPFC. We hypothesize that blockade of prefrontal glucocorticoid receptors can reduce activity of descending glutamatergic input to the VTA, thereby attenuating stress-evoked DA efflux in the mPFC. Using in vivo microdialysis, we demonstrate that acute tail-pinch stress leads to a significant increase in glutamate efflux in the VTA. Blockade of prefrontal glucocorticoid receptors with the selective antagonist CORT 108297 attenuates stress-evoked glutamate efflux in the VTA together with DA efflux in the mPFC. Furthermore, blockade of ionotrophic glutamate receptors in the VTA attenuates stress-evoked DA efflux in the mPFC. We also examine the possible role of glucocorticoid-induced synthesis and release of endocannabinoids acting presynaptically via cannabinoid CB1 receptors to inhibit GABA release onto prefrontal pyramidal cells, thus enhancing descending glutamatergic input to the VTA leading to an increase in mPFC DA efflux during stress. However, administration of the cannabinoid CB1 receptor antagonist into the mPFC does not attenuate stress-evoked DA efflux in the mPFC. Taken together, our data indicate that glucocorticoids act locally within the mPFC to modulate mesocortical DA efflux by potentiation of glutamatergic drive onto DA neurons in the VTA. PMID:23590841

  15. Long-range projection neurons of the mouse ventral tegmental area: a single-cell axon tracing analysis.

    PubMed

    Aransay, Ana; Rodríguez-López, Claudia; García-Amado, María; Clascá, Francisco; Prensa, Lucía

    2015-01-01

    Pathways arising from the ventral tegmental area (VTA) release dopamine and other neurotransmitters during the expectation and achievement of reward, and are regarded as central links of the brain networks that create drive, pleasure, and addiction. While the global pattern of VTA projections is well-known, the actual axonal wiring of individual VTA neurons had never been investigated. Here, we labeled and analyzed the axons of 30 VTA single neurons by means of single-cell transfection with the Sindbis-pal-eGFP vector in mice. These observations were complemented with those obtained by labeling the axons of small populations of VTA cells with iontophoretic microdeposits of biotinylated dextran amine. In the single-cell labeling experiments, each entire axonal tree was reconstructed from serial sections, the length of terminal axonal arbors was estimated by stereology, and the dopaminergic phenotype was tested by double-labeling for tyrosine hydroxylase immunofluorescence. We observed two main, markedly different VTA cell morphologies: neurons with a single main axon targeting only forebrain structures (FPN cells), and neurons with multibranched axons targeting both the forebrain and the brainstem (F + BSPN cells). Dopaminergic phenotype was observed in FPN cells. Moreover, four "subtypes" could be distinguished among the FPN cells based on their projection targets: (1) "Mesocorticolimbic" FPN projecting to both neocortex and basal forebrain; (2) "Mesocortical" FPN innervating the neocortex almost exclusively; (3) "Mesolimbic" FPN projecting to the basal forebrain, accumbens and caudateputamen; and (4) "Mesostriatal" FPN targeting only the caudateputamen. While the F + BSPN cells were scattered within VTA, the mesolimbic neurons were abundant in the paranigral nucleus. The observed diversity in wiring architectures is consistent with the notion that different VTA cell subpopulations modulate the activity of specific sets of prosencephalic and brainstem structures

  16. Anatomical and pharmacological characterization of catecholamine transients in the medial prefrontal cortex evoked by ventral tegmental area stimulation.

    PubMed

    Shnitko, Tatiana A; Robinson, Donita L

    2014-04-01

    Voltammetric measurements of catecholamines in the medial prefrontal cortex (mPFC) are infrequent because of lack of chemical selectivity between dopamine and norepinephrine and their overlapping anatomical inputs. Here, we examined the contribution of norepinephrine to the catecholamine release in the mPFC evoked by electrical stimulation of the ventral tegmental area (VTA). Initially, electrical stimulation was delivered in the midbrain at incremental depths of -5 to -9.4 mm from bregma while catecholamine release was monitored in the mPFC. Although catecholamine release was observed at dorsal stimulation sites that may correspond to the dorsal noradrenergic bundle (DNB, containing noradrenergic axonal projections to the mPFC), maximal release was evoked by stimulation of the VTA (the source of dopaminergic input to the mPFC). Next, VTA-evoked catecholamine release was monitored in the mPFC before and after knife incision of the DNB, and no significant changes in the evoked catecholamine signals were found. These data indicated that DNB fibers did not contribute to the VTA-evoked catecholamine release observed in the mPFC. Finally, while the D2-receptor antagonist raclopride significantly altered VTA-evoked catecholamine release, the α₂-adrenergic receptor antagonist idazoxan did not. Specifically, raclopride reduced catecholamine release in the mPFC, opposite to that observed in the striatum, indicating differential autoreceptor regulation of mesocortical and mesostriatal neurons. Together, these findings suggest that the catecholamine release in the mPFC arising from VTA stimulation was predominately dopaminergic rather than noradrenergic. PMID:24285555

  17. Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors.

    PubMed

    Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L; McElvain, Maureen A; Sakharkar, Amul J; You, Chang; Pandey, Subhash C; Brodie, Mark S

    2013-08-01

    Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons have an important role in alcohol addiction. Acute ethanol increases the activity of pDAergic neurons, and withdrawal from repeated ethanol administration produces a decreased sensitivity of pDAergic VTA neurons to GABA. Recent studies show that behavioral changes induced by chronic alcohol are reversed by inhibitors of histone deacetylases (HDACs). Whether HDAC-induced histone modifications regulate changes in GABA sensitivity of VTA pDAergic neurons during withdrawal is unknown. Here, we investigated modulation of withdrawal-induced changes in GABA sensitivity of pDAergic VTA neurons by HDAC inhibitors (HDACi), and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-Aα1 receptor (GABA (A-α1) R) subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally (ip) with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50-500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDAergic VTA neurons from saline-treated mice. In addition, ethanol withdrawal was associated with an increase in levels of HDAC2 and a decrease in histone (H3-K9) acetylation and levels of GABA (A-α1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDACi normalizes GABA hyposensitivity of pDAergic neurons developed during withdrawal after chronic ethanol treatment, which suggests the possibility that inhibition of HDACs can reverse ethanol-induced neuroadaptational changes in reward circuitry. PMID:23474591

  18. Phasic excitation of ventral tegmental dopamine neurons potentiates the initiation of conditioned approach behavior: parametric and reinforcement-schedule analyses

    PubMed Central

    Ilango, Anton; Kesner, Andrew J.; Broker, Carl J.; Wang, Dong V.; Ikemoto, Satoshi

    2014-01-01

    Midbrain dopamine neurons are implicated in motivation and learning. However, it is unclear how phasic excitation of dopamine neurons, which is implicated in learning, is involved in motivation. Here we used a self-stimulation procedure to examine how mice seek for optogenetically-induced phasic excitation of dopamine neurons, with an emphasis on the temporal dimension. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin-2 into the ventral tegmental area, resulting in selective expression of the opsin in dopamine neurons. These mice were trained to press on a lever for photo-pulse trains that phasically excited dopamine neurons. They learned to self-stimulate in a fast, constant manner, and rapidly reduced pressing during extinction. We first determined effective parameters of photo-pulse trains in self-stimulation. Lever-press rates changed as a function of the manipulation of pulse number, duration, intensity, and frequency. We then examined effects of interval and ratio schedules of reinforcement on photo-pulse train reinforcement, which was contrasted with food reinforcement. Reinforcement with food inhibited lever pressing for a few seconds, after which pressing was robustly regulated in a goal-directed manner. In contrast, phasic excitation of dopamine neurons robustly potentiated the initiation of lever pressing; however, this effect did not last more than 1 s and quickly diminished. Indeed, response rates markedly decreased when lever pressing was reinforced with inter-reinforcement interval schedules of 3 or 10 s or ratio schedules requiring multiple responses per reinforcement. Thus, phasic excitation of dopamine neurons briefly potentiates the initiation of approach behavior with apparent lack of long-term motivational regulation. PMID:24834037

  19. NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala.

    PubMed

    Kenny, Paul J; Chartoff, Elena; Roberto, Marisa; Carlezon, William A; Markou, Athina

    2009-01-01

    Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug. PMID:18418357

  20. Dopamine alters AMPA receptor synaptic expression and subunit composition in dopamine neurons of the ventral tegmental area cultured with prefrontal cortex neurons.

    PubMed

    Gao, Can; Wolf, Marina E

    2007-12-26

    Excitatory synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA) represent a critical site of psychostimulant-induced synaptic plasticity. This plasticity involves alterations in synaptic strength through AMPA receptor (AMPAR) redistribution. Here, we report an in vitro model for studying regulation of AMPAR trafficking in DA neurons under control conditions and after elevation of DA levels, mimicking cocaine exposure. We used cocultures containing rat VTA neurons and prefrontal cortex (PFC) neurons from enhanced cyan fluorescent protein-expressing mice. In VTA-PFC cocultures, D1 receptor activation (10 min) increased synaptic and nonsynaptic glutamate receptor subunit 1 (GluR1) and GluR2 surface expression on DA neurons. NMDA or AMPA receptor antagonists blocked this effect, and it was not observed in pure VTA cultures, suggesting that DA agonists acted on D1 receptors on PFC neurons, altering their excitatory transmission onto VTA DA neurons and, thus, influencing AMPARs. To mimic the longer elevation in extracellular DA levels produced by systemic cocaine, cocultures were incubated with DA for 1 h. Synaptic GluR1 was increased 24 h later, reminiscent of the increased AMPA/NMDA ratio at excitatory synapses onto VTA DA neurons 24 h after cocaine injection (Ungless et al., 2001). In contrast, GluR2 was unchanged. Analysis of colocalization of surface GluR1-3 labeling suggested that control DA neurons express a substantial number of GluR1/2, GluR2/3, and homomeric GluR1 receptors and that the increase in surface AMPARs 24 h after DA exposure may in part reflect increased GluR1/3-containing receptors. These results help define the cellular basis for plasticity underlying the development of behavioral sensitization. PMID:18160635

  1. Tribute to: Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area [William Corrigall, Kathleen Coen and Laurel Adamson, Brain Res. 653 (1994) 278-284].

    PubMed

    Leri, Francesco; Vaccarino, Franco J

    2016-08-15

    In this paper, Dr. Corrigall and collaborators described elegant experiments designed to elucidate the neurobiology of nicotine reinforcement. The nicotinic receptor antagonist dihydro-β-erythroidine (DHβE) was infused in the ventral tegmental area (VTA) or nucleus accumbens (NAC) of rats trained to self-administer nicotine intravenously. Additionally, DHβE was infused in the VTA of rats trained to self-administer food or cocaine, and nicotine self-administration was assessed in rats with lesions to the peduculopontine tegmental nucleus (PPT). A number of key themes emerged from this fundamental study that remain relevant today. The primary finding was that infusions of DHβE in the VTA, but not in the NAC, lowered nicotine self-administration, suggesting that nicotinic receptors in VTA are involved in the reinforcing action of nicotine. This conclusion has been confirmed by subsequent findings, and the nature of the nicotinic receptors has also been elucidated. The authors also reported that DHβE in the VTA had no effect on food or cocaine self-administration, and that lesions to the PPT did not alter nicotine self-administration. Since this initial investigation, the question of whether nicotinic receptors in the VTA are necessary for the reinforcing action of other stimuli, and by which mechanisms, has been extensively explored. Similarly, many groups have further investigated the role of mesopontine cholinergic nuclei in reinforcement. This paper not only contributed in important ways to our understanding of the neurochemical basis of nicotine reinforcement, but was also a key catalyst that gave rise to several research themes central to the neuropharmacology of substance abuse. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26867702

  2. Loss of the trpc4 gene is associated with a reduction in cocaine self-administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards.

    PubMed

    Klipec, William D; Burrow, Kristin R; O'Neill, Casey; Cao, Jun-Li; Lawyer, Chloe R; Ostertag, Eric; Fowler, Melissa; Bachtell, Ryan K; Illig, Kurt R; Cooper, Donald C

    2016-06-01

    Among the canonical transient receptor potential (TRPC) channels, the TRPC4 non-selective cation channel is one of the most abundantly expressed subtypes within mammalian corticolimbic brain regions, but its functional and behavioral role is unknown. To identify a function for TRPC4 channels we compared the performance of rats with a genetic knockout of the trpc4 gene (trpc4 KO) to wild-type (WT) controls on the acquisition of simple and complex learning for natural rewards, and on cocaine self-administration (SA). Despite the abundant distribution of TRPC4 channels through the corticolimbic brain regions, we found trpc4 KO rats exhibited normal learning in Y-maze and complex reversal shift paradigms. However, a deficit was observed in cocaine SA in the trpc4 KO group, which infused significantly less cocaine than WT controls despite displaying normal sucrose SA. Given the important role of ventral tegmental area (VTA) dopamine neurons in cocaine SA, we hypothesized that TRPC4 channels may regulate basal dopamine neuron excitability. Double-immunolabeling showed a selective expression of TRPC4 channels in a subpopulation of putative dopamine neurons in the VTA. Ex vivo recordings of spontaneous VTA dopamine neuronal activity from acute brain slices revealed fewer cells with high-frequency firing rates in trpc4 KO rats compared to WT controls. Since deletion of the trpc4 gene does not impair learning involving natural rewards, but reduces cocaine SA, these data demonstrate a potentially novel role for TRPC4 channels in dopamine systems and may offer a new pharmacological target for more effective treatment of a variety of dopamine disorders. PMID:26988269

  3. Cocaine sensitization inhibits the hyperpolarization-activated cation current Ih and reduces cell size in dopamine neurons of the ventral tegmental area.

    PubMed

    Arencibia-Albite, Francisco; Vázquez, Rafael; Velásquez-Martinez, María C; Jiménez-Rivera, Carlos A

    2012-04-01

    The progressive augmentation of motor activity that results from repeated cocaine administration is termed behavioral sensitization. This phenomenon is thought to be a critical component in compulsive drug taking and relapse. Still, the cellular mechanisms that underlie sensitization remain elusive. Cocaine abuse, nonetheless, is known to evoke neuroplastic adaptations in dopamine (DA) neurotransmission originating from the midbrain's ventral tegmental area (VTA). Here, we report that concomitant with the development of locomotor sensitization to cocaine the hyperpolarization-activated cation current (I(h)) amplitude is depressed by ∼40% in VTA DA cells. Such effect did not result from a negative shift in I(h) voltage dependence. Nonstationary fluctuation analysis indicates that this inhibition was caused by an ∼45% reduction in the number of h-channels with no change in their unitary properties. The cocaine-induced I(h) depression was accompanied by a reduction in cell capacitance of similar magnitude (∼33%), leaving h-current density unaltered. Two implications follow from these data. First, I(h) inhibition may contribute to cocaine addiction by increasing bursting probability in DA cells and this effect could be intensified by the decrease in cell capacitance. Second, the cocaine-induced diminution of DA cell capacitance may also lead to reward tolerance promoting drug-seeking behaviors. PMID:22262829

  4. Resting-State Functional Connectivity of the Locus Coeruleus in Humans: In Comparison with the Ventral Tegmental Area/Substantia Nigra Pars Compacta and the Effects of Age.

    PubMed

    Zhang, Sheng; Hu, Sien; Chao, Herta H; Li, Chiang-Shan R

    2016-08-01

    The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging. PMID:26223261

  5. Inhibitory effect of A10 dopaminergic neurons of the ventral tegmental area on the orienting response evoked by acoustic stimulation in the cat.

    PubMed

    Crescimanno, G; Sorbera, F; Emmi, A; Amato, G

    1998-01-01

    The effect of bilateral electric stimulation of A10 dopaminergic neurons of the ventral tegmental area (80-300 microA, 20-50 Hz, 0.1-0.5 ms, 2 s duration) on latency and duration of the orienting response, evoked by acoustic stimuli (4500-8000 Hz, 2 s), was studied in the cat. A10 neuron stimulation, simultaneous with the acoustic one, was performed with threshold parameters inducing minimal behavioral signs (head searching movement, sniffing, increase in alertness). By means of a videoanalysis system, a statistically significant increase, both of latency and duration of the response, was observed. The possible role of dopamine was studied administrating sulpiride (20 mg/kg i.p.), a dopaminergic antagonist prevalently acting on the mesolimbic-mesocortical system. In this condition, the disappearance of A10 neuron effect occurred. Sulpiride injection did not affect the parameters of the orienting response to acoustic stimulus alone, suggesting a direct effect on A10 dopaminergic neurons. Moreover, when saline administration was carried out, no significant modification of the effects, obtained following A10 neuron activation, was observed. The data suggest that A10 dopaminergic neurons, origin of the mesolimbic-mesocortical system, may be involved in the control of the response to sensory stimuli, likely by influencing sensorimotor integration processes. An involvement in the inhibitory regulation of the switching of attention is also discussed. PMID:9434203

  6. Differential distribution of hypoxia-inducible factor 1-beta (ARNT or ARNT2) in mouse substantia nigra and ventral tegmental area.

    PubMed

    Dela Cruz, J A D; Schmidt-Kastner, R; Stevens, J A A; Steinbusch, H W M; Rutten, B P F

    2014-11-01

    Hypoxia has been proposed as a mechanism underlying gene-environment interactions in the neurodevelopmental model of schizophrenia, and hypoxia-inducible factor 1 (HIF-1) could mediate the interactions. In the current study, we analyzed the HIF-1 beta subunit, as formed by aryl hydrocarbon receptor nuclear translocator (ARNT) or ARNT2, in the mouse substantia nigra (SN) and the ventral tegmental area (VTA). We performed immunohistochemical studies of ARNT and ARNT2 in the adult mouse brain, and colocalization analyses, with specific emphasis on dopaminergic cells, i.e. tyrosine hydroxylase (TH) immunoreactive cells. Bioinformatic analyses identified shared protein partners for ARNT and ARNT2. ARNT immunoreactivity showed widespread neuronal labeling without overt regional specificity. We observed co-localization of ARNT and TH in the SN compacta and VTA. Nuclei strongly labeled for ARNT2 were observed in the SN reticulata, while only weak immunoreactivity for ARNT2 was found in TH-immunoreactive neurons in SN compacta and VTA. Stereological analysis showed that ARNT was preferentially expressed in dopaminergic neurons in SN compacta and VTA. Nuclei strongly labeled for ARNT2 were present in neocortex and CA1 of hippocampus. Differential expression of ARNT and ARNT2 in dopaminergic neurons may relate to the vulnerability of distinct dopaminergic projections to hypoxia and to functional vulnerability in schizophrenia and other neuropsychiatric disorders. PMID:25017895

  7. A cytoarchitectonic and TH-immunohistochemistry characterization of the dopamine cell groups in the substantia nigra, ventral tegmental area and retrorubral field in the rock cavy (Kerodon rupestris).

    PubMed

    Cavalcanti, José R L P; Soares, Joacil G; Oliveira, Francisco G; Guzen, Fausto P; Pontes, André L B; Sousa, Twyla B; Cavalcante, Jeferson S; Nascimento, Expedito S; Cavalcante, Judney C; Costa, Miriam S M O

    2014-01-01

    The 3-hydroxytyramine/dopamine is a monoamine of the catecholamine group and it is a precursor of the noradrenaline and adrenaline synthesis, in which the enzyme tyrosine hydroxylase acts as a rate-limiting enzyme. The dopaminergic nuclei retrorubral field (A8 group), substantia nigra pars compacta (A9 group) and ventral tegmental area (A10 group) are involved in three complex circuitries named mesostriatal, mesocortical and mesolimbic, which are directly related to various behavioral manifestations such as motor control, reward signaling in behavioral learning, motivation and pathological manifestations of Parkinson's disease and schizophrenia. The aim of this study was to describe the delimitation of A8, A9 and A10 groups and the morphology of their neurons in the brain of the rock cavy (Kerodon rupestris), a typical Brazilian Northeast rodent belonging to the suborder Hystricomorpha, family Caviidae. Coronal and sagittal sections of the rock cavy brains were submitted to Nissl staining and TH immunohistochemistry. The organization of these dopaminergic nuclei in the rock cavy brain is very similar to that found in other animals of the Rodentia order, except for the presence of the tail of the substantia nigra, which is found only in the species under study. The results revealed that, apart some morphological variations, A8, A9 and A10 groups are phylogenetically stable brain structures. PMID:24444614

  8. Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential 'up' states in pyramidal neurons via D(1) dopamine receptors.

    PubMed

    Lewis, B L; O'Donnell, P

    2000-12-01

    The electrophysiological nature of dopamine actions has been controversial for years, with data supporting both inhibitory and excitatory actions. In this study, we tested whether stimulation of the ventral tegmental area (VTA), the source of the dopamine innervation of the prefrontal cortex, would exert different responses depending on the membrane potential states that pyramidal neurons exhibit when recorded in vivo, and whether VTA stimulation would have a role in controlling transitions between these states. Prefrontal cortical neurons have a very negative resting membrane potential (down state) interrupted by plateau depolarizations (up state). Although the up state had been shown to be dependent on hippocampal afferents in nucleus accumbens neurons, our results indicate that neither hippocampal nor thalamic inputs are sufficient to drive up events in prefrontal cortical neurons. Electrical VTA stimulation resulted in a variety of actions, in many cases depending on the neuron membrane potential state. Trains of stimuli resembling burst firing evoked a long-lasting transition to the up state, an effect blocked by a D(1) antagonist and mimicked by chemical VTA stimulation. These results indicate that projections from the VTA to the prefrontal cortex may be involved in controlling membrane potential states that define assemblies of activable pyramidal neurons in this region. PMID:11073866

  9. Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.

    PubMed

    Blacktop, Jordan M; Seubert, Chad; Baker, David A; Ferda, Nathan; Lee, Geng; Graf, Evan N; Mantsch, John R

    2011-08-01

    Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA. PMID:21813699

  10. Neural correlates for angular head velocity in the rat dorsal tegmental nucleus

    NASA Technical Reports Server (NTRS)

    Bassett, J. P.; Taube, J. S.; Oman, C. M. (Principal Investigator)

    2001-01-01

    Many neurons in the rat lateral mammillary nuclei (LMN) fire selectively in relation to the animal's head direction (HD) in the horizontal plane independent of the rat's location or behavior. One hypothesis of how this representation is generated and updated is via subcortical projections from the dorsal tegmental nucleus (DTN). Here we report the type of activity in DTN neurons. The majority of cells (75%) fired as a function of the rat's angular head velocity (AHV). Cells exhibited one of two types of firing patterns: (1) symmetric, in which the firing rate was positively correlated with AHV during head turns in both directions, and (2) asymmetric, in which the firing rate was positively correlated with head turns in one direction and correlated either negatively or not at all in the opposite direction. In addition to modulation by AHV, some of the AHV cells (40.1%) were weakly modulated by the rat's linear velocity, and a smaller number were modulated by HD (11%) or head pitch (15.9%). Autocorrelation analyses indicated that with the head stationary, AHV cells displayed irregular discharge patterns. Because afferents from the DTN are the major source of information projecting to the LMN, these results suggest that AHV information from the DTN plays a significant role in generating the HD signal in LMN. A model is proposed showing how DTN AHV cells can generate and update the LMN HD cell signal.

  11. Neural correlates for angular head velocity in the rat dorsal tegmental nucleus.

    PubMed

    Bassett, J P; Taube, J S

    2001-08-01

    Many neurons in the rat lateral mammillary nuclei (LMN) fire selectively in relation to the animal's head direction (HD) in the horizontal plane independent of the rat's location or behavior. One hypothesis of how this representation is generated and updated is via subcortical projections from the dorsal tegmental nucleus (DTN). Here we report the type of activity in DTN neurons. The majority of cells (75%) fired as a function of the rat's angular head velocity (AHV). Cells exhibited one of two types of firing patterns: (1) symmetric, in which the firing rate was positively correlated with AHV during head turns in both directions, and (2) asymmetric, in which the firing rate was positively correlated with head turns in one direction and correlated either negatively or not at all in the opposite direction. In addition to modulation by AHV, some of the AHV cells (40.1%) were weakly modulated by the rat's linear velocity, and a smaller number were modulated by HD (11%) or head pitch (15.9%). Autocorrelation analyses indicated that with the head stationary, AHV cells displayed irregular discharge patterns. Because afferents from the DTN are the major source of information projecting to the LMN, these results suggest that AHV information from the DTN plays a significant role in generating the HD signal in LMN. A model is proposed showing how DTN AHV cells can generate and update the LMN HD cell signal. PMID:11466446

  12. Vasopressin cells in the medial amygdala of the rat project to the lateral septum and ventral hippocampus.

    PubMed

    Caffé, A R; van Leeuwen, F W; Luiten, P G

    1987-07-01

    The rat brain contains a large number of vasopressin (VP) immunoreactive fibers, the sites of origin of which have not yet been established completely. For instance, the sources of VP fiber systems in the amygdala, ventral hippocampus (VH), mediodorsal thalamic nucleus, ventral tegmental area, and dorsal raphe yet remain obscure. These VP fibers may originate in any of the recently described extrahypothalamic VP cell groups, viz., medial amygdaloid nucleus (AME), dorsomedial hypothalamic nucleus, or locus coeruleus, since VP efferents from these cells still remain to be demonstrated. In search of AME VP efferents three approaches were followed: (1) the Phaseolus vulgaris anterograde tracing method, (2) immunocytochemistry after AME lesioning, and (3) retrograde transport of a fluorescent dye in combination with immunofluorescence. The results demonstrate that VP cells in the AME project to (1) the lateral septum (LS) by the ventral amygdalofugal pathway and (2) the VH via the amygdalohippocampal transition zone. In addition, the VP projection from the bed nucleus of the stria terminalis (BST) to the LS was confirmed. There was no indication that VP cells in the AME project through the amygdalotegmental pathway to the medulla oblongata and spinal cord. The results support the possibility that the BST and AME are an anatomical entity that may be part of the central loci controlling sexual processes in the rat. PMID:3305600

  13. Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels

    PubMed Central

    Steffensen, Scott C.; Taylor, Seth R.; Horton, Malia L.; Barber, Elise N.; Lyle, Laura T.; Stobbs, Sarah H.; Allison, David W.

    2010-01-01

    The aim of this study was to evaluate the effects of cocaine on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. PMID:19046384

  14. Transient inactivation of the ventral tegmental area selectively disrupts the expression of conditioned place preference for pup- but not cocaine-paired contexts

    PubMed Central

    Seip, Katharine M.; Morrell, Joan I.

    2010-01-01

    The ventral tegmental area (VTA) plays a critical role in motivated behavior. However, it remains unclear whether intact VTA function is necessary for motivated behavior to seek contexts repeatedly paired with natural stimuli and/or pharmacological stimuli. In the present study, conditioned place preference (CPP) was induced using highly salient natural or drug stimuli attributed with strong incentive-motivational value in each of two female models: postpartum females were conditioned to associate one unique context in the CPP apparatus with young offspring (pups) and a second context with a neutral stimulus, and virgin females were conditioned to associate unique contexts with cocaine (5mg/kg i.p.) and saline injections. Immediately prior to CPP testing, each female received a microinfusion of bupivacaine bilaterally into the VTA to transiently inactivate the region; subjects were also tested following saline microinfusion into the VTA. Postpartum females’ preference for the pup-paired context was abolished by VTA inactivation but was restored to high control levels following saline microinfusion. In separate tests, VTA inactivation also reduced motivated pup licking and pup retrieval in postpartum females, suggesting that intact VTA function is required for the expression of both pup CPP and motivated pup-directed behaviors. Cocaine CPP remained unaffected by VTA inactivation. Locomotion was not affected by VTA microinfusions but was severely impaired by bupivacaine microinfusions into the substantia nigra. We conclude that the VTA is differentially involved in the expression of conditioned preference for contexts paired with pups, a salient natural stimulus, and contexts paired with cocaine. PMID:20001116

  15. The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults

    PubMed Central

    Kline, Ryan L.; Zhang, Sheng; Farr, Olivia M.; Hu, Sien; Zaborszky, Laszlo; Samanez-Larkin, Gregory R.; Li, Chiang-Shan R.

    2016-01-01

    Background: Methylphenidate (MPH) influences catecholaminergic signaling. Extant work examined the effects of MPH on the neural circuits of attention and cognitive control, but few studies have investigated the effect of MPH on the brain's resting-state functional connectivity (rsFC). Methods: In this observational study, we compared rsFC of a group of 24 healthy adults who were administered an oral 45 mg dose of MPH with a group of 24 age and gender matched controls who did not receive MPH. We focused on three seed regions: basal nucleus of Meynert (BNM), locus coeruleus (LC), and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc), each providing cholinergic, noradrenergic and dopaminergic inputs to the cerebral cortex. Images were pre-processed and analyzed as in our recent work (Li et al., 2014; Zhang et al., 2015). We used one-sample t-test to characterize group-specific rsFC of each seed region and two-sample t-test to compare rsFC between groups. Results: MPH reversed negative connectivity between BNM and precentral gyri. MPH reduced positive connectivity between LC and cerebellum, and induced positive connectivity between LC and right hippocampus. MPH decreased positive VTA/SNc connectivity to the cerebellum and putamen, and reduced negative connectivity to left middle occipital gyrus. Conclusion: MPH had distinct effects on the rsFC of BNM, LC, and VTA/SNc in healthy adults. These new findings may further our understanding of the role of catecholaminergic signaling in Attention Deficit Hyperactivity Disorder (ADHD) and Parkinson's disease and provide insights into the therapeutic mechanisms of MPH in the treatment of clinical conditions that implicate catecholaminergic dysfunction. PMID:27148006

  16. Increased desensitization of dopamine D₂ receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors.

    PubMed

    Al-Hasani, R; Foster, J D; Metaxas, A; Ledent, C; Hourani, S M O; Kitchen, I; Chen, Y

    2011-09-01

    G-protein coupled receptors interact to provide additional regulatory mechanisms for neurotransmitter signaling. Adenosine A(2A) receptors are expressed at a high density in striatal neurons, where they closely interact with dopamine D₂ receptors and modulate effects of dopamine and responses to psychostimulants. A(2A) receptors are expressed at much lower densities in other forebrain neurons but play a more prominent yet opposing role to striatal receptors in response to psychostimulants in mice. It is, therefore, possible that A(2A) receptors expressed at low levels elsewhere in the brain may also regulate neurotransmitter systems and modulate neuronal functions. Dopamine D₂ receptors play an important role in autoinhibition of neuronal firing in dopamine neurons of the ventral tegmental area (VTA) and dopamine release in other brain areas. Here, we examined the effect of A(2A) receptor deletion on D₂ receptor-mediated inhibition of neuronal firing in dopamine neurons in the VTA. Spontaneous activity of dopamine neurons was recorded in midbrain slices, and concentration-dependent effects of the dopamine D₂ receptor agonist, quinpirole, was compared between wild-type and A(2A) knockout mice. The potency of quinpirole applied in single concentrations and the expression of D₂ receptors were not altered in the VTA of the knockout mice. However, quinpirole applied in stepwise escalating concentrations caused significantly reduced maximal inhibition in A(2A) knockout mice, indicating an enhanced agonist-induced desensitization of D₂ receptors in the absence of A(2A) receptors. The A(2A) receptor agonist, CGS21680, did not exert any effect on dopamine neuron firing or response to quinpirole, revealing a novel non-pharmacological interaction between adenosine A(2A) receptors and dopaminergic neurotransmission in midbrain dopamine neurons. Altered D₂ receptor desensitization may result in changes in dopamine neuron firing rate and pattern and dopamine

  17. GABAergic neurons in the ventral tegmental area receive dual GABA/enkephalin-mediated inhibitory inputs from the bed nucleus of the stria terminalis.

    PubMed

    Kudo, Takehiro; Konno, Kohtarou; Uchigashima, Motokazu; Yanagawa, Yuchio; Sora, Ichiro; Minami, Masabumi; Watanabe, Masahiko

    2014-06-01

    Activation of mu-opioid receptor (MOR) disinhibits dopaminergic neurons in the ventral tegmental area (VTA) through inhibition of γ-aminobutyric acid (GABA)ergic neurons. This mechanism is thought to play a pivotal role in mediating reward behaviors. Here, we characterised VTA-projecting enkephalinergic neurons in the anterior division of the bed nucleus of the stria terminalis (BST) and investigated their targets by examining MOR expression in the VTA. In the BST, neurons expressing preproenkephalin mRNA were exclusively GABAergic, and constituted 37.2% of the total GABAergic neurons. Using retrograde tracer injected into the VTA, 21.6% of VTA-projecting BST neurons were shown to express preproenkephalin mRNA. Enkephalinergic projections from the BST exclusively formed symmetrical synapses onto the dendrites of VTA neurons. In the VTA, 74.1% of MOR mRNA-expressing neurons were GABAergic, with the rest being glutamatergic neurons expressing type-2 vesicular glutamate transporter mRNA. However, MOR mRNA was below the detection threshold in dopaminergic neurons. By immunohistochemistry, MOR was highly expressed on the extrasynaptic membranes of dendrites in GABAergic VTA neurons, including dendrites innervated by BST-VTA projection terminals. MOR was also expressed weakly on GABAergic and glutamatergic terminals in the VTA. Given that GABAA α1 is expressed at GABAergic BST-VTA synapses on dendrites of GABAergic neurons [T. Kudo et al. (2012) J. Neurosci., 32, 18035-18046], our results collectively indicate that the BST sends dual inhibitory outputs targeting GABAergic VTA neurons; GABAergic inhibition via 'wired' transmission, and enkephalinergic inhibition via 'volume' transmission. This dual inhibitory system provides the neural substrate underlying the potent disinhibitory control over dopaminergic VTA neurons exerted by the BST. PMID:24580812

  18. Acute and chronic cocaine differentially alter the subcellular distribution of AMPA GluR1 subunits in region-specific neurons within the mouse ventral tegmental area

    PubMed Central

    Lane, D.A.; Jaferi, A.; Kreek, M.J.; Pickel, V.M.

    2010-01-01

    Cocaine administration increases AMPA GluR1 expression and receptor-mediated activation of the ventral tegmental area (VTA). Functionality is determined, however, by surface availability of these receptors in transmitter- and VTA-region-specific neurons, which may also be affected by cocaine. To test this hypothesis, we used electron microscopic immunolabeling of AMPA GluR1 subunits and tyrosine hydroxylase (TH; the enzyme needed for dopamine synthesis), in the cortical-associated parabrachial (PB) and in the limbic-associated paranigral (PN) VTA of adult male C57BL/6 mice receiving either a single injection (acute) or repeated escalating-doses for 14 days (chronic) of cocaine. Acute cocaine resulted in opposing VTA-region-specific changes in TH-containing dopaminergic dendrites. TH-labeled dendrites within the PB VTA showed increased cytoplasmic GluR1 immunogold particle density consistent with decreased AMPA receptor-mediated glutamatergic transmission. Conversely, TH-labeled dendrites within the PN VTA showed greater surface expression of GluR1 with increases in both synaptic and plasmalemmal GluR1 immunogold density after a single injection of cocaine. These changes diminished in both VTA subregions after chronic cocaine administration. In contrast, non-TH-containing (presumably GABAergic) dendrites showed VTA-region-specific changes only after repeated cocaine administration such that synaptic GluR1 decreased in the PB, but increased in the PN VTA. Taken together, these findings provide ultrastructural evidence suggesting that chronic cocaine not only reverses the respective depression and facilitation of mesocortical (PB) and mesolimbic (PN) dopaminergic neurons elicited by acute cocaine, but also differentially affects synaptic availability of these receptors in non-dopaminergic neurons of each region. These adaptations may contribute to increased cocaine seeking/relapse and decreased reward that is reported with chronic cocaine use. PMID:20553819

  19. Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin

    PubMed Central

    Zhang, Yong; Landthaler, Markus; Schlussman, Stefan D.; Yuferov, Vadim; Ho, Ann; Tuschl, Thomas; Kreek, Mary Jeanne

    2014-01-01

    Mu opioid receptors (MOP-r) play an important role in the rewarding and locomotor stimulatory effects of heroin. The aim of the current study was to determine whether infusion of small interfering RNAs (siRNA) targeting MOP-r into the midbrain could knock down MOP-r mRNA and affect heroin-induced locomotor activity or heroin-induced conditioned place preference. Ten week old male C57BL/6J mice were surgically implanted bilaterally with guide cannulae directed between the substantia nigra and ventral tegmental area. After 4 days recovery, mice were infused bilaterally with siRNAs that target the MOP-r (2mM × 0.75 μl/side/day for 3 days) or control siRNA. Seven days after the last infusion, a procedure for conditioned place preference was begun with four heroin (3mg/kg i.p.) administration sessions alternating with four saline sessions. While heroin induced an increase in locomotor activity in all groups, siRNAs targeting specific regions of MOP-r significantly attenuated this effect. Of particular interest, mice infused with specific siRNAs targeting the MOP-r failed to develop and express conditioned place preference to heroin, or showed a significantly attenuated preference. These alterations in reward related behaviors are likely due to the reduction in MOP-r mRNA and protein, shown in separate studies by in situ hybridization and autoradiography using the same MOP-r- siRNA infusions. Taken together, these studies demonstrate the utility of siRNA in the neurobiological study of specific components of the reward system and should contribute to the study of other complex behaviors. PMID:18938225

  20. Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

    PubMed Central

    Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

    2015-01-01

    Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between

  1. DECREASED EXPRESSION OF ErbB4 AND TYROSINE HYDROXYLASE mRNA AND PROTEIN IN THE VENTRAL MIDBRAIN OF AGED RATS

    PubMed Central

    DICKERSON, J. W.; HEMMERLE, A. M.; NUMAN, S.; LUNDGREN, K. H.; SEROOGY, K. B.

    2009-01-01

    Decreased availability or efficacy of neurotrophic factors may underlie an increased susceptibility of mesencephalic dopaminergic cells to age-related degeneration. Neuregulins (NRGs) are pleotrophic growth factors for many cell types including mesencephalic dopamine cells in culture and in vivo. The functional NRG receptor ErbB4 is expressed by virtually all midbrain dopamine neurons. To determine if levels of the NRG receptor are maintained during aging in the dopaminergic ventral mesencephalon, expression of ErbB4 mRNA and protein was examined in young (3 months), middle-aged (18 months), and old (24–25 months) Brown Norway/Fischer 344 F1 rats. ErbB4 mRNA levels in the substantia nigra pars compacta (SNpc), but not the adjacent ventral tegmental area (VTA) or subtantia nigra pars lateralis (SNl), were significantly reduced in the middle-aged and old animals when compared to young rats. Protein expression of ErbB4 in the ventral midbrain was significantly decreased in the old rats when compared to the young rats. Expression of tyrosine hydroxylase (TH) mRNA levels were significantly reduced in the old rats when compared to young animals in the SNpc, but not in the VTA or SNl. Tyrosine hydroxylase protein levels in the ventral midbrain were also decreased in the old animals when compared to the young animals. These data demonstrate a progressive decline of ErbB4 expression, coinciding with a loss of the dopamine-synthesizing enzyme TH, in the ventral midbrain of aged rats, particularly in the SNpc. These findings may implicate a role for diminished NRG/ErbB4 trophic support in dopamine-related neurodegenerative disorders of aging such as Parkinson’s disease. PMID:19505538

  2. A food restriction protocol that increases drug reward decreases tropomyosin receptor kinase B in the ventral tegmental area, with no effect on brain-derived neurotrophic factor or tropomyosin receptor kinase B protein levels in dopaminergic forebrain regions.

    PubMed

    Pan, Y; Chau, L; Liu, S; Avshalumov, M V; Rice, M E; Carr, K D

    2011-12-01

    Food restriction (FR) decreases brain-derived neurotrophic factor (BDNF) expression in hypothalamic and hindbrain regions that regulate feeding and metabolic efficiency, while increasing expression in hippocampal and neocortical regions. Drugs of abuse alter BDNF expression within the mesocorticolimbic dopamine (DA) pathway, and modifications of BDNF expression within this pathway alter drug-directed behavior. Although FR produces a variety of striatal neuroadaptations and potentiates the rewarding effects of abused drugs, the effects of FR on BDNF expression and function within the DA pathway are unknown. The primary purpose of the present study was to examine the effect of FR on protein levels of BDNF and its tropomyosin receptor kinase B (TrkB) receptor in component structures of the mesocorticolimbic pathway. Three to four weeks of FR, with stabilization of rats at 80% of initial body weight, did not alter BDNF or TrkB levels in nucleus accumbens, caudate-putamen, or medial prefrontal cortex. However, FR decreased TrkB levels in the ventral tegmental area (VTA), without change in levels of BDNF protein or mRNA. The finding that FR also decreased TrkB levels in substantia nigra, with elevation of BDNF protein, suggests that decreased TrkB in VTA could be a residual effect of increased BDNF during an earlier phase of FR. Voltage-clamp recordings in VTA DA neurons indicated decreased glutamate receptor transmission. These data might predict lower average firing rates in FR relative to ad libitum fed subjects, which would be consistent with previous evidence of decreased striatal DA transmission and upregulation of postsynaptic DA receptor signaling. However, FR subjects also displayed elevated VTA levels of phospho-ERK1/2, which is an established mediator of synaptic plasticity. Because VTA neurons are heterogeneous with regard to neurochemistry, function, and target projections, the relationship(s) between the three changes observed in VTA, and their involvement

  3. Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat.

    PubMed

    Monti, Jaime M; Torterolo, Pablo; Jantos, Héctor; Lagos, Patricia

    2016-09-01

    A study was performed on the effects of local microinjection of melanin-concentrating hormone (MCH) into the right sublaterodorsal tegmental nucleus (SLD) on sleep and wakefulness in rats prepared for chronic sleep recordings. MCH 200ng significantly decreased rapid-eye-movement sleep (REMS) time during the first and second 2-h of the recording period which was related to the reduction of the number of REMS periods and the increase of REMS latency. It is proposed that REMS inhibition was related to the direct deactivation of SLD glutamatergic neurons by the peptide. PMID:27461793

  4. Inhibitory control deficits in rats with ventral hippocampal lesions.

    PubMed

    Abela, Andrew R; Dougherty, Stephen D; Fagen, Erin D; Hill, Carolyn J R; Chudasama, Y

    2013-06-01

    Two experiments are reported in which rats with selective hippocampal lesions were tested on 2 prefrontal-dependent tasks. In Experiment 1, we compared the effects of lesions of the ventral hippocampus (vHC), dorsal hippocampus (dHC), and sham control surgery on the 5-choice reaction time task. Whereas rats with lesions of the dHC were indistinguishable from sham controls, those with vHC lesions showed increased premature responses and reduced accuracy throughout the experiment. The subsequent administration of systemic escitalopram (5 mg/kg), a selective serotonin reuptake inhibitor, reduced the number of premature responses in the vHC animals to control levels. In contrast, systemic injections of GBR 12909, a dopamine reuptake inhibitor, failed to ameliorate the impulsive deficit in the vHC group and, in addition, elevated perseverative responding in the vHC group only. In Experiment 2, we tested a separate group of rats with vHC lesions on a touchscreen visual discrimination and reversal learning task. Rats with vHC lesions acquired the visual discrimination as well as sham controls and showed normal inhibitory control of a previously reinforced response during reversal learning. These data support a role for the vHC in inhibitory control functions, especially in the inhibitory control of impulsive actions. PMID:22615141

  5. Anticipatory reward signals in ventral striatal neurons of behaving rats.

    PubMed

    Khamassi, Mehdi; Mulder, Antonius B; Tabuchi, Eiichi; Douchamps, Vincent; Wiener, Sidney I

    2008-11-01

    It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information. PMID:18973599

  6. Oxytocin injected into the ventral subiculum or the posteromedial cortical nucleus of the amygdala induces penile erection and increases extracellular dopamine levels in the nucleus accumbens of male rats.

    PubMed

    Melis, Maria Rosaria; Succu, Salvatora; Sanna, Fabrizio; Boi, Antonio; Argiolas, Antonio

    2009-10-01

    Oxytocin (20-100 ng) was found to be able to induce penile erection when injected unilaterally into the ventral subiculum or the posteromedial cortical nucleus of the amygdala of male rats. The pro-erectile effect started mostly 30 min after treatment and was abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (1-2 microg), an oxytocin receptor antagonist, into the ventral subiculum or posteromedial cortical nucleus. Oxytocin-induced penile erection occurred 15 min after the increase in the concentration of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the dialysate obtained from the nucleus accumbens, which was also abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin. The pro-erectile effect of oxytocin was also reduced by cis-flupentixol (2 and 5 microg), a dopamine receptor antagonist, injected into the nucleus accumbens, and by (+)MK-801 (5 microg), a noncompetitive N-methyl-d-aspartate receptor antagonist, injected into the ventral tegmental area, but not into the nucleus accumbens. Together with studies showing that glutamatergic efferents from the ventral subiculum/posteromedial cortical nucleus of the amygdala to other areas of the limbic system modulate the activity of mesolimbic dopaminergic neurons, these findings suggest that oxytocin injected into these areas increases glutamatergic neurotransmission in the ventral tegmental area. This, in turn, activates mesolimbic dopaminergic neurons, leading to penile erection. These results provide evidence that the ventral subiculum and the posteromedial cortical nucleus of the amygdala participate in a neural circuit that controls not only the consummatory aspects of sexual behaviour (e.g. penile erection and copulatory performance), but also its motivational/reward aspects, confirming a key role of oxytocin and dopamine in these processes. PMID:19769589

  7. Enhanced Endocannabinoid-Mediated Modulation of Rostromedial Tegmental Nucleus Drive onto Dopamine Neurons in Sardinian Alcohol-Preferring Rats

    PubMed Central

    Sagheddu, Claudia; De Felice, Marta; Casti, Alberto; Madeddu, Camilla; Spiga, Saturnino; Muntoni, Anna Lisa; Mackie, Kenneth; Marsicano, Giovanni; Colombo, Giancarlo; Castelli, Maria Paola; Pistis, Marco

    2014-01-01

    The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake. PMID:25232109

  8. Extent of colocalization of serotonin and GABA in neurons of the ventral medulla oblongata in rat.

    PubMed

    Millhorn, D E; Hökfelt, T; Seroogy, K; Verhofstad, A A

    1988-09-27

    The colocalization of serotonin (5-hydroxytryptamine; 5-HT) and gamma-aminobutyric acid (GABA) in the ventral aspect of the rat medulla oblongata was studied using antibodies directed against 5-HT and GABA. Although 5-HT- and GABA-immunoreactive cell bodies were observed over the entire rostral-caudal extent of the ventral medulla, the colocalization of these two classical neurotransmitters in single cells was, for the most part, limited to a region that corresponds anatomically to nucleus raphe magnus/nucleus paragigantocellularis. Schematic drawings showing the distribution of 5-HT/GABA cell bodies in the ventral medulla are provided. PMID:3066433

  9. Theta Phase Precession in Rat Ventral Striatum Links Place and Reward Information

    PubMed Central

    Redish, A. David

    2011-01-01

    A functional interaction between the hippocampal formation and the ventral striatum is thought to contribute to the learning and expression of associations between places and rewards. However, the mechanism of how such associations may be learned and used is currently unknown. We recorded neural ensembles and local field potentials from the ventral striatum and CA1 simultaneously as rats ran a modified T-maze. Theta-modulated cells in ventral striatum almost invariably showed firing phase precession relative to the hippocampal theta rhythm. Across the population of ventral striatal cells, phase precession was preferentially associated with an anticipatory ramping of activity up to the reward sites. In contrast, CA1 population activity and phase precession were distributed more uniformly. Ventral striatal phase precession was stronger to hippocampal than ventral striatal theta and was accompanied by increased theta coherence with hippocampus, suggesting that this effect is hippocampally derived. These results suggest that the firing phase of ventral striatal neurons contains motivationally relevant information and that phase precession serves to bind hippocampal place representations to ventral striatal representations of reward. PMID:21414906

  10. Increase in brain /sup 125/I-cholecystokinin (CCK) receptor binding following chronic haloperidol treatment, intracisternal 6-hydroxydopamine or ventral tegmental lesions

    SciTech Connect

    Chang, R.S.L.; Lotti, V.J.; Martin, G.E.; Chen, T.B.

    1983-02-21

    Specific /sup 125/I-CCK receptor binding was significantly increased in brain tissue taken from guinea pig or mouse following chronic (2-3 week) daily administration of haloperidol (2-3 mg/kg/day). Scatchard analysis indicated the increase in CCK binding was due to an increased receptor number (B max) with no change in affinity (Kd). In guinea pigs, the increased CCK binding was observed in the mesolimbic regions and frontal cortex, but not in striatum, hippocampus nor posterior cortex. In mice, however, the increases occurred in both pooled cerebral cortical-hippocampal tissue, and in the remainder of the brain. Enhanced CCK receptor binding was also observed in membranes prepared from whole brain of mice one month following intracisternal injection of 6-hydroxydopamine. Additionally, an increase in CCK binding was observed in mesolimbic regions and frontal cortex, but not striatum or hippocampus, of guinea pigs 3 weeks after an unilateral radiofrequency lesions of the ipsilateral ventral tegmentum. The present studies demonstrate that three different procedures which reduce dopaminergic function in the brain enhance CCK receptor binding. The data provide further support for a functional interrelationship between dopaminergic systems and CCK in some brain regions and raise the possibility that CCK may play a role in the antipsychotic action of neuroleptics.

  11. Modulation of locomotor activation by the rostromedial tegmental nucleus.

    PubMed

    Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S

    2015-02-01

    The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABAA) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABAA receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired. PMID:25164249

  12. GENE ARRAY ANALYSIS OF THE VENTRAL PROSTATE IN RATS EXPOSED TO EITHER VINCLOZOLIN OR PROCYMIDONE

    EPA Science Inventory

    GENE ARRAY ANALYSIS OF THE VENTRAL PROSTATE IN RATS EXPOSED TO EITHER VINCLOZOLIN OR PROCYMIDONE. MB Rosen, VS Wilson, JE Schmid, and LE Gray Jr. US EPA, ORD, NHEERL, RTP, NC.

    Vinclozolin (Vi) and procymidone (Pr) are antiandrogenic fungicides. While changes in gene expr...

  13. Ventral Lateral Geniculate Input to the Medial Pons Is Necessary for Visual Eyeblink Conditioning in Rats

    ERIC Educational Resources Information Center

    Halverson, Hunter E.; Freeman, John H.

    2010-01-01

    The conditioned stimulus (CS) pathway that is necessary for visual delay eyeblink conditioning was investigated in the current study. Rats were initially given eyeblink conditioning with stimulation of the ventral nucleus of the lateral geniculate (LGNv) as the CS followed by conditioning with light and tone CSs in separate training phases.…

  14. Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior.

    PubMed

    Kamii, Hironori; Kurosawa, Ryo; Taoka, Naofumi; Shinohara, Fumiya; Minami, Masabumi; Kaneda, Katsuyuki

    2015-05-01

    The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. PMID:25712572

  15. Supplemental morphine infusion into the posterior ventral tegmentum extends the satiating effects of self-administered intravenous heroin

    PubMed Central

    Steidl, S; Myal, S; Wise, RA

    2015-01-01

    Rats learn to self-administer intravenous heroin; well-trained animals lever-press at a slow and regular pace over a wide range of intravenous doses. The pauses between successive earned infusions are proportional to the dose of the previous injection and are thought to reflect periods of drug satiety. Rats will also self-administer opiates by microinjection directly into sites in the posterior regions of the ventral tegmentum. To determine if the pauses between self-administered intravenous injections are due to opiate actions in posterior ventral tegmentum, we delivered supplemental morphine directly into this region during intravenous self-administration sessions in well-trained rats. Reverse dialysis of morphine into the posterior ventral tegmentum increased the intervals between earned injections. The inter-response intervals were greatest for infusion into the most posterior ventral tegmental sites, sites in a region variously known as the tail of the ventral tegmental area or as the rostromedial tegmental nucleus. These sites at which morphine prolongs inter-response intervals, correspond to the sites at which opiates have been found most effective in reinforcing instrumental behavior. PMID:25913296

  16. Angular velocity and head direction signals recorded from the dorsal tegmental nucleus of gudden in the rat: implications for path integration in the head direction cell circuit.

    PubMed

    Sharp, P E; Tinkelman, A; Cho, J

    2001-06-01

    When a rat navigates through space, head direction (HD) cells provide an ongoing signal of the rat's directional heading. It is thought that these cells rely, in part, on angular path integration of the rat's head movements. This integration requires that the HD cell system receive information about angular head movements and that this information be combined with the current directional signal, to generate the next "predicted" direction. Recent data suggest that the dorsal tegmental nucleus (DTN) may play a critical role in helping to generate the HD cell signal. To test this, recordings were made from cells in the DTN in freely moving rats. The following cell types were found: (a) "classic" HD cells, (b) angular velocity cells, and (c) cells that fired as a function of both head direction and angular velocity. Thus, DTN cells exhibit firing characteristics that are critical to the neural circuit hypothesized for generation of the HD cell signal. PMID:11439447

  17. Cannabinoid transmission in the prefrontal cortex bi-phasically controls emotional memory formation via functional interactions with the ventral tegmental area.

    PubMed

    Draycott, Brittany; Loureiro, Michael; Ahmad, Tasha; Tan, Huibing; Zunder, Jordan; Laviolette, Steven R

    2014-09-24

    Disturbances in cortical cannabinoid CB1 receptor signaling are well established correlates of various neuropsychiatric disorders, including depression and schizophrenia. Importantly, the ability of cannabinoid transmission to modulate emotional processing is functionally linked to interactions with subcortical DA systems. While considerable evidence demonstrates that CB1 receptor-mediated modulation of emotional processing and related behaviors follows a biphasic functional curve, little is known regarding how CB1 signaling within cortical networks may interact with subcortical DAergic systems involved in emotional behavior regulation. Using a combination of in vivo electrophysiological recordings and behavioral pharmacology in rats, we investigated the relationship between mPFC cannabinoid transmission, fear memory formation, and subcortical DA neuron activity patterns. We report that direct intra-mPFC CB1 activation biphasically modulates spontaneous, subcortical VTA DA neuron activity in a dose-dependent fashion; while lower doses of a CB1 receptor agonist, WIN 55,212-2, significantly increased spontaneous firing and bursting rates of VTA DA neurons, higher doses strongly inhibited spontaneous DA neuron activity. Remarkably, this same dose-related functional difference was observed with the regulation of fear-related emotional memory formation. Thus, lower levels of CB1 activation potentiated the emotional salience of normally subthreshold fear memory, whereas higher levels completely blocked fear memory acquisition. Furthermore, while the potentiation of subthreshold fear memory salience was blocked by DA receptor antagonism, CB1-mediated blunting of suprathreshold fear memory was rescued by intra-VTA administration of a GABAB receptor antagonist, demonstrating that reversal of GABAergic inhibitory mechanisms in the VTA can reverse the inhibitory influence of intra-PFC CB1 transmission on mesolimbic DA activity. PMID:25253856

  18. Muscarinic control of rostromedial tegmental nucleus GABA neurons and morphine-induced locomotion.

    PubMed

    Wasserman, David I; Tan, Joel M J; Kim, Jun Chul; Yeomans, John S

    2016-07-01

    Opioids induce rewarding and locomotor effects by inhibiting rostromedial tegmental GABA neurons that express μ-opioid and nociceptin receptors. These GABA neurons then strongly inhibit dopamine neurons. Opioid-induced reward, locomotion and dopamine release also depend on pedunculopontine and laterodorsal tegmental cholinergic and glutamate neurons, many of which project to and activate ventral tegmental area dopamine neurons. Here we show that laterodorsal tegmental and pedunculopontine cholinergic neurons project to both rostromedial tegmental nucleus and ventral tegmental area, and that M4 muscarinic receptors are co-localized with μ-opioid receptors associated with rostromedial tegmental GABA neurons. To inhibit or excite rostromedial tegmental GABA neurons, we utilized adeno-associated viral vectors and DREADDs to express designed muscarinic receptors (M4D or M3D respectively) in GAD2::Cre mice. In M4D-expressing mice, clozapine-N-oxide increased morphine-induced, but not vehicle-induced, locomotion. In M3D-expressing mice, clozapine-N-oxide blocked morphine-induced, but not vehicle-induced, locomotion. We propose that cholinergic inhibition of rostromedial tegmental GABA neurons via M4 muscarinic receptors facilitates opioid inhibition of the same neurons. This model explains how mesopontine cholinergic systems and muscarinic receptors in the rostromedial tegmental nucleus and ventral tegmental area are important for dopamine-dependent and dopamine-independent opioid-induced rewards and locomotion. PMID:26990801

  19. α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

    PubMed Central

    Engle, Staci E.; Shih, Pei-Yu; McIntosh, J. Michael

    2013-01-01

    Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine’s action in humans. However, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing α6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9′S mice). In voltage-clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via α6β2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through α6β2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, α6β2* activation did not enhance N-methyl-d-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from α6L9′S mice lacking α4 nAChR subunits, suggesting that α4α6β2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of α4α6β2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. α4α6β2* nAChRs may be a promising target for future smoking cessation pharmacotherapy. PMID:23788655

  20. Dorsal and ventral respiratory groups of neurons in the medulla of the rat.

    PubMed

    Saether, K; Hilaire, G; Monteau, R

    1987-09-01

    The aim of the present work was to identify and localize in rat the medullary neurons involved in respiration. Neural activity was recorded in ketamine-anesthetized, paralyzed and artificially ventilated rats. Active sites were marked by electrocoagulation. Neurons firing in relation to phrenic nerve activity were located between 0.5 and 2 mm lateral to the midline, extending from 0.5 mm caudal to 2 mm rostral to the posterior end of the area postrema. Two groups of respiratory neurons were found: a dorsal group located ventrolateral to the tractus solitarius and a ventral group located in the ventrolateral reticular formation close to the nucleus ambiguus. Neurons were classified as bulbospinal or laryngeal if stimulation of the spinal cord or the vagus nerve, respectively, elicited antidromic action potentials, or as propriobulbar if they were not activated. Neurons firing synchronously with lung inflation were termed pump (P) cells. The dorsal respiratory group includes inspiratory (I) bulbospinal and propriobulbar neurons, P cells, but few expiratory (E) propriobulbar neurons. The ventral respiratory group includes bulbospinal, laryngeal and propriobulbar I and E neurons. Laryngeal motoneurons project ipsilaterally whereas bulbospinal neurons project contralaterally. Cross-correlations between inspiratory bulbospinal neuronal activity and phrenic discharge suggest that bulbospinal I neurons of dorsal and ventral groups project monosynaptically to contralateral phrenic motoneurons. These results indicate a similarity of the medullary respiratory centers of rats and cats, suggesting that rats may profitably be used in studies of respiratory rhythmogenesis. PMID:3676744

  1. Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate

    PubMed Central

    Sarobo, Carolina; Lacorte, Lívia M; Martins, Marcela; Rinaldi, Jaqueline C; Moroz, Andrei; Scarano, Wellerson R; Delella, Flavia K; Felisbino, Sérgio L

    2012-01-01

    Coffee intake has been associated with a low risk of developing cancer, including prostate cancer, which is one of the most commonly diagnosed cancer in men. However, few studies have evaluated the chronic effects of caffeine, which is the most abundant methylxanthine in coffee, on prostate morphology and physiology. In the present study, we investigated the effects of chronic, low-dose caffeine intake on rat prostate morphology from puberty to adulthood. Five-week-old male Wistar rats were randomized into two experimental groups: caffeine-treated (20 ppm in drinking water, n = 12) and control (n = 12). The ventral and dorsolateral prostates were dissected, weighted and submitted to morphological, morphometrical and immunohistochemical analysis of cellular proliferation, apoptosis and androgen receptor (AR) tissue expression. The testosterone (T) and dihydrotestosterone (DHT) concentrations were measured in the plasma. Our results show that caffeine intake increased the concentrations of T and DHT, organ weight, epithelial cell proliferation and AR tissue expression in the ventral prostatic lobe. All the ventral prostates from the caffeine-treated animals presented various degrees of epithelial and stromal hyperplasia. Our results suggest that chronic caffeine intake from puberty increases androgenic signalling and cell proliferation in the rat prostate gland and can be related to the development of benign prostatic hyperplasia. PMID:23136995

  2. Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats.

    PubMed

    Pentkowski, Nathan S; Blanchard, D Caroline; Lever, Colin; Litvin, Yoav; Blanchard, Robert J

    2006-04-01

    This study investigated the role of the hippocampus in both unconditioned and conditioned defensive behaviors by examining the effects of pretraining ibotenic acid lesions to the dorsal and ventral hippocampus in male Long-Evans hooded rats exposed to three types of threat stimuli: cat-odor, a live cat and footshock. Defensive behaviors were assessed during exposure to cat-odor and a live cat, and immediately following the presentation of footshock. Conditioned defensive behaviors were also assessed in each context 24 h after initial threat exposure. During both unconditioned and conditioned trials, dorsal hippocampal lesions failed to significantly alter any behavioral measure in each test of defense. In contrast, ventral hippocampal lesions significantly reduced unconditioned defensive behaviors during exposure to cat-odor without producing any observable effects during cat exposure. Furthermore, ventral lesions significantly attenuated conditioned defensive behaviors following the administration of footshock and during re-exposure to each context. These results suggest a specific role for the ventral, not dorsal, hippocampus in modulating anxiety-like behaviors in certain animal models of defense. PMID:16630065

  3. Diabetes induces stromal remodelling and increase in chondroitin sulphate proteoglycans of the rat ventral prostate

    PubMed Central

    Ribeiro, Daniele Lisboa; Taboga, Sebastião Roberto; Góes, Rejane Maira

    2009-01-01

    Extracellular matrix (ECM) remodelling is an important process involved in prostate cancer progression. Alterations in ECM caused by diabetes in different tissues such as kidney is well described; however, it is poorly investigated in prostate. The aim of this study was to evaluate changes in ECM of rat prostate showing gland atrophy caused by diabetes and their implications in development of malignant lesions. Diabetes was induced in Wistar rats using alloxan (45 mg/kg bw). After 90 days of diabetes onset, animals were killed and ventral prostate was removed and prepared for light microscopy following immunoreaction for fibronectin, chondroitin sulphate and Picrossirius staining for collagen fibres. Proteoglycans (PG) were identified at transmission electron microscopy after fixation with Cuprolinic Blue. Diabetes led to a thickening of 25% in the acinar basement membrane accompanied by increase and disorganization of its proteoglycans (P1). Three additional populations of prostatic stromal PGs were identified: collagen fibril linked (P2) and interstitial (P3) and (P4) PGs. Diabetes increased P3 and mainly P4 which had higher dimension and accumulated around the smooth muscle cells. In addition, an increase in chondrotin sulphate (33%, mainly in sites where P4 were noted) and collagen (44%) was noted in diabetic rats, whereas fibronectin did not change. Atrophic changes observed in rat ventral prostate after diabetes are accompanied by stromal remodelation related to increase in collagen and chondroitin sulphate proteoglycans. Thus, diabetes can promote a stromal microenvironment rich in elements that could favour cell migration, proliferation and pathological process. PMID:19659898

  4. Malignant lesions in the ventral prostate of alloxan-induced diabetic rats

    PubMed Central

    Ribeiro, Daniele Lisboa; Marques, Silvio Fernando Guideti; Alberti, Sandra; Spadella, César Tadeu; Manzato, Antônio José; Taboga, Sebastião Roberto; Dizeyi, Nishtman; Abrahamsson, Per-Anders; Góes, Rejane Maira

    2008-01-01

    The aim of this study was to evaluate the changes caused by chronic diabetes in the rat ventral prostate and to establish a correlation between diabetes and the development of prostatic lesions. Male rats received alloxan (42 mg/kg b.w.) to induce diabetes. Ninety days after diabetes diagnosis, animals were sacrificed and the ventral prostate was removed and prepared for general and immunohistochemical analyses. The total area showing different types of lesions was estimated. Diabetes led to a decrease in the body and prostatic weights, as well as in testosterone levels. The prostate morphology and stereology showed high variation in the diabetic group. Some animals had light changes; the great majority had an intense epithelial atrophy; and other rats showed premalignant and malignant lesions in the prostate. Such epithelial atrophy was, in some samples, combined with chronic inflammation, similar to proliferative inflammatory atrophy (PIA). The diabetic group also presented high incidence of prostatitis, adenocarcinoma and prostatic intra-epithelial neoplasia (PIN). Samples with adenocarcinoma had poorly differentiated acini with high levels of cellular proliferation and nuclear atypia. These lesions exhibited an invasive feature showing Bcl-2-positive cells and interruptions in the basement membrane. An association of PIA, PIN and adenocarcinoma was detected in one sample. Reduced androgen levels have a synergic effect to insulin dysfunction promoting negative effects in the rat prostate. Diabetic individuals had a high incidence of prostatitis, and this inflammation could stimulate the incidence of other forms of prostatic pathology. PMID:18715471

  5. Apparent quiescence of the metallothionein gene in the rat ventral prostate: association with cadmium-induced prostate tumors in rats.

    PubMed

    Coogan, T P; Shiraishi, N; Waalkes, M P

    1994-09-01

    Several chronic studies in rats indicating that cadmium exposure can induce tumors of the ventral prostate have recently been completed in our laboratory. In one such study, a single dose of cadmium, s.c., increased prostatic tumor incidence only at doses below 5.0 mumol/kg, the approximate threshold for cadmium-induced testicular damage. In a further study, prostatic tumors were elevated with higher doses of cadmium (30 mumol/kg, s.c.) if testicular damage was prevented by zinc pretreatment. Most recently, we found that dietary cadmium (25 to 200 micrograms/g) also can increase prostatic neoplastic lesions, but these were reduced by zinc-deficient diets. Thus it appears that cadmium produces prostatic tumors only if testicular function is maintained. Furthermore, we find that metallothionein (MT), a protein associated with cadmium tolerance, may be deficient in the rat prostate, and the prostatic MT gene, at least in the ventral lobe, is unresponsive to metal stimuli. In liver, MT gene expression, as assessed by MT-1 mRNA, was quite apparent in control tissue and was induced in a dose-dependent manner 24 hr following cadmium exposure (1 to 10 mumol/kg, s.c.). However, in the ventral prostate very low constitutive levels of MT-1 mRNA were detected and increases did not occur with cadmium exposure. Cadmium concentrations in the ventral prostate were in excess of those that cause significant induction in the liver. In sharp contrast to the gene in the ventral prostate, in the dorsal prostate the MT gene was quite active. The dorsal prostate is not susceptible to cadmium carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7843088

  6. The effect of CIS hydroxyproline on ventral prostatic growth in rats.

    PubMed

    Uke, E; Lee, C; Grayhack, J T

    1983-01-01

    Changes in prostatic collagen were measured in Sprague-Dawley rats to gain further insight into the relationship between this stromal component and androgen mediated prostatic growth. Regulation of prostatic collagen by other endocrine factors was also studied. Collagen content per prostate was estimated by determination of tissue levels of hydroxyproline. The 1st experiment examined changes in the content of hydroxyproline in the prostate during pre- and post-pubertal growth with the use of rats between 21 and 80 days of age. As the animals grew, their prostatic weights and hydroxyproline contents increased in a parallel fashion (correlation coefficient R = 0.977, p less than 0.01). In the 2nd experiment, rats were castrated for a period up to 28 days. The hydroxyproline content in the prostate did not change significantly by castration despite a marked decrease in prostatic weights. Results of the 3rd experiment indicated that castration-hypophysectomy or castration-hypophysectomy plus estrogen treatment did not significantly change the content of prostatic hydroxyproline from that in the untreated intact animals. The 4th experiment studied the effect of the collagen synthesis inhibitor, cis-4-hydroxyproline, on prostatic growth. Subcutaneous injection of cis-4-hydroxyproline to castrated testosterone treated rats caused a significantly slower increase in total ventral prostatic weights and contents of protein, DNA and hydroxyproline than those of saline treated controls. This inhibition in prostatic growth is unlikely to be related to any antiandrogenic effect of cis hydroxyproline as the protein/DNA ratio in the prostate was the same for both saline and cis-4-hydroxyproline treated groups. Electron microscopic studies revealed that cis-4-hydroxyproline treatment resulted in a derangement of the basement membrane in the ventral prostate. The above results suggest that collagen plays an important role in limiting prostatic growth since inhibition of collagen

  7. Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

    PubMed Central

    Bai, Qunhua; He, Junlin; Tang, Yong; Wang, Shibo; Qiu, Jingfu; Wang, Yang; Yu, Chao

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the hallmark feature of loss of dopaminergic neurons in the substantia nigra. Energy metabolic disorder is associated with the pathogenesis of PD; however, the development of this disorder is yet to be elucidated. PD-like characteristics have been demonstrated in a rotenone rat model. In the present study, energy metabolism status was investigated in a rat model following intraperitoneal treatment with 1.0 mg/kg rotenone every 48 h. The behavior and tyrosine hydroxylase-positive levels in the substantia nigra of rats that were treated with rotenone for 24 weeks demonstrated that these rats developed more severe parkinsonism, as compared with that were treated for 16 weeks. Detection of ATP, lactic acid, NADH dehydrogenase 1 mRNA and lactate dehydrogenase B mRNA levels in the ventral mesocerebrum (VM) and skeletal muscle (SM) of the rats that had been treated with rotenone for 16 and 24 weeks demonstrated that the energy stress induced by rotenone progressed in both VM and SM. Notably, the energy stress detected in VM was more severe, and this energy stress was decompensated in the VM of rats that had been treated with rotenone for 24 weeks. The progression of energy stress and the incidence of energy decompensation in VM may be important for the improvement of PD pathology. PMID:27446321

  8. Generation of rhythmic patterns of activity by ventral interneurones in rat organotypic spinal slice culture

    PubMed Central

    Ballerini, Laura; Galante, Micaela; Grandolfo, Micaela; Nistri, Andrea

    1999-01-01

    In the presence of certain excitatory substances the rat isolated spinal cord generates rhythmic oscillations believed to be an in-built locomotor programme (fictive locomotion). However, it is unknown whether a long-term culture of the same tissue can express rhythmic activity. Such a simplified model system would provide useful data on the minimal circuitry involved and the cellular mechanisms mediating this phenomenon. For this purpose we performed patch clamp recording (under whole-cell voltage or current clamp conditions) from visually identified ventral horn interneurones of an organotypic slice culture of the rat spinal cord. Ventral horn interneurones expressed rhythmic bursting when the extracellular [K+] was raised from 4 to 6-7 mM. Under voltage clamp this activity consisted of composite synaptic currents grouped into bursts lasting 0.9 ± 0.5 s (2.8 ± 1.5 s period) and was generated at network level as it was blocked by tetrodotoxin or low-Ca2+-high-Mg2+ solution and its periodicity was unchanged at different potential levels. In current clamp mode bursting was usually observed as episodes comprising early depolarizing potentials followed by hyperpolarizing events with tight temporal patterning. Bursting was fully suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and reduced in amplitude and duration by N-methyl-D-aspartate (NMDA) receptor antagonism without change in periodicity. Extracellular field recording showed bursting activity over a wide area of the ventral horn. Regular, rhythmic activity similar to that induced by K+ also appeared spontaneously in Mg2+-free solution. The much slower rhythmic pattern induced by strychnine and bicuculline was also accelerated by high-K+ solution. The fast and regular rhythmic activity of interneurones in the spinal organotypic culture is a novel observation which suggests that the oversimplified circuit present in this culture is a useful model for investigating spinal rhythmic activity. PMID:10332095

  9. Primary structure and androgen regulation of a 20-kilodalton protein specific to rat ventral prostate.

    PubMed

    Ho, K C; Snoek, R; Quarmby, V; Viskochil, D H; Rennie, P S; Wilson, E M; French, F S; Bruchovsky, N

    1989-07-25

    Nuclear and cytosolic forms of a 20-kdalton rat ventral prostate protein were purified and partially sequenced from their N-termini. Isolated nuclei were treated with micrococcal nuclease and extracted in 0.6 M NaCl, and proteins were separated by affinity chromatography on Matrex gel green A, ammonium sulfate fractionation, and fast protein liquid chromatography on Superose 12. The 43 amino acid N-terminal sequence of the nuclear 20-kdalton protein was identical with the cytosolic protein except it lacked 7 N-terminal amino acids present in the cytosolic form. The DNA sequence of a full-length complementary DNA clone isolated from a ventral prostate gt11 library extended the N-terminal sequence of the cytosolic form by an additional nine amino acids from the predicted initiation methionine. The cDNA included the nucleotide sequence for the 43 amino acid N-terminal sequence of the purified 20-kdalton protein and predicted molecular weights of 16,686, 17,521, and 18,650, respectively, for the nuclear, cytoplasmic, and nonprocessed proteins. Northern blot analyses of reproductive tract tissue RNAs using the 20-kdalton protein cDNA as probe revealed a single mRNA species of 0.92 kb detectable only in extracts of rat ventral prostate. Expression of the 0.92-kb mRNA was androgen dependent since the mRNA was undetectable in extracts obtained 4 days after castration and was restored 16 h after restimulation with androgen. PMID:2477055

  10. Terazosin Treatment Induces Caspase-3 Expression in the Rat Ventral Prostate

    PubMed Central

    Papadopoulos, Georgios; Vlachodimitropoulos, Dimitrios; Kyroudi, Aspasia; Kouloukoussa, Mirsini; Perrea, Despina; Mitropoulos, Dionisios

    2013-01-01

    Background Quinazoline-based alpha1-adrenergic receptor antagonists may not act solely on smooth muscle contractility. We evaluated the in vivo effect of terazosin on the expression of caspase-3 in the rat ventral prostate. Methods Fifteen Wistar rats were treated with terazosin (1.2 mg/kg body weight, given orally every second day) for 120 days. Another 15 control animals received the same amount of distilled water. The expression of caspase-3 was assessed immunohistochemically in formalin-fixed, paraffin-embedded tissue sections. Results Terazosin treatment did not affect prostate weight and histomorphology. In controls caspase-3 was expressed weakly and sporadically. In contrast, strong and weak expression was evident in 67% and 33% of the terazosin-treated specimens, respectively. Conclusions These findings implicate the induction of caspase-3 expression by terazosin as a potential molecular mechanism of its apoptotic action on prostate cells. PMID:23518907

  11. Increased latencies to initiate cocaine self-administration following laterodorsal tegmental nucleus lesions

    PubMed Central

    Steidl, Stephan; Cardiff, Katherine M.; Wise, Roy A.

    2015-01-01

    Cholinergic input to the ventral tegmental area (VTA), origin of the mesocorticolimbic dopamine system that is critical for cocaine reward, is important for both cocaine seeking and cocaine taking. The laterodorsal tegmental nucleus (LDTg) provides one of the two major sources of excitatory cholinergic input to the VTA, but little is known of the role of the LDTg in cocaine reward. LDTg cholinergic cells express urotensin-II receptors and here we used local microinjections of a conjugate of the endogenous ligand for these receptors with diphtheria toxin (Dtx::UII) to lesion the cholinergic cells of the LDTg in rats previously trained to self-administer cocaine (1 mg/kg/infusion, i.v.). Lesioned rats showed long latencies to initiate cocaine self-administration after treatment with the toxin, which resulted in a reduction in cocaine intake per session. Priming injections reduced latencies to initiate responding for cocaine in lesioned rats, and once they began to respond the rats regulated their moment-to-moment cocaine intake within normal limits. Thus we conclude that while LDTg cholinergic cell loss does not significantly alter the rewarding effects of cocaine, LDTg lesions can reduce the rat’s responsiveness to cocaine-predictive stimuli. PMID:25746513

  12. THE ROLE OF VENTRAL MIDLINE THALAMUS IN CHOLINERGIC-BASED RECOVERY IN THE AMNESTIC RAT

    PubMed Central

    Bobal, Michael G.; Savage, Lisa M.

    2014-01-01

    The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist. PMID:25446352

  13. The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat.

    PubMed

    Bobal, M G; Savage, L M

    2015-01-29

    The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist. PMID:25446352

  14. The ventral surface of the medulla in the rat: pharmacologic and autoradiographic localization of GABA-induced cardiovascular effects.

    PubMed

    Keeler, J R; Shults, C W; Chase, T N; Helke, C J

    1984-04-16

    Experiments were done to evaluate a rat model for studying the cardiovascular effects of pharmacological manipulations of the ventral surface of the medulla. GABAergic drugs were used because of their well-characterized actions at the ventral surface of the medulla in the cat. GABA and muscimol, applied to the exposed ventral surface with filter paper pledgets, produced dose-dependent decreases in heart rate (HR) and mean arterial pressure (MAP) which were reversed with bicuculline but not with strychnine. Bicuculline alone raised HR and MAP. The GABA- or bicuculline-induced cardiovascular effects were mediated primarily by inhibition of sympathetic outflow. The most sensitive site was localized to an intermediate area on the ventral surface of the medulla, between the trapezoid body and exits of the hypoglossal nerves and just lateral to the pyramids. Topical application of [3H]GABA to the intermediate area resulted in labeling that was concentrated at the site of application, and which penetrated the parenchyma 1 mm dorsally. The heaviest labeling was found primarily in the ventral halves of the lateral paragigantocellular nuclei. No tritium was detected in peripheral blood. These data provide evidence for a neuronal system at the ventral medullary surface of the rat which influences sympathetic outflow and is modulated by GABA. PMID:6326937

  15. Dynamic secondary degeneration in the spinal cord and ventral root after a focal cerebral infarction among hypertensive rats

    PubMed Central

    Dang, Ge; Chen, Xinran; Chen, Yicong; Zhao, Yuhui; Ouyang, Fubing; Zeng, Jinsheng

    2016-01-01

    Cerebral infarction can cause secondary damage to nonischemic brain regions. However, whether this phenomenon will appear in central nervous system regions outside the brain remains unclear. Here we investigated pathological changes in the spinal cord and ventral root after ischemic stroke. All rats exhibited apparent neurological deficits post-MCAO, which improved gradually but could still be detected 12-weeks. Neuronal filaments in the corticospinal tract (CST) and neurons in the ventral horn were significantly declined in the contralateral cervical and lumbar enlargement 1-week post-MCAO. These decreases remained stable until 12-weeks, accompanied by progressively increased glial activation in the ventral horn. Axonal degeneration and structural derangement were evident in the contralateral cervical and lumbar ventral root 1-week post-MCAO; these changes spontaneously attenuated over time, but abnormalities could still be observed 12-weeks. The number of neural fibers in the contralateral CST and neurons in the contralateral ventral horn were positively correlated with neurological scores 12-weeks post-MCAO. Additionally, GFAP+cell density in the contralateral CST and ventral horn was negatively correlated with neurological scores. Our results suggest that cerebral infarction can elicit secondary degeneration in the cervical and lumbar spinal cord, as well as the projecting ventral root, which may hamper functional recovery after stroke. PMID:26949108

  16. Influence of chronic amphetamine treatment and acute withdrawal on serotonin synthesis and clearance mechanisms in the rat ventral hippocampus.

    PubMed

    Barr, Jeffrey L; Scholl, Jamie L; Solanki, Rajeshwari R; Watt, Michael J; Lowry, Christopher A; Renner, Kenneth J; Forster, Gina L

    2013-02-01

    Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis (in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal. PMID:23157166

  17. Influence of spaceflight on succinate dehydrogenase activity and soma size of rat ventral horn neurons

    NASA Technical Reports Server (NTRS)

    Ishihara, A.; Ohira, Y.; Roy, R. R.; Nagaoka, S.; Sekiguchi, C.; Hinds, W. E.; Edgerton, V. R.

    1996-01-01

    Succinate dehydrogenase (SDH) activities and soma cross-sectional areas (CSA) of neurons in the dorsolateral region of the ventral horn at the L5 segmental level of the spinal cord in the rat were determined after 14 days of spaceflight and after 9 days of recovery on earth. The results were compared to those in age-matched ground-based control rats. Spinal cords were quick-frozen, and the SDH activity and CSA of a sample of neurons with a visible nucleus were determined using a digitizer and a computer-assisted image analysis system. An inverse relationship between CSA and SDH activity of neurons was observed in all groups of rats. No change in mean CSA or mean SDH activity or in the size distribution of neurons was observed following spaceflight or recovery. However, there was a selective decrease in the SDH activity of neurons with soma CSA between 500 and 800 microns2 in the flight rats, and this effect persisted for at least 9 days following return to 1 g. It remains to be determined whether the selected population of motoneurons or the specific motor pools affected by spaceflight may be restricted to specific muscles.

  18. Early development of rat ventral root transitional zone: an immunohistochemical and morphometric study.

    PubMed

    O'Brien, D; Dockery, P; McDermott, K; Fraher, J

    2001-01-01

    Bundles of ventral motoneuron axons cross the white matter of the spinal cord, emerge through the cord surface at the CNS-PNS transitional zone (TZ) and continue in the PNS as ventral rootlets. This study identifies immunohistochemical and morphometric changes which characterise the key events in early TZ formation in the rat. E18 is a landmark stage, since it is then that the major events of TZ differentiation are initiated. In the glial processes associated with the TZ, vimentin expression decreases, while that of GFAP increases. In the proximal rootlets the transient expression of CNS markers such as GFAP and of neural adhesion molecules such as HNK-1/N-CAM begin to decrease. Their resulting differential expression clearly defines the CNS-PNS interface. These changes coincide with the arrival of glial nuclei at the TZ. Cell clusters which appear on proximal ventral rootlet surfaces shortly after their emergence from the cord, have by E18 formed an extensive matrix of processes which segregates the axon bundle. This comprises the earliest of two well-defined barriers across the axon bundle. An important function may be to prevent Schwann cell invasion of the cord. Cluster cells display some immunohistochemical features in common with Schwann cells. The second barrier becomes fully established only at P2 and forms the definitive CNS-PNS interface. It consists of processes arising from astrocytes surrounding the TZ. Changes in the nuclear density of the cell types correspond closely to their segregating activity. The immunohistochemical and ultrastructural changes complement one another to deepen and enhance understanding of TZ development. PMID:11577242

  19. Differential effects of GDF5 on the medial and lateral rat ventral mesencephalon.

    PubMed

    Clayton, Kevin B; Sullivan, Aideen M

    2007-11-12

    Growth/differentiation factor 5 (GDF5) is a member of the transforming growth factor-beta (TGF-beta) superfamily that has potent neurotrophic and protective effects on dopaminergic neurones and is expressed in the developing rat substantia nigra (the ventral mesencephalon; VM). GDF5 has the potential to be used in the treatment of Parkinson's disease (PD), a neurodegenerative disorder characterised by the selective degeneration of nigrostriatal dopaminergic neurones. One therapy being explored for PD involves transplantation of fetal VM tissue into the striatum in order to replace lost dopaminergic neurones. The majority of transplantation studies have used transplants incorporating the whole VM. The principal location of dopaminergic neurones in the E14 rat VM is in the medial VM. In the present study, the effects of GDF5 on cultures prepared from medial, lateral and whole E14 rat VM tissue were compared. GDF5 treatment increased the number of dopaminergic neurones in whole and lateral, but not in medial, VM cultures, whereas it increased total cell number in medial, but not in whole or lateral, VM cultures. RT-PCR studies showed that the receptors for GDF5 were differentially expressed in E14 VM; the expression of BMPR-IB and Ror2 was low in medial but high in lateral VM tissue. This study suggests that GDF5 increases the number of dopaminergic neurones in whole VM cultures by acting on BMPR-IB and Ror2-expressing cells in the lateral VM. PMID:17935884

  20. Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin

    PubMed Central

    Dickenson, Anthony H.

    2016-01-01

    Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a “WDR phenotype.” After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. PMID:27098028

  1. Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate

    SciTech Connect

    Labrie, C.; Simard, J.; Zhao, H.F.; Belanger, A.; Pelletier, G.; Labrie, F. )

    1989-06-01

    Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels.

  2. Nerve growth factor signaling following unilateral pelvic ganglionectomy in the rat ventral prostate is age dependent.

    PubMed

    Podlasek, Carol A; Ghosh, Rudrani; Onur Cakir, Omer; Bond, Christopher; McKenna, Kevin E; McVary, Kevin T

    2013-11-01

    Benign prostatic hyperplasia (BPH) is a serious health concern and is an underlying cause of lower urinary tract symptoms (LUTS) in many men. In affected men, LUTS/BPH is believed to result from benign proliferation of the prostate resulting in bladder outlet obstruction. Postnatal growth of the prostate is controlled via growth factor and endocrine mechanisms. However, little attention had been given to the function of the autonomic nervous system in prostate growth and differentiation. Nerve growth factor (NGF) is a prostatic mitogen that has a trophic role in autonomic sensory end organ interaction. In this study, we examine how the autonomic nervous system influences prostate growth as a function of age by quantifying NGF in the rat ventral prostate (VP) after pelvic ganglionectomy. Unilateral pelvic ganglionectomy was performed on postnatal days 30 (P30), 60 and 120 Sprague-Dawley rats in comparison to sham controls (n=39). Semiquantitative RT-PCR, Western blotting and immunohistochemical analysis for NGF were performed on denervated, intact (contralateral side) and sham control VP 7 days after surgery. Ngf RNA expression was significantly increased in the denervated and intact hyperplastic VP. Western blotting showed age-dependent increases in NGF protein at P60 in the contralateral intact VP. NGF was localized in the nerves, basal cells and columnar epithelium of the prostatic ducts. Denervation causes age-dependent increases in NGF in the VP, which is a potential mechanism by which the autonomic nervous system may regulate prostate growth and lead to BPH/LUTS. PMID:23872662

  3. Muscarinic and alpha(1)-adrenergic mechanisms contribute to the spinal mediation of stimulation-induced antinociception from the pedunculopontine tegmental nucleus in the rat.

    PubMed

    Dias, Quintino M; Crespilho, Simone F; Silveira, João Walter S; Prado, Wiliam A

    2009-05-01

    The effects of intraperitoneal (i.p.) or intrathecal (i.t.) injection of antagonists of acetylcholine, noradrenaline, serotonin, dopamine, opioids and GABA on stimulation-produced antinociception (SPA) from the pedunculopontine tegmental nucleus (PPTg) of rats were studied using the tail-flick test. The electrical stimulation of the PPTg produced a strong and long-lasting increase in tail-flick latency. The intensity and duration of the effect were significantly reduced in rats pretreated with i.p. or i.t. atropine (a non-selective muscarinic cholinergic antagonist), or i.t. phenoxybenzamine or WB 4101 (non-selective and selective alpha(1)-adrenergic antagonists, respectively). Intraperitoneal phenoxybenzamine, i.p. or i.t. methysergide or naloxone (non-selective serotonin and opioid antagonists, respectively), or i.t. idazoxan (a selective alpha(2)-adrenergic antagonist) only reduced the duration of the effect. The duration of SPA from the PPTg was increased by i.t. phaclofen (a GABA(B) antagonist). The effect from the nucleus was not altered following i.t. bicuculline (a GABA(A) antagonist), or i.p. or i.t. mecamylamine, propranolol or haloperidol (non-selective nicotinic cholinergic, beta-adrenergic and dopaminergic antagonists, respectively). Thus, SPA from the PPTg involves the spinal activation of muscarinic and alpha(1)-adrenergic but not nicotinic cholinergic, beta-adrenergic and dopaminergic mechanisms. Serotonergic, endogenous opioid and alpha(2)-adrenergic mechanisms are involved in the duration but not in the intensity of the effect. PMID:19463264

  4. Both dorsal and ventral spinal cord pathways contribute to overground locomotion in the adult rat.

    PubMed

    Loy, David N; Talbott, Jason F; Onifer, Stephen M; Mills, Michael D; Burke, Darlene A; Dennison, Jessica B; Fajardo, Lili C; Magnuson, David S K; Whittemore, Scott R

    2002-10-01

    Identification of long tracts responsible for spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. We recently demonstrated that extensive demyelination of adult rat thoracic ventral columns, ventromedial, and ventrolateral white matter produces persistent, significant open-field hindlimb locomotor deficits. Locomotor movements resulting from stimulation of the pontomedullary locomotor region are inhibited by dorsolateral funiculus (DLF) lesions suggesting that important pathways for locomotion may also exist in the dorsal white matter. However, dorsal hemisections that interrupt dorsal columns/dorsal corticospinal tract (DC/CST) and DLF pathways do not produce persistent, severe locomotor deficits in the adult rat. We studied the contributions of myelinated tracts in the DLF and DC/CST to overground locomotion following complete conduction blockade of axons in the ventrolateral funiculus (VLF), a region important for locomotor movements and for transcranial magnetic motor-evoked potentials (tcMMEP). Animals received ethidium bromide plus photon irradiation to produce discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, combined VLF + DLF, or combined VLF + DC/CST. Open-field BBB scores and tcMMEPs were studied at 1, 2, 3, and 4 weeks postlesion. VLF lesions resulted in mean BBB scores of 17 at 4 weeks. VLF + DC/CST and VLF + DLF lesions resulted in mean BBB scores of 15.9 and 11.1, respectively. TcMMEPs were absent in all lesion types confirming VLF conduction blockade throughout the study. Our data indicate that significant contributions to locomotion from myelinated pathways within the rat DLF can be revealed when combined with simultaneous compromise of the VLF. PMID:12429203

  5. Electron microscopic localization of M2-muscarinic receptors in cholinergic and noncholinergic neurons of the laterodorsal tegmental and pedunculopontine nuclei of the rat mesopontine tegmentum.

    PubMed

    Garzón, Miguel; Pickel, Virginia M

    2016-10-15

    Muscarinic m2 receptors (M2Rs) are implicated in autoregulatory control of cholinergic output neurons located within the pedunculopontine (PPT) and laterodorsal tegmental (LTD) nuclei of the mesopontine tegmentum (MPT). However, these nuclei contain many noncholinergic neurons in which activation of M2R heteroceptors may contribute significantly to the decisive role of the LTD and PPT in sleep-wakefulness. We examined the electron microscopic dual immunolabeling of M2Rs and the vesicular acetylcholine transporter (VAchT) in the MPT of rat brain to identify the potential sites for M2R activation. M2R immunogold labeling was predominately seen in somatodendritic profiles throughout the PPT/LTD complex. In somata, M2R immunogold particles were often associated with Golgi lamellae and cytoplasmic endomembrannes, but were rarely in contact with the plasma membrane, as was commonly seen in dendrites. Approximately 36% of the M2R-labeled somata and 16% of the more numerous M2R-labeled dendrites coexpressed VAchT. M2R and M2R/VAchT-labeled dendritic profiles received synapses from inhibitory- and excitatory-type axon terminals, over 88% of which were unlabeled and others contained exclusively M2R or VAchT immunoreactivity. In axonal profiles M2R immunogold was localized to plasmalemmal and cytoplasmic regions and showed a similar distribution in many VAchT-negative glial profiles. These results provide ultrastructural evidence suggestive of somatic endomembrane trafficking of M2Rs, whose activation serves to regulate the postsynaptic excitatory and inhibitory responses in dendrites of cholinergic and noncholinergic neurons in the MPT. They also suggest the possibility that M2Rs in this brain region mediate the effects of acetylcholine on the release of other neurotransmitters and on glial signaling. J. Comp. Neurol. 524:3084-3103, 2016. © 2016 Wiley Periodicals, Inc. PMID:27038330

  6. Neuronal-enriched cultures from embryonic rat ventral mesencephalon for pharmacological studies of dopamine neurons.

    PubMed

    Pardo, B; Paíno, C L; Casarejos, M J; Mena, M A

    1997-05-01

    The method described herein provides a convenient and rapid procedure to obtain enriched neuronal cultures containing reproducible numbers of dopamine (DA) cells. These cultures allow experimental paradigms designed to study the effect of drugs on DA neurons without astroglial mediation. Neuronal-enriched cultures are prepared from the mesencephalon of rat embryos at the 14th day of gestation (E14). At that moment, DA cells of the developing substantia nigra are located ventrally at the level of the mesencephalic flexure. Because the neurons of the pars compacta are mostly born between E12 and E15, E14 corresponds to an optimal stage for obtaining a high survival of DA cells. A defined medium (EF12) allows the maturation of DA neurons and reduces drastically the number of astrocytes. After 7 days in vitro (DIV) in EF12, the cultures contain 2-5% astrocytes (GFAP+ cells) and DA neurons represent 0.5-2% of the cells, as assessed by immunostaining to tyrosine hydroxylase (TH). The function of DA neurons is assessed by [3H]DA uptake and of those non-DA neurons by the high affinity [3H]GABA uptake. Cell survival is assessed by Trypan blue dye exclusion. PMID:9385075

  7. Galanin inhibits acetylcholine release in the ventral hippocampus of the rat: histochemical, autoradiographic, in vivo, and in vitro studies

    SciTech Connect

    Fisone, G.; Wu, C.F.; Consolo, S.; Nordstroem, O.; Brynne, N.; Bartfai, T.; Melander, T.; Hoekfelt, T.

    1987-10-01

    A high density of galanin binding sites was found by using /sup 125/I-labeled galanin, iodinated by chloramine-T, followed by autoradiography in the ventral, but not in the dorsal, hippocampus of the rat. Lesions of the fimbria and of the septum caused disappearance of a major population of these binding sites, suggesting that a large proportion of them is localized on cholinergic nerve terminals of septal afferents. As a functional correlate to these putative galanin receptor sites, it was shown, both in vivo and in vitro, that galanin, in a concentration-dependent manner, inhibited the evoked release of acetylcholine in the ventral, but not in the dorsal, hippocampus. Intracerebroventricularly applied galanin fully inhibited the scopolamine stimulated release of acetylcholine in the ventral, but not in the dorsal, hippocampus, as measured by the microdialysis technique. In vitro, galanin inhibited the 25 mM K/sup +/-evoked release of (/sup 3/H)acetylcholine from slices of the ventral hippocampus, with an IC/sub 50/ value of approx. = 50 nM. These results are discussed with respect to the colocalization of galanin- and choline acetyltransferase-like immunoreactivity in septal somata projecting to the hippocampus.

  8. Dorsal-ventral differences in the glia limitans of the spinal cord: an ultrastructural study in developing normal and irradiated rats

    SciTech Connect

    Sims, T.J.; Gilmore, S.A.; Waxman, S.G.; Klinge, E.

    1985-07-01

    The dorsal and ventral surfaces of the lumbosacral spinal cord were examined in normal and irradiated postnatal rats. In normal rats between three and 13 days postnatal (DP), the glia limitans (GL) of the ventral surface was a more complex structure than the dorsal GL. This greater degree of complexity was manifested in a greater number of subpial astrocytes, a greater number of radial glial processes and a more advanced state in differentiation of its constituents. In rats irradiated at three DP and examined at 13 DP, the ventral GL remained intact and relatively unaffected by the radiation. In contrast, the dorsal GL was disrupted, and Schwann cells were seen within the dorsal funiculus. The ventral GL of the rat lumbosacral spinal cord is a more substantial structure than the dorsal GL during normal development. This factor alone may account for the integrity of the barrier properties of the ventral GL following radiation. However, these observations suggest that subpial astrocytes of the dorsal GL are more susceptible to radiation damage at three DP than the subpial astrocytes and radial glia of the ventral GL.

  9. Basal and thirst-evoked vasopressin secretion in rats with electrolytic lesion of the medio-ventral septal area.

    PubMed

    Iovino, M; Poenaru, S; Annunziato, L

    1983-01-01

    Electrolytic lesion of the medio-ventral septal (MVS) area produces, 3 days after the surgery, a remarkable increase of daily diuresis and water intake in the rat. This polyuria and polydipsia is associated with decreased levels of circulating radioimmunoassayable vasopressin. In addition, if these lesioned animals were water-deprived (48 h), the usual vasopressin release observed in sham-lesioned and normal controls was markedly blunted. These results suggest that the MVS area exerts a modulatory control on vasopressin secretion both in basal and thirst-evoked conditions. PMID:24010174

  10. Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats

    PubMed Central

    Pentkowski, Nathan S.; Litvin, Yoav; Blanchard, D. Caroline; Vasconcellos, Amy; King, Lanikea B.; Blanchard, Robert J.

    2009-01-01

    This study investigated a possible role for ventral hippocampal corticotropin-releasing factor (CRF) in modulating both unconditioned and conditioned defensive behaviors by examining the effects of pre-training ventral hippocampal ovine-CRF (oCRF) or acidic-astressin ([Glu11,16]Ast) microinfusions in male Long Evans hooded rats exposed to various threat stimuli including the elevated plus-maze (EPM) (oCRF), cat odor (oCRF and [Glu11,16]Ast) and a live cat ([Glu11,16]Ast). Unconditioned defensive behaviors were assessed during threat exposure, while conditioned defensive behaviors were assessed in each predator context 24 h after the initial threat encounter. Pre-training infusions of the CRF1 and CRF2 receptor agonist oCRF significantly increased defensive behaviors during both the unconditioned and conditioned components of the cat odor test, as well as exposure to the EPM. In contrast to the behavioral effects of oCRF microinfusions, the CRF1 and CRF2 receptor antagonist [Glu11,16]Ast significantly decreased defensive behaviors during exposure to cat odor, while producing no discernible effects following a second injection in the cat exposure test. During conditioned test trials, pre-training infusions of [Glu11,16]Ast also significantly reduced defensive behaviors during re-exposure to both predator contexts. These results suggest a specific role for ventral hippocampal CRF receptors in modulating anxiety-like behaviors in several ethologically relevant animal models of defense. PMID:19269291

  11. Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats.

    PubMed

    Pentkowski, Nathan S; Litvin, Yoav; Blanchard, D Caroline; Vasconcellos, Amy; King, Lanikea B; Blanchard, Robert J

    2009-06-01

    This study investigated a possible role for ventral hippocampal corticotropin-releasing factor (CRF) in modulating both unconditioned and conditioned defensive behaviors by examining the effects of pre-training ventral hippocampal ovine-CRF (oCRF) or acidic-astressin ([Glu(11,16)]Ast) microinfusions in male Long-Evans hooded rats exposed to various threat stimuli including the elevated plus-maze (EPM) (oCRF), cat odor (oCRF and [Glu(11,16)]Ast) and a live cat ([Glu(11,16)]Ast). Unconditioned defensive behaviors were assessed during threat exposure, while conditioned defensive behaviors were assessed in each predator context 24 h after the initial threat encounter. Pre-training infusions of the CRF(1) and CRF(2) receptor agonist oCRF significantly increased defensive behaviors during both the unconditioned and conditioned components of the cat odor test, as well as exposure to the EPM. In contrast to the behavioral effects of oCRF microinfusions, the CRF(1) and CRF(2) receptor antagonist [Glu(11,16)]Ast significantly decreased defensive behaviors during exposure to cat odor, while producing no discernible effects following a second injection in the cat exposure test. During conditioned test trials, pre-training infusions of [Glu(11,16)]Ast also significantly reduced defensive behaviors during re-exposure to both predator contexts. These results suggest a specific role for ventral hippocampal CRF receptors in modulating anxiety-like behaviors in several ethologically relevant animal models of defense. PMID:19269291

  12. A novel turning behavior control method for rat-robot through the stimulation of ventral posteromedial thalamic nucleus.

    PubMed

    Xu, Kedi; Zhang, Jiacheng; Zhou, Hong; Lee, Ji Chao Tristan; Zheng, Xiaoxiang

    2016-02-01

    The concept of a rat-robot was initially introduced in 2002, bringing to the field, a novel area of research using modern research into neuroscience and robotics. This paper brings to the table, a study into the method best used for navigation systems in a rat-robot. Current research is epitomized by the use of reward-based spatial navigation, combining the concept of an induced reward sensation as well as a 'virtual touch' sensation to control the movement of the rat-robot. However, such methods are plagued by limitations affecting the success rate as well as preparation procedures which may have varying effects on different rats, even under similar conditions. Hence, this paper studies the stimulation of two different portions of the brain to induce a turning motion within the rat, namely the Ventral Posteromedial (VPM) thalamic nucleus as well as the Barrel-Field (BF) cortex and demonstrates the preferential usage of VPM as the choice use of navigational control in a rat-robot. PMID:26546880

  13. Amphetamine-induced c-fos mRNA expression is altered in rats with neonatal ventral hippocampal damage.

    PubMed

    Lillrank, S M; Lipska, B K; Bachus, S E; Wood, G K; Weinberger, D R

    1996-08-01

    To further characterize the mechanisms underlying enhanced dopamine-related behaviors expressed during adulthood in rats with neonatal excitotoxic ventral hippocampal (VH) damage, we studied the expression of c-fos mRNA in these rats after a single saline or amphetamine (AMPH) (10 mg/kg, i.p.) injection using in situ hybridization. The VH of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). At the age of 90 days, rats were challenged with AMPH or saline, and the expression of c-fos mRNA using an oligonucleotide probe was assessed 30, 90, and 180 min later. AMPH significantly increased c-fos mRNA expression in medial prefrontal cortex, piriform cortex, cingulate cortex, septal region, and dorsolateral and ventromedial striatum in control and lesioned rats. However, this response to AMPH was attenuated 30 min after AMPH injection in all of these regions in the lesioned as compared to the sham-operated rats. No significant changes were seen at other time points. These results indicate that the neonatal VH lesion alters time-dependent intracellular signal transduction mechanisms measured by AMPH-induced c-fos mRNA expression in cortical and subcortical brain regions. Changes in c-fos mRNA expression in this putative animal model of schizophrenia may have implications for long-term alterations in cellular phenotype because of altered regulation of certain target genes. PMID:8855514

  14. Dietary zinc deficiency effects dorso-lateral and ventral prostate of Wistar rats: histological, biochemical and trace element study.

    PubMed

    Joshi, Sangeeta; Nair, Neena; Bedwal, R S

    2014-10-01

    Zinc deficiency has become a global problem affecting the developed and developing countries due to inhibitors in the diet which prevents its absorption or due to a very low concentration of bioavailable zinc in the diet. Being present in high concentration in the prostate and having diverse biological function, we investigated the effects of dietary zinc deficiency for 2 and 4 weeks on dorso-lateral and ventral prostate. Sixty prepubertal rats were divided into three groups: zinc control (ZC), pair fed (PF) and zinc deficient (ZD) and fed on 100 μg/g (zinc control and pair fed groups) and 1 μg/g (zinc deficient) diet. Zinc deficiency was associated with degenerative changes in dorso-lateral and ventral prostate as made evident by karyolysis, karyorhexis, cytoplasmolysis, loss of cellularisation, decreased intraluminar secretion and degeneration of fibromuscular stroma. In response, protein carbonyl, nitric oxide, acid phosphatase, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase increased, exhibiting variable level of significance. Total protein and total zinc concentration in dorso-lateral and ventral prostate as well as in serum decreased (P < 0.001). Decrease (P < 0.001) was recorded in serum FSH and testosterone after 2 and 4 weeks of zinc deficiency. The changes were more prominent after 4 weeks of synthetic zinc deficient diet. The results indicate that zinc deficiency during prepubertal period affects the prostate structure, total protein concentration, enhanced protein carbonyl concentration, nitric oxide as well as acid phosphatase activities and impaired hydroxysteroid dehydrogenase activities. Evidently these changes could be attributed to dysfunction of dorso-lateral and ventral prostate after dietary zinc deficiency as well as impairment of metabolic and secretory activity, reduced gonadotropin levels by hypothalamus -hypophysial system which is indicative of a critical role of zinc in maintaining the prostate integrity. PMID

  15. Intranigral grafts of fetal ventral mesencephalic tissue in adult 6-hydroxydopamine-lesioned rats can induce behavioral recovery.

    PubMed

    Johnston, R E; Becker, J B

    1997-01-01

    Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease. PMID:9171159

  16. Chronic cerebrolysin administration attenuates neuronal abnormalities in the basolateral amygdala induced by neonatal ventral hippocampus lesion in the rat.

    PubMed

    Vázquez-Roque, Rubén Antonio; Ubhi, Kiren; Masliah, Eliezer; Flores, Gonzalo

    2014-01-01

    The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders. PMID:24123373

  17. Effect of Silodosin, an Alpha1A-Adrenoceptor Antagonist, on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat

    PubMed Central

    Shimizu, Shogo; Shimizu, Takahiro; Tsounapi, Panagiota; Higashi, Youichirou; Martin, Darryl T.; Nakamura, Kumiko; Honda, Masashi; Inoue, Keiji; Saito, Motoaki

    2015-01-01

    Background A decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow. Methods Twelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining. Results There was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR. Conclusions Silodosin can inhibit the

  18. The A9 dopamine neuron component in grafts of ventral mesencephalon is an important determinant for recovery of motor function in a rat model of Parkinson's disease.

    PubMed

    Grealish, Shane; Jönsson, Marie E; Li, Meng; Kirik, Deniz; Björklund, Anders; Thompson, Lachlan H

    2010-02-01

    Grafts of foetal ventral mesencephalon, used in cell replacement therapy for Parkinson's disease, are known to contain a mix of dopamine neuronal subtypes including the A9 neurons of the substantia nigra and the A10 neurons of the ventral tegmental area. However, the relative importance of these subtypes for functional repair of the brain affected by Parkinson's disease has not been studied thoroughly. Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared. The results show that the A9 component of intrastriatal grafts is of critical importance for recovery in tests on motor performance, in a rodent model of Parkinson's disease. Analysis at the histological level indicates that this is likely to be due to the unique ability of A9 neurons to innervate and functionally activate their target structure, the dorsolateral region of the host striatum. The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies. Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells. PMID:20123725

  19. Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet.

    PubMed

    Francis, Heather M; Mirzaei, Mehdi; Pardey, Margery C; Haynes, Paul A; Cornish, Jennifer L

    2013-10-01

    The typical Western diet, rich in high saturated fat and refined sugar (HFS), has been shown to increase cognitive decline with aging and Alzheimer's disease, and to affect cognitive functions that are dependent on the hippocampus, including memory processes and reversal learning. To investigate neurophysiological changes underlying these impairments, we employed a proteomic approach to identify differentially expressed proteins in the rat dorsal and ventral hippocampus following maintenance on an HFS diet. Rats maintained on the HFS diet for 8 weeks were impaired on a novel object recognition task that assesses memory and on a Morris Water Maze task assessing reversal learning. Quantitative label-free shotgun proteomic analysis was conducted on biological triplicates for each group. For the dorsal hippocampus, 59 proteins were upregulated and 36 downregulated in the HFS group compared to controls. Pathway ana-lysis revealed changes to proteins involved in molecular transport and cellular and molecular signaling, and changes to signaling pathways including calcium signaling, citrate cycle, and oxidative phosphorylation. For the ventral hippocampus, 25 proteins were upregulated and 27 downregulated in HFS fed rats. Differentially expressed proteins were involved in cell-to-cell signaling and interaction, and cellular and molecular function. Changes to signaling pathways included protein ubiquitination, ubiquinone biosynthesis, oxidative phosphorylation, and mitochondrial dysfunction. This is the first shotgun proteomics study to examine protein changes in the hippocampus following long-term consumption of a HFS diet, identifying changes to a large number of proteins including those involved in synaptic plasticity and energy metabolism. All MS data have been deposited in the ProteomeXchange with identifier PXD000028. PMID:23963966

  20. Up-regulated uridine kinase gene identified by RLCS in the ventral horn after crush injury to rat sciatic nerves.

    PubMed

    Yuh, I; Yaoi, T; Watanabe, S; Okajima, S; Hirasawa, Y; Fushiki, S

    1999-12-01

    Rat sciatic nerve crush injury is one of the models commonly employed for studying the mechanisms of nerve regeneration. In this study, we analyzed the temporal change of gene expression after injury in this model, to elucidate the molecular mechanisms involved in nerve regeneration. First, a cDNA analysis method, Restriction Landmark cDNA Scanning (RLCS), was applied to cells in the ventral horn of the spinal cord during a 7-day period after the crush injury. A total of 1991 cDNA species were detected as spots on gels, and 37 of these were shown to change after the injury. Temporally changed patterns were classified into three categories: the continuously up-regulated type (10 species), the transiently up-regulated type (22 species), and the down-regulated type (5 species). These complex patterns of gene expression demonstrated after the injury suggest that precise regulation in molecular pathways is required for accomplishing nerve regeneration. Secondly, the rat homologue of uridine kinase gene was identified as one of the up-regulated genes. Northern blot analysis on rat ventral horn tissue and brain revealed that the UK gene had three transcripts with different sizes (4.3, 1. 4, and 1.35 kb, respectively). All of the transcripts, especially the 4.3 kb one, were up-regulated mainly in a bimodal fashion during the 28-day period after the injury. The RLCS method that we employed in the present study shows promise as a means to fully analyze molecular changes in nerve regeneration in detail. PMID:10581173

  1. Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray.

    PubMed

    Wang, Peng; Li, Hui; Barde, Swapnali; Zhang, Ming-Dong; Sun, Jing; Wang, Tong; Zhang, Pan; Luo, Hanjiang; Wang, Yongjun; Yang, Yutao; Wang, Chuanyue; Svenningsson, Per; Theodorsson, Elvar; Hökfelt, Tomas G M; Xu, Zhi-Qing David

    2016-08-01

    The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects. PMID:27457954

  2. Effect of cardiopulmonary C fibre activation on the firing activity of ventral respiratory group neurones in the rat.

    PubMed Central

    Wilson, C G; Bonham, A C

    1997-01-01

    1. Cardiopulmonary C fibre receptor stimulation elicits apnoea and rapid shallow breathing, but the effects on the firing activity of central respiratory neurones are not well understood. This study examined the responses of ventral respiratory group neurones: decrementing expiratory (Edec), augmenting expiratory (Eaug), and inspiratory (I) neurones during cardiopulmonary C fibre receptor-evoked apnoea and rapid shallow breathing. 2. Extracellular neuronal activity, phrenic nerve activity and arterial pressure were recorded in urethane-anaesthetized rats. Cardiopulmonary C fibre receptors were stimulated by right atrial injections of phenylbiguanide. Neurones were tested for antidromic activation from the contra- and ipsilateral ventral respiratory group (VRG), spinal cord and cervical vagus nerve. 3. Edec neurones discharged tonically during cardiopulmonary C fibre-evoked apnoea and rapid shallow breathing, displaying increased burst durations, number of impulses per burst, and mean impulse frequencies. Edec neurones recovered either with the phrenic nerve activity (25 s) or much later (3 min). 4. By contrast, the firing activity of Eaug and most I neurones was decreased, featuring decreased burst durations and number of impulses per burst and increased interburst intervals. Eaug activity recovered in approximately 3 min and inspiratory activity in approximately 1 min. 5. The results indicate that cardiopulmonary C fibre receptor stimulation causes tonic firing of Edec neurones and decreases in Eaug and I neuronal activity coincident with apnoea or rapid shallow breathing. PMID:9365917

  3. Long Hydrocarbon Chains Serve as Unique Molecular Features Recognized by Ventral Glomeruli of the Rat Olfactory Bulb

    PubMed Central

    Ho, Sabrina L.; Johnson, Brett A.; Leon, Michael

    2008-01-01

    In an effort to understand mammalian olfactory processing, we have been describing the responses to systematically different odorants in the glomerular layer of the main olfactory bulb of rats. To understand the processing of pure hydrocarbon structures in this system, we used the [14C]2-deoxyglucose method to determine glomerular responses to a homologous series of alkanes (from six to sixteen carbons) that are straight-chained hydrocarbons without functional groups. We found two rostral regions of activity evoked by these odorants, one lateral and one medial, that were observed to shift ventrally with increasing alkane carbon chain length. Furthermore, we successfully predicted that the longest alkanes with carbon chain length greater than our previous odorant selections would stimulate extremely ventral glomerular regions where no activation had been observed with the hundreds of odorants that we had previously studied. Overlaps in response profiles were observed in the patterns evoked by alkanes and by other aliphatic odorants of corresponding carbon chain length despite possessing different oxygen-containing functional groups, which demonstrated that hydrocarbon chains could serve as molecular features in the combinatorial coding of odorant information. We found a close and predictable relationship among the molecular properties of odorants, their induced neural activity, and their perceptual similarities. PMID:16856178

  4. Voxelized computational model for convection-enhanced delivery in the rat ventral hippocampus: comparison with in vivo MR experimental studies.

    PubMed

    Kim, Jung Hwan; Astary, Garrett W; Kantorovich, Svetlana; Mareci, Thomas H; Carney, Paul R; Sarntinoranont, Malisa

    2012-09-01

    Convection-enhanced delivery (CED) is a promising local delivery technique for overcoming the blood-brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, therapeutics are infused directly into brain tissue and the drug agent is spread through the extracellular space, considered to be highly tortuous porous media. In this study, 3D computational models developed using magnetic resonance (MR) diffusion tensor imaging data sets were used to predict CED transport in the rat ventral hippocampus using a voxelized modeling previously developed by our group. Predicted albumin tracer distributions were compared with MR-measured distributions from in vivo CED in the ventral hippocampus up to 10 μL of Gd-DTPA albumin tracer infusion. Predicted and measured tissue distribution volumes and distribution patterns after 5 and 10 μL infusions were found to be comparable. Tracers were found to occupy the underlying landmark structures with preferential transport found in regions with less fluid resistance such as the molecular layer of the dentate gyrus. Also, tracer spread was bounded by high fluid resistance layers such as the granular cell layer and pyramidal cell layer of dentate gyrus. Leakage of tracers into adjacent CSF spaces was observed towards the end of infusions. PMID:22532321

  5. Voxelized Computational Model for Convection-Enhanced Delivery in the Rat Ventral Hippocampus: Comparison with In Vivo MR Experimental Studies

    PubMed Central

    Kim, Jung Hwan; Astary, Garrett W.; Kantorovich, Svetlana; Mareci, Thomas H.; Carney, Paul R.; Sarntinoranont, Malisa

    2012-01-01

    Convection-enhanced delivery (CED) is a promising local delivery technique for overcoming the blood–brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, therapeutics are infused directly into brain tissue and the drug agent is spread through the extracellular space, considered to be highly tortuous porous media. In this study, 3D computational models developed using magnetic resonance (MR) diffusion tensor imaging data sets were used to predict CED transport in the rat ventral hippocampus using a voxelized modeling previously developed by our group. Predicted albumin tracer distributions were compared with MR-measured distributions from in vivo CED in the ventral hippocampus up to 10 μL of Gd-DTPA albumin tracer infusion. Predicted and measured tissue distribution volumes and distribution patterns after 5 and 10 μL infusions were found to be comparable. Tracers were found to occupy the underlying landmark structures with preferential transport found in regions with less fluid resistance such as the molecular layer of the dentate gyrus. Also, tracer spread was bounded by high fluid resistance layers such as the granular cell layer and pyramidal cell layer of dentate gyrus. Leakage of tracers into adjacent CSF spaces was observed towards the end of infusions. PMID:22532321

  6. PERINATAL EXPOSURE TO ESTROGENIC COMPOUNDS AND THE SUBSEQUENT EFFECTS ON THE PROSTRATE OF THE ADULT RAT: EVALUATION OF INFLAMMATION IN THE VENTRAL AND LATERAL LOBES

    EPA Science Inventory

    Perinatal exposure to estrogenic compounds and the subsequent effects on the prostate of the adult rat: evaluation of inflammation in the ventral and lateral lobes.

    Stoker TE, Robinette CL, Cooper RL.

    Endocrinology Branch, Reproductive Toxicology Division, National ...

  7. Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

    PubMed Central

    Espinosa, Pedro; Silva, Roxana A.; Sanguinetti, Nicole K.; Venegas, Francisca C.; Riquelme, Raul; González, Luis F.; Cruz, Gonzalo; Renard, Georgina M.; Moya, Pablo R.; Sotomayor-Zárate, Ramón

    2016-01-01

    We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area. PMID:26904299

  8. Organization of Multisynaptic Inputs to the Dorsal and Ventral Dentate Gyrus: Retrograde Trans-Synaptic Tracing with Rabies Virus Vector in the Rat

    PubMed Central

    Ohara, Shinya; Sato, Sho; Tsutsui, Ken-Ichiro; Witter, Menno P.; Iijima, Toshio

    2013-01-01

    Behavioral, anatomical, and gene expression studies have shown functional dissociations between the dorsal and ventral hippocampus with regard to their involvement in spatial cognition, emotion, and stress. In this study we examined the difference of the multisynaptic inputs to the dorsal and ventral dentate gyrus (DG) in the rat by using retrograde trans-synaptic tracing of recombinant rabies virus vectors. Three days after the vectors were injected into the dorsal or ventral DG, monosynaptic neuronal labeling was present in the entorhinal cortex, medial septum, diagonal band, and supramammillary nucleus, each of which is known to project to the DG directly. As in previous tracing studies, topographical patterns related to the dorsal and ventral DG were seen in these regions. Five days after infection, more of the neurons in these regions were labeled and labeled neurons were also seen in cortical and subcortical regions, including the piriform and medial prefrontal cortices, the endopiriform nucleus, the claustrum, the cortical amygdala, the medial raphe nucleus, the medial habenular nucleus, the interpeduncular nucleus, and the lateral septum. As in the monosynaptically labeled regions, a topographical distribution of labeled neurons was evident in most of these disynaptically labeled regions. These data indicate that the cortical and subcortical inputs to the dorsal and ventral DG are conveyed through parallel disynaptic pathways. This second-order input difference in the dorsal and ventral DG is likely to contribute to the functional differentiation of the hippocampus along the dorsoventral axis. PMID:24223172

  9. NK1 receptor and the ventral medulla of the rat: bulbospinal and catecholaminergic neurons.

    PubMed

    Makeham, J M; Goodchild, A K; Pilowsky, P M

    2001-12-01

    Bulbospinal C1 neurons are sympathoexcitatory and excited by substance P. However the substance P receptor (NK1 receptor), has been reported to be absent from the somata of C1 neurons. In this study, using double and triple labelling immunofluorescence and retrograde tracing, we provide evidence that the NK1 receptor is present on 5.3% of C1 neurons, and that 4.7% of C1 neurons receive close oppositions from NK1 receptor immunoreactive terminals, indicating a pre-synaptic and post-synaptic site for the action of substance P. These results provide support for the sympathoexcitatory actions of substance P on C1 neurons. We also demonstrate the NK1 receptor on bulbospinal neurons of the ventral respiratory group, in a region overlapping the pre-Bötzinger Complex. PMID:11726770

  10. Directing dopaminergic fiber growth along a preformed molecular pathway from embryonic ventral mesencephalon transplants in the rat brain.

    PubMed

    Jin, Y; Zhang, C; Ziemba, K S; Goldstein, G A; Sullivan, P G; Smith, G M

    2011-05-01

    To identify guidance molecules to promote long-distance growth of dopaminergic axons from transplanted embryonic ventral mesencephalon (VM) tissue, three pathways were created by expressing green fluorescent protein (GFP), glial cell line-derived neurotrophic factor (GDNF), or a combination of GDNF/GDNF receptor α1 (GFRα1) along the corpus callosum. To generate the guidance pathway, adenovirus encoding these transcripts was injected at four positions along the corpus callosum. In all groups, GDNF adenovirus was also injected on the right side 2.5 mm from the midline at the desired transplant site. Four days later, a piece of VM tissue from embryonic day 14 rats was injected at the transplant site. All rats also received daily subcutaneous injections of N-acetyl-L-cysteinamide (NACA; 100 μg per rat) as well as chondroitinase ABC at transplant site (10 U/ml, 2 μl). Two weeks after transplantation, the rats were perfused and the brains dissected out. Coronal sections were cut and immunostained with antibody to tyrosine hydroxylase (TH) to identify and count dopaminergic fibers in the corpus callosum. In GFP-expressing pathways, TH(+) fibers grew out of the transplants for a short distance in the corpus callosum. Very few TH(+) fibers grew across the midline. However, pathways expressing GDNF supported more TH(+) fiber growth across the midline into the contralateral hemisphere. Significantly greater numbers of TH(+) fibers grew across the midline in animals expressing a combination of GDNF and GFRα1 in the corpus callosum. These data suggest that expression of GDNF or a combination of GDNF and GFRα1 can support the long-distance dopaminergic fiber growth from a VM transplant, with the combination having a superior effect. PMID:21337366

  11. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex

    PubMed Central

    Ikemoto, Satoshi

    2007-01-01

    Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that: (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive, and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization. PMID:17574681

  12. Blockade of prostaglandin E1 hyperthermia by sodium salicylate given into the ventral septal area of the rat brain.

    PubMed Central

    Alexander, S J; Cooper, K E; Veale, W L

    1987-01-01

    1. Sodium salicylate (30.0 micrograms microliter-1) or artificial cerebrospinal fluid (ACSF) was infused bilaterally into the ventral septal area (v.s.a.) of the unrestrained rat for 1 h before and 1 h after the injection of prostaglandin E1 at a concentration of 20.0 ng microliter-1 into a lateral cerebral ventricle. 2. During control (ACSF) infusions, 200.0 ng of prostaglandin E1 evoked a hyperthermic response (0.95 +/- 0.16 degrees C). During sodium salicylate infusions, the prostaglandin E1-evoked hyperthermia was significantly reduced (P less than 0.025) to 0.31 +/- 0.16 degrees C. 3. The fever index (degrees C h for 1.0 h) during the infusion of sodium salicylate was reduced 66% below that of control infusions (P less than 0.01). 4. These data indicate that sodium salicylate infused in the v.s.a. of rats can antagonize a prostaglandin E-evoked hyperthermia. This suggests that there may be an additional mechanism of action for sodium salicylate antipyresis other than inhibition of prostaglandin E synthesis. PMID:3656145

  13. No effect of hypergravity on adult rat ventral horn neuron size or SDH activity

    NASA Technical Reports Server (NTRS)

    Roy, R. R.; Ishihara, A.; Moran, M. M.; Wade, C. E.; Edgerton, V. R.

    2001-01-01

    BACKGROUND: Spaceflights of short duration (approximately 2 wk) result in adaptations in the size and/or metabolic properties of a select population of motoneurons located in the lumbosacral region of the rat spinal cord. A decrease in succinate dehydrogenase (SDH, an oxidative marker enzyme) activity of moderately sized (500-800 microm2) motoneurons in the retrodorsolateral region of the spinal cord (L6) has been observed after a 14-d flight. HYPOTHESIS: Our hypothesis was that exposure to short-term hypergravity would result in adaptations in the opposite direction, reflecting a continuum of morphological and biochemical responses in the spinal motoneurons from zero gravity to hypergravity. METHODS: Young, male rats were centrifuged at either 1.5 or 2.0 G for 2 wk. The size and SDH activity of a population of motoneurons in the retrodorsolateral region of the spinal cord (L5) were determined and compared with age-matched rats maintained at 1.0 G. The absolute and relative (to body weight) masses of the soleus, gastrocnemius, adductor longus and tibialis anterior muscles were compared among the three groups. RESULTS: There were no effects of either hypergravity intervention on the motoneuron properties. Rats maintained under hypergravity conditions gained less body mass than rats kept at 1.0 G. For the 1.5 and 2.0 G groups, the muscle absolute mass was smaller and relative mass similar to that observed in the 1.0 G rats, except for the adductor longus. The adductor longus absolute mass was similar to and the relative mass larger in both hypergravity groups than in the 1.0 G group. CONCLUSIONS: Our hypothesis was rejected. The findings suggest that rat motoneurons are more responsive to short-term chronic exposure to spaceflight than to hypergravity conditions.

  14. Activation of cannabinoid CB1 receptors in the ventral hippocampus improved stress-induced amnesia in rat.

    PubMed

    Mohammadmirzaei, Negin; Rezayof, Ameneh; Ghasemzadeh, Zahra

    2016-09-01

    The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories. The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats. In order to induce acute stress, the animals were placed on an elevated platform for different time periods (10, 20 and 30min). Our results indicated that post-training 20 and 30min exposure to stress, but not 10min, induced amnesia. Post-training microinjection of a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 2.5-7.5ng/rat) into the VH (intra-VH) induced amnesia. Interestingly, post-training intra-VH microinjection of the same doses of ACPA improved stress-induced amnesia. On the other hand, post-training intra-VH microinjection of a selective CB1 receptor antagonist, AM-251 (20-50ng/rat) with exposure to an ineffective stress (10min) potentiated the effect of stress on memory consolidation and induced amnesia. It should be noted that post-training intra-VH microinjection of the same doses of AM-251 alone had no effect on memory consolidation. Our results revealed that post-training intra-VH microinjection of AM-251, prior to ACPA microinjection, inhibited the reversal effect of ACPA on acute elevated platform stress. Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors. PMID:27282634

  15. Stimulation of vasopressin release in the ventral septum of the rat brain suppresses prostaglandin E1 fever.

    PubMed Central

    Naylor, A M; Pittman, Q J; Veale, W L

    1988-01-01

    1. Infusion of prostaglandin E1 (PGE1) into a lateral cerebral ventricle of the rat evoked a rise in core temperature which could be attenuated by electrical stimulation of the bed nucleus of the stria terminalis (BST). Electrical stimulation of the BST in the absence of PGE1 did not alter body temperature in the afebrile rat. 2. When the intracerebroventricular (I.C.V.) infusion of PGE1 was preceded by a bilateral injection of saline or vasopressin V2 antagonist d(CH2)5D-ValVAVP into the ventral septal area (VSA), electrical stimulation of the BST suppressed the PGE1 hyperthermia. However, when the vasopressin V1 antagonist d(CH2)5Tyr(Me)AVP was injected into the VSA prior to I.C.V. infusion of PGE1, electrical stimulation of the BST did not alter the hyperthermic response to PGE1. 3. These actions were site specific in that the suppression of PGE1 hyperthermia was observed only when the electrode tips were located in the area of the BST. Similarly, the V1 antagonist only blocked the effect of electrical stimulation when injected into the VSA. 4. When the vasopressin V1 antagonist was injected into the VSA, the PGE1 fever was prolonged when compared to the controls with saline. 5. Injection of saline, vasopressin V1 and V2 antagonist into the VSA, without PGE1 or BST stimulation, did not evoke any significant change in the core temperature of the rats. 6. These data are consistent with the hypothesis that vasopressin may function within the brain as an endogenous antipyretic and that vasopressin may act in a BST-VSA neuronal pathway concerned with endogenous antipyresis. PMID:3404461

  16. Cochlear implantation in pontine tegmental cap dysplasia.

    PubMed

    Bacciu, Andrea; Ormitti, Francesca; Pasanisi, Enrico; Vincenti, Vincenzo; Zanetti, Diego; Bacciu, Salvatore

    2010-08-01

    Pontine tegmental cap dysplasia (PTCD) is an exceptionally rare brain stem and cerebellar malformation characterized by ventral pontine hypoplasia, vaulted pontine tegmentum, hypoplasia of the vermis, subtotal absence of middle cerebellar peduncles, lateralized course of the superior cerebellar peduncles, and absence or alteration of the inferior olivary nucleus. The main clinical features are multiple cranial neurophaties and ataxia. Sensorineural hearing loss of varying severity is almost always present. To date, 14 cases of PTCD have been reported in the literature. We present a child with PTCD and profound bilateral sensorineural hearing loss who underwent cochlear implantation. To the best of our knowledge, cochlear implantation in PTCD has not been previously reported. Functional outcome was assessed using the Speech Perception Categories and the Speech Intelligibility Rating scale. At 22 months' postoperative evaluation, the patient who was placed into speech perception category 0 (no detection of speech) preoperatively progressed to category 3 (beginning word identification). Before implantation, the child had connected speech unintelligible. At the last follow-up, she had connected speech intelligible to a listener who has little experience of a deaf person's speech. Cochlear implantation allowed this child to improve her quality of life, increasing her self-confidence, independence, and social integration. PMID:20627414

  17. Ventral hippocampal kappa opioid receptors mediate the renewal of fear following extinction in the rat.

    PubMed

    Cole, Sindy; Richardson, Rick; McNally, Gavan P

    2013-01-01

    The hippocampus is part of a neural network which regulates the renewal of fear following extinction. Both the ventral (VH) and dorsal (DH) hippocampus have been shown to be necessary for renewal, however the critical receptors and neurotransmitters mediating these contributions are poorly understood. One candidate mechanism is the kappa opioid receptor (KOR) system, which has been implicated in fear learning and anxiety. Here we examined the effect of the KOR antagonist norbinaltorphamine hydrochloride (norBNI), infused into either the VH or DH, on the renewal of extinguished fear. We found that an infusion of norBNI into the VH significantly reduced the relapse of fear on test compared to that seen in saline controls (Experiment 1), while similar infusions of norBNI into the DH had no effect on renewal (Experiment 2). These findings show that hippocampal KORs are involved in fear renewal and also identify a dissociation in the contribution of VH and DH KORs to the expression of renewed fear. PMID:23675405

  18. Ventral Hippocampal Kappa Opioid Receptors Mediate the Renewal of Fear following Extinction in the Rat

    PubMed Central

    Cole, Sindy; Richardson, Rick; McNally, Gavan P.

    2013-01-01

    The hippocampus is part of a neural network which regulates the renewal of fear following extinction. Both the ventral (VH) and dorsal (DH) hippocampus have been shown to be necessary for renewal, however the critical receptors and neurotransmitters mediating these contributions are poorly understood. One candidate mechanism is the kappa opioid receptor (KOR) system, which has been implicated in fear learning and anxiety. Here we examined the effect of the KOR antagonist norbinaltorphamine hydrochloride (norBNI), infused into either the VH or DH, on the renewal of extinguished fear. We found that an infusion of norBNI into the VH significantly reduced the relapse of fear on test compared to that seen in saline controls (Experiment 1), while similar infusions of norBNI into the DH had no effect on renewal (Experiment 2). These findings show that hippocampal KORs are involved in fear renewal and also identify a dissociation in the contribution of VH and DH KORs to the expression of renewed fear. PMID:23675405

  19. Delayed Recall of Fear Extinction in Rats with Lesions of Ventral Medial Prefrontal Cortex

    ERIC Educational Resources Information Center

    Lebron, Kelimer; Milad, Mohammed R.; Quirk, Gregory J.

    2004-01-01

    Extinction of auditory fear conditioning is thought to form a new memory. We previously found that rats with vmPFC lesions could extinguish fear to the tone within a session, but showed no recall of extinction 24 h later. One interpretation is that the vmPFC is the sole storage site of extinction memory. However, it is also possible that lesioned…

  20. Enhanced Extracellular Glutamate and Dopamine in the Ventral Pallidum of Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats after Morphine

    PubMed Central

    Kemppainen, Heidi; Nurmi, Harri; Raivio, Noora; Kiianmaa, Kalervo

    2015-01-01

    The purpose of the present study was to investigate the role of ventral pallidal opioidergic mechanisms in the control of ethanol intake by studying the effects of acute administration of morphine on the levels of GABA, glutamate, and dopamine in the ventral pallidum. The study was conducted using the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding Alko Non-Alcohol (ANA) rat lines that have well-documented differences in their voluntary ethanol intake and brain opioidergic systems. Therefore, examination of neurobiological differences between the lines is supposed to help to identify the neuronal mechanisms underlying ethanol intake, since selection pressure is assumed gradually to lead to enrichment of alleles promoting high or low ethanol intake, respectively. The effects of an acute dose of morphine (1 or 10 mg/kg s.c.) on the extracellular levels of GABA and glutamate in the ventral pallidum were monitored with in vivo microdialysis. The concentrations of GABA and glutamate in the dialyzates were determined with a high performance liquid chromatography system using fluorescent detection, while electrochemical detection was used for dopamine. The levels of glutamate in the rats injected with morphine 1 mg/kg were significantly above the levels found in the controls and in the rats receiving morphine 10 mg/kg. Morphine 10 mg/kg also increased the levels of dopamine. Morphine could not, however, modify the levels of GABA. The rat lines did not differ in any of the effects of morphine. The data suggest that the glutamatergic and dopaminergic systems in the ventral pallidum may mediate some effects of morphine. Since there were no differences between the AA and ANA lines, the basic hypothesis underlying the use of the genetic animal model suggests that the effects of morphine detected probably do not underlie the different intake of ethanol by the lines and contribute to the control of ethanol intake in these animals. PMID:25653621

  1. Effects of Salt Loading on the Morphology of Astrocytes in the Ventral Glia Limitans of the Rat Supraoptic Nucleus.

    PubMed

    Choe, K Y; Prager-Khoutorsky, M; Farmer, W T; Murai, K K; Bourque, C W

    2016-04-01

    In the ventral glial limitans (VGL) of the supraoptic nucleus (SON) of the rat, a unique astrocyte type is found with an ability to undergo striking morphological plasticity in response to a wide range of physiological stimulations such as chronic hypernatraemia. This includes a thinning of the VGL, which contains the somata and proximal processes of these astrocytes, as well as an almost complete withdrawal of their vertically-oriented distal processes. Currently, there is little information available on the types of astrocytes that reside in the SON-VGL and which of these exhibit state-dependent structural plasticity. To address this, we enabled the visualisation of single SON-VGL glia using two novel cell labelling techniques with fluorescence microscopy. First, we used an inducible genetic reporter mouse line that allowed the specific labelling of a low density of astrocytes expressing glutamate and aspartate transporter (GLAST)/excitatory amino acid transporter 1. This approach revealed a high degree of variability in the morphology of mouse SON-VGL astrocytes, in contrast to what has been reported for cortical astrocytes. Next, we used the DiOlistlic labelling approach to label single glial cells with DiI in the SON-VGL of rats. Astrocytes observed using this approach shared the morphological features of GLAST-expressing astrocytes in the mouse SON-VGL. Specific structural aspects of these cells were modified by chronic hypernatraemia achieved by 7-day salt loading. Notably, the average area of cells exhibiting protoplasmic features was significantly reduced in the horizontal plane, and the size of varicosities present on fibrous projections was significantly enlarged. These observations indicate that novel cell labelling methods can significantly advance our understanding of SON-VGL cells and reveal specific forms of morphological plasticity that can be driven by chronic hypernatraemia. PMID:26813227

  2. Proteins of the rat prostate. II. Synthesis of new proteins in the ventral lobe during castration-induced regression

    SciTech Connect

    Lee, C.; Sensibar, J.A.

    1987-10-01

    Ventral prostates from adult Sprague-Dawley rats at different days postcastration were cut into one to two mm.3 pieces and incubated in medium containing S-35-methionine (100 uCi/ml.) at 37 C under 95% oxygen and 5% carbon dioxide for four hours. The incubated tissues were subjected to two-dimensional electrophoresis and radiofluorography. Over 100 spots were developed in the fluorograms. Three groups of spots, representing cytoskeletal proteins, androgen-dependent proteins and castration-induced proteins, were further evaluated by a computer-based densitometer. The level of densitometry absorption is proportional to the amount of radioactivity in each spot. The synthesis of cytoskeletal proteins, such as actin and tropomyosin, were relatively constant throughout the course of prostatic regression. The rate of synthesis of androgen-dependent proteins declined rapidly from a high level of synthesis before castration to a non-detectable level by Day 3 postcastration. However, three proteins, which were either not synthesized (spot G and spot H) or synthesized at a very low level (spot I) before castration, were the major proteins synthesized by the prostate during early stages of its regression. The rate of synthesis of these proteins reached a peak by Day 4 postcastration, declined rapidly and remained at a low level thereafter. The respective molecular weights and isoelectric points for these three proteins were 33 Kd and 7.2 for spot G, 38 Kd and 5.3 for spot H and 64 Kd and 6.0 for spot I. Previous findings showed that prostatic regression in rats was associated with a surge of activities in proteolytic enzymes which peaked five to six days postcastration.

  3. Impaired adrenergic-mediated plasticity of prefrontal cortical glutamate synapses in rats with developmental disruption of the ventral hippocampus.

    PubMed

    Bhardwaj, Sanjeev K; Tse, Yiu Chung; Ryan, Richard; Wong, Tak Pan; Srivastava, Lalit K

    2014-12-01

    Neonatal ventral hippocampus (nVH) lesion in rats is a useful model to study developmental origins of adult cognitive deficits and certain features of schizophrenia. nVH lesion-induced reorganization of excitatory and inhibitory neurotransmissions within prefrontal cortical (PFC) circuits is widely believed to be responsible for many of the behavioral abnormalities in these animals. Here we provide evidence that development of an aberrant medial PFC (mPFC) α-1 adrenergic receptor (α-1AR) function following neonatal lesion markedly affects glutamatergic synaptic plasticity within PFC microcircuits and contributes to PFC-related behavior abnormalities. Using whole-cell patch-clamp recording, we report that norepinephrine-induced α-1AR-dependent long-term depression (LTD) in a subset of cortico-cortical glutamatergic inputs is strikingly diminished in mPFC slices from nVH-lesioned rats. The LTD impairment occurs in conjunction with completely blunted α-1AR signaling through extracellular signal-regulated kinase 1/2. These α-1AR abnormalities have functional significance in a mPFC-related function, that is, extinction of conditioned fear memory. Post-pubertal animals with nVH lesion show significant resistance to extinction of fear by repeated presentations of the conditioned tone stimulus. mPFC infusion of an α-1AR antagonist (benoxathian) or LTD blocking peptide (Tat-GluR23Y) impaired fear extinction in sham controls, but had no significant effect in the lesioned animals. The data suggest that impaired α-1 adrenergic regulation of cortical glutamatergic synaptic plasticity may be an important mechanism in cognitive dysfunctions reported in neurodevelopmental psychiatric disorders. PMID:24917197

  4. Effects of somatostatin and related peptides on the membrane potential and input resistance of rat ventral subicular neurons, in vitro.

    PubMed

    Greene, J R; Mason, A

    1996-02-01

    The effects of bath-applied somatostatin (SS), and related peptides on the membrane potential and input resistance of 117 ventral subicular neurons were investigated by intracellular recording in rat brain slices. Electrophysiological properties, which included burst-firing in response to depolarizing current pulses, indicated that the neurons studied were of the pyramidal type. For the 89 cells analyzed quantitatively, membrane potential was -69.1 +/- 0.3 mV (mean +/- S.E.) and input resistance was 23.9 +/- 0.5 megohms. SS (5 microM) caused a hyperpolarization of 3.4 +/- 0.3 mV (n = 9) and reduced input resistance by 16 +/- 3.1% (n = 6). SS D-Trp8, somatostatin, octreotide, CGP 23996 and MK 678 shared these effects, but somatostatin was inactive. SS effects persisted when bathing solutions contained tetrodotoxin, reduced calcium and elevated magnesium concentrations and when both of these treatments were combined. They were unaltered by antagonists at gamma-aminobutyric acid receptors or at ionotropic glutamate receptors. The effects of MK 678, SS, SS D-Trp8 and somatostatin were concentration-dependent, and these peptides were equipotent at 500 nM and at 5 microM. For MK 678, the EC50 was 316 nM for the hyperpolarization and 90 nM for the reduction in input resistance. We conclude that SS acts directly on pyramidal neurons of the rat subiculum to cause a hyperpolarization and a decrease in input resistance. We suggest that these effects are mediated by the SSTR2 receptor subtype. PMID:8632306

  5. Ventral medial prefrontal cortex inactivation impairs impulse control but does not affect delay-discounting in rats.

    PubMed

    Feja, Malte; Koch, Michael

    2014-05-01

    Maladaptive levels of impulsivity are found in several neuropsychiatric disorders, such as ADHD, addiction, aggression and schizophrenia. Intolerance to delay-of-gratification, or delay-discounting, and deficits in impulse control are dissociable forms of impulsivity top-down controlled by the prefrontal cortex, with the ventral medial prefrontal cortex (vmPFC) suggested to be critically involved. The present study used transient inactivation of the rats' vmPFC via bilateral microinfusion of the GABAA receptor agonist muscimol (0.05, 0.5 μg/0.3 μl) to analyse its relevance for impulse control in a 5-choice serial reaction time task (5-CSRTT) and delay-discounting in a Skinner box. Intra-vmPFC injection of low-dose muscimol impaired impulse control indicated by enhanced premature responding in the 5-CSRTT, while flattening the delay-dependent shift in the preference of the large reward in the delay-discounting task. Likewise, high-dose muscimol did not affect delay-discounting, though raising the rate of omissions. On the contrary, 5-CSRTT performance was characterised by deficits in impulse and attentional control. These data support the behavioural distinction of delay-discounting and impulse control on the level of the vmPFC in rats. Reversible inactivation with muscimol revealed an obvious implication of the vmPFC in the modulation of impulse control in the 5-CSRTT. By contrast, delay-discounting processes seem to be regulated by other neuronal pathways, with the vmPFC playing, if at all, a minor role. PMID:24556205

  6. Local glutamate release in the rat ventral lateral thalamus evoked by high-frequency stimulation

    NASA Astrophysics Data System (ADS)

    Agnesi, Filippo; Blaha, Charles D.; Lin, Jessica; Lee, Kendall H.

    2010-04-01

    Thalamic deep brain stimulation (DBS) is proven therapy for essential tremor, Parkinson's disease and Tourette's syndrome. We tested the hypothesis that high-frequency electrical stimulation results in local thalamic glutamate release. Enzyme-linked glutamate amperometric biosensors were implanted in anesthetized rat thalamus adjacent to the stimulating electrode. Electrical stimulation was delivered to investigate the effect of frequency, pulse width, voltage-controlled or current-controlled stimulation, and charge balancing. Monophasic electrical stimulation-induced glutamate release was linearly dependent on stimulation frequency, intensity and pulse width. Prolonged stimulation evoked glutamate release to a plateau that subsequently decayed back to baseline after stimulation. Glutamate release was less pronounced with voltage-controlled stimulation and not present with charge balanced current-controlled stimulation. Using fixed potential amperometry in combination with a glutamate bioprobe and adjacent microstimulating electrode, the present study has shown that monophasic current-controlled stimulation of the thalamus in the anesthetized rat evoked linear increases in local extracellular glutamate concentrations that were dependent on stimulation duration, frequency, intensity and pulse width. However, the efficacy of monophasic voltage-controlled stimulation, in terms of evoking glutamate release in the thalamus, was substantially lower compared to monophasic current-controlled stimulation and entirely absent with biphasic (charge balanced) current-controlled stimulation. It remains to be determined whether similar glutamate release occurs with human DBS electrodes and similar charge balanced stimulation. As such, the present results indicate the importance of evaluating local neurotransmitter dynamics in studying the mechanism of action of DBS.

  7. Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors.

    PubMed

    Fu, Rao; Chen, Xing; Zuo, Wanhong; Li, Jing; Kang, Seungwoo; Zhou, Li-Hua; Siegel, Allan; Bekker, Alex; Ye, Jiang-Hong

    2016-08-01

    There has been increasing interest in the rostromedial tegmental nucleus (RMTg), given its potential regulatory role in many aversion-related behaviors. The RMTg contains mostly GABAergic neurons, sends a dense inhibitory projection to dopamine neurons in the midbrain, and is rich with μ-opioid receptors (MOR). Like most addictive drugs, ethanol has both aversive and rewarding properties. However, the cellular mechanisms underlying the effects of ethanol, particularly the aversive effect that limits its intake are not well understood. Recent studies have linked aversion with synaptic inhibition of dopamine neurons in the ventral tegmental area. To determine a potential role that the RMTg plays in the effect of ethanol, in this study, we employed a neurotoxin, dermorphin-saporin (DS), to lesion RMTg neurons prior to assessing ethanol-related behaviors. Rats were infused with DS bilaterally into the RMTg. This manipulation substantially increased the intake and preference for ethanol but not sucrose. It also reduced the number of neurons with MOR and glutamic acid decarboxylase 67 immunoreactivity within the RMTg. These changes did not occur after intra-RMTg infusion of blank saporin or vehicle. Importantly, intra-RMTg DS infusion significantly enhanced expression of conditioned place preference induced by ethanol (2 g/kg, i.p.), and slowed the extinction process. These results suggest that MOR-expressing GABAergic neurons in the RMTg contribute significantly to the regulation of ethanol consumption and related behaviors. PMID:26921770

  8. Photoaffinity labelling of nuclear steroid 5 alpha-reductase of rat ventral prostate.

    PubMed

    Enderle-Schmitt, U; Seitz, J; Aumüller, G

    1989-09-01

    In order to get more information on the molecular structure of the rat prostatic 5 alpha-reductase (3-oxo-5 alpha-steroid: NADP+ 4-ene-oxidoreductase, EC 1.3:1.22) a systematic photoaffinity labelling study has been performed. To irreversibly freeze the status quo of interaction, either testosterone, the physiological ligand, or diazo-MAPD (21-diazo-4-methyl-4-aza-5 alpha-pregnane-3,20-dione), a specific 5 alpha-reductase inhibitor, was irradiated with isolated nuclei or with purified nuclear membranes or with solubilized nuclear membrane proteins and checked for optimal labelling conditions. The principal substances covalently labelled were phospholipids and at a minor ratio proteins. Analysis by SDS-PAGE and autoradiofluorography revealed two labelled polypeptides with molecular weights of 20 kDa and 26 kDa. The following evidence indicates that these polypeptides might be derived from the enzyme 5 alpha-reductase: both proteins are labelled only when specific ligands for 5 alpha-reductase are used; binding can be reduced by the addition of an excess of unlabelled ligand; enzyme activity is irreversibly suppressed when irradiated in the presence of these ligands; only subcellular fractions containing 5 alpha-reductase reveal the labelled proteins; in all 5 alpha-reductase containing preparations with increasing specific activity, independent of the polypeptide pattern, the same proteins are labelled. PMID:2779229

  9. Transitions between sleep and feeding states in rat ventral striatum neurons

    PubMed Central

    Tellez, Luis A.; Perez, Isaac O.; Simon, Sidney A.

    2012-01-01

    Neurons in the nucleus accumbens (NAc) have been shown to participate in several behavioral states, including feeding and sleep. However, it is not known if the same neuron participates in both states and, if so, how similar are the responses. In addition, since the NAc contains several cell types, it is not known if each type participates in the transitions associated with feeding and sleep. Such knowledge is important for understanding the interaction between two different neural networks. For these reasons we recorded ensembles of NAc neurons while individual rats volitionally transitioned between the following states: awake and goal directed, feeding, quiet-awake, and sleeping. We found that during both feeding and sleep states, the same neurons could increase their activity (be activated) or decrease their activity (be inactivated) by feeding and/or during sleep, thus indicating that the vast majority of NAc neurons integrate sleep and feeding signals arising from spatially distinct neural networks. In contrast, a smaller population was modulated by only one of the states. For the majority of neurons in either state, we found that when one population was excited, the other was inhibited, suggesting that they act as a local circuit. Classification of neurons into putative interneurons [fast-spiking interneurons (pFSI) and choline acetyltransferase interneurons (pChAT)] and projection medium spiny neurons (pMSN) showed that all three types are modulated by transitions to and from feeding and sleep states. These results show, for the first time, that in the NAc, those putative inhibitory interneurons respond similarly to pMSN projection neurons and demonstrate interactions between NAc networks involved in sleep and feeding. PMID:22745464

  10. Hydrogen peroxide modulates neuronal excitability and membrane properties in ventral horn neurons of the rat spinal cord.

    PubMed

    Ohashi, Masayuki; Hirano, Toru; Watanabe, Kei; Shoji, Hirokazu; Ohashi, Nobuko; Baba, Hiroshi; Endo, Naoto; Kohno, Tatsuro

    2016-09-01

    Hydrogen peroxide (H2O2), a reactive oxygen species, is an important signaling molecule for synaptic and neuronal activity in the central nervous system; it is produced excessively in brain ischemia and spinal cord injury. Although H2O2-mediated modulations of synaptic transmission have been reported in ventral horn (VH) neurons of the rat spinal cord, the effects of H2O2 on neuronal excitability and membrane properties remain poorly understood. Accordingly, the present study investigated such effects using a whole-cell patch-clamp technique. The bath-application of H2O2 decreased neuronal excitability accompanied by decreased input resistance, firing frequency, and action potential amplitude and by increased rheobase. These H2O2-mediated changes were induced by activation of extrasynaptic, but not synaptic, GABAA receptors. Indeed, GABAergic tonic currents were enhanced by H2O2. On the other hand, the amplitude of medium and slow afterhyperpolarization (mAHP and sAHP), which plays important roles in controlling neuronal excitability and is mediated by small-conductance calcium-activated potassium (SK) channels, was significantly decreased by H2O2. When extrasynaptic GABAA receptors were completely blocked, these decreases of mAHP and sAHP persisted, and H2O2 increased excitability, suggesting that H2O2 per se might have the potential to increase neuronal excitability via decreased SK channel conductance. These findings indicate that activating extrasynaptic GABAA receptors or SK channels may attenuate acute neuronal damage caused by H2O2-induced hyperexcitability and therefore represent a novel therapeutic target for the prevention and treatment of H2O2-induced motor neuron disorders. PMID:27343829

  11. Responses of neurons in the rat's ventral nucleus of the lateral lemniscus to amplitude-modulated tones.

    PubMed

    Zhang, Huiming; Kelly, Jack B

    2006-12-01

    Recordings were made from single neurons in the rat's ventral nucleus of the lateral lemniscus (VNLL) to determine responses to amplitude-modulated (AM) tones. The neurons were first characterized on the basis of their response to tone bursts presented to the contralateral ear and a distinction was made between those with transient onset responses and those with sustained responses. Sinusoidal AM tones were then presented to the contralateral ear with a carrier that matched the neuron's characteristic frequency (CF). Modulation transfer functions were generated on the basis of firing rate (MTF(FR)) and vector strength (MTF(VS)). Ninety-two percent of onset neurons that responded continuously to AM tones had band-pass MTF(FR)s with best modulation frequencies from 10 to 300 Hz. Fifty-four percent of sustained neurons had band-pass MTF(FR)s with best modulation frequencies from 10 to 500 Hz; other neurons had band-suppressed, all-pass, low-pass, or high-pass functions. Most neurons showed either band-pass or low-pass MTF(VS). Responses were well synchronized to the modulation cycle with maximum vector strengths ranging from 0.37 to 0.98 for sustained neurons and 0.78 to 0.99 for onset neurons. The upper frequency limit for response synchrony was higher than that reported for inferior colliculus, but lower than that seen in more peripheral structures. Results suggest that VNLL neurons, especially those with onset responses to tone bursts, are sensitive to temporal features of sounds and narrowly tuned to different modulation rates. However, there was no evidence of a topographic relation between dorsoventral position along the length of VNLL and best modulation frequency as determined by either firing rate or vector strength. PMID:16928797

  12. Dorsal and Ventral Hippocampus Modulate Autonomic Responses but Not Behavioral Consequences Associated to Acute Restraint Stress in Rats

    PubMed Central

    Scopinho, América A.; Lisboa, Sabrina F. S.; Guimarães, Francisco S.; Corrêa, Fernando M. A.; Resstel, Leonardo B. M.; Joca, Sâmia R. L.

    2013-01-01

    Recent evidence has suggested that the dorsal (DH) and the ventral (VH) poles of the hippocampus are structurally, molecularly and functionally different regions. While the DH is preferentially involved in the modulation of spatial learning and memory, the VH modulates defensive behaviors related to anxiety. Acute restraint is an unavoidable stress situation that evokes marked and sustained autonomic changes, which are characterized by elevated blood pressure (BP), intense heart rate (HR) increases, skeletal muscle vasodilatation and cutaneous vasoconstriction, which are accompanied by a rapid skin temperature drop followed by body temperature increases. In addition to those autonomic responses, animals submitted to restraint also present behavioral changes, such as reduced exploration of the open arms of an elevated plus-maze (EPM), an anxiogenic-like effect. In the present work, we report a comparison between the effects of pharmacological inhibition of DH and VH neurotransmission on autonomic and behavioral responses evoked by acute restraint stress in rats. Bilateral microinjection of the unspecific synaptic blocker cobalt chloride (CoCl2, 1mM) into the DH or VH attenuated BP and HR responses, as well as the decrease in the skin temperature, elicited by restraint stress exposure. Moreover, DH or VH inhibition before restraint did not change the delayed increased anxiety behavior observed 24 h later in the EPM. The present results demonstrate for the first time that both DH and VH mediate stress-induced autonomic responses to restraint but they are not involved in the modulation of the delayed emotional consequences elicited by such stress. PMID:24147071

  13. Infant rats with chronic neonatal isolation experience show decreased extracellular serotonin levels in ventral striatum at baseline and in response to cocaine.

    PubMed

    Kosten, Therese A; Zhang, Xiang Yang; Kehoe, Priscilla

    2004-08-18

    Previously, we demonstrated that the early life stress of neonatal isolation enhances extracellular dopamine (DA) levels in ventral striatum in response to psychostimulants in infant rats. Yet, neonatal isolation does not alter baseline DA levels. DA levels are affected by serotonin (5-HT) and striatal levels of this transmitter are also enhanced by cocaine. Other early life stresses are reported to alter various 5-HT neural systems. Thus, the purpose of this study is to test whether neonatal isolation alters ventral striatal 5-HT levels at baseline or in response to cocaine. Litters were subjected to neonatal isolation (1-h individual isolation/day on postnatal days 2-9) or to non-handled conditions and pups assigned to one of three cocaine doses (0, 2.5, or 5.0 mg/kg) groups. On postnatal day 10, probes were implanted in the ventral striatum. Dialysate samples obtained over a 60-min baseline period and for 120 min post cocaine injections were assessed for levels of 5-HT and its metabolite, 5-HIAA. ISO decreased ventral striatal 5-HT levels at baseline and after cocaine administration but did not alter 5-HIAA levels. These data add to the literature on the immediate effects of early life stress on 5-HT systems by showing alterations in the ventral striatal system. Because serotonergic effects in this neural area are associated with reward and with emotion and affect regulation, the results of this study suggest that early life stress may be a risk factor for addiction and other psychiatric disorders. PMID:15283991

  14. Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

    PubMed

    Chambers, R Andrew; Self, David W

    2002-12-01

    The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia. PMID:12464446

  15. Long term exposure to combination paradigm of environmental enrichment, physical exercise and diet reverses the spatial memory deficits and restores hippocampal neurogenesis in ventral subicular lesioned rats.

    PubMed

    Kapgal, Vijayakumar; Prem, Neethi; Hegde, Preethi; Laxmi, T R; Kutty, Bindu M

    2016-04-01

    Subiculum is an important structure of the hippocampal formation and plays an imperative role in spatial learning and memory functions. We have demonstrated earlier the cognitive impairment following bilateral ventral subicular lesion (VSL) in rats. We found that short term exposure to enriched environment (EE) did not help to reverse the spatial memory deficits in water maze task suggesting the need for an appropriate enriched paradigm towards the recovery of spatial memory. In the present study, the efficacy of long term exposure of VSL rats to combination paradigm of environmental enrichment (EE), physical exercise and 18 C.W. diet (Combination Therapy - CT) in reversing the spatial memory deficits in Morris water maze task has been studied. Ibotenate lesioning of ventral subiculum produced significant impairment of performance in the Morris water maze and reduced the hippocampal neurogenesis in rats. Post lesion exposure to C.T. restored the hippocampal neurogenesis and improved the spatial memory functions in VSL rats. Our study supports the hypothesis that the combination paradigm is critical towards the development of an enhanced behavioral and cognitive experience especially in conditions of CNS insults and the associated cognitive dysfunctions. PMID:26851129

  16. Motivational Responses to Natural and Drug Rewards in Rats with Neonatal Ventral Hippocampal Lesions: An Animal Model of Dual Diagnosis Schizophrenia

    PubMed Central

    Chambers, R. Andrew; Self, David W.

    2010-01-01

    The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection “time-out” periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia. PMID:12464446

  17. Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

    PubMed Central

    Chen, Li; Lodge, Daniel J

    2015-01-01

    Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511

  18. Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [¹⁸F]fluoroethoxybenzovesamicol.

    PubMed

    Cyr, Marilyn; Parent, Maxime J; Mechawar, Naguib; Rosa-Neto, Pedro; Soucy, Jean-Paul; Clark, Stewart D; Aghourian, Meghmik; Bedard, Marc-Andre

    2015-02-01

    Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals. PMID:25257103

  19. Bridging nigrostriatal pathway with fibroblast growth factor-primed peripheral nerves and fetal ventral mesencephalon transplant recuperates from deficits in parkinsonian rats.

    PubMed

    Chiang, Yung-Hsiao; Lin, Shinn-Zong; Zhou, Feng C

    2006-01-01

    Previous studies have indicated that the nigrostriatal dopaminergic (DA) pathway can be reconstructed in hemiparkinsonian rats with a bridge transplantation technique involving fetal ventral mesencephalic transplants and glial cell line-derived neurotrophic factor. In this study, we examined if the nigrostriatal pathway can be restored by combining peripheral nervous tissue with the fetal ventral mesencephalon transplants. Adult rats were injected with 6-hydroxydopamine into left median forebrain bundle. Those with marked rotational behavior, which has been previously shown to indicate complete DA dennervtion, were used for transplant treatments. One month after the lesion, fetal ventral mesencephalic cells were transplanted into the nigral region followed by nigral-striatal grafting of peripheral nerves as a bridge. The bridging nerves (sciatic or intercostals) were pretreated with basic fibrous growth factor (nerve+bFGF+) or Hank's saline (nerve+bFGF-). We found that (a) animals receiving transplants of VM and bFGF+ nerve had a reduction in rotational behavior; (b) animals receiving bFGF-- nerve bridge only had a partial improvement in rotation. Reinnervation of tyrosine hydroxylase (TH)-immunoreactive (ir) fibers into the striatum was found in both of the above groups with more innervation in the former than in the latter. No TH-ir fibers in lesioned striatum or reduction in rotational behavior were found in animals receiving VM only, or VM plus bFGF. Taken together, our data indicate that peripheral nerve, with the aid of bFGF, greatly facilitates the reconstitution of the TH pathway from nigra to striatum and improves motor function in hemiparkinsonian rats. PMID:17121158

  20. Ventral Midbrain NTS1 Receptors Mediate Conditioned Reward Induced by the Neurotensin Analog, D-Tyr[11]neurotensin

    PubMed Central

    Rouibi, Khalil; Bose, Poulomee; Rompré, Pierre-Paul; Warren, Richard A.

    2015-01-01

    The present study was aimed at characterizing the mechanisms by which neurotensin (NT) is acting within the ventral midbrain to induce a psychostimulant-like effect. In a first experiment, we determine which subtype(s) of NT receptors is/are involved in the reward-inducing effect of ventral midbrain microinjection of NT using the conditioned place-preference (CPP) paradigm. In a second study, we used in vitro patch clamp recording technique to characterize the NT receptor subtype(s) involved in the modulation of glutamatergic neurotransmission (excitatory post-synaptic current, EPSC) in ventral tegmental neurons that expressed (Ih+), or do not express (Ih-), a hyperpolarization-activated cationic current. Behavioral studies were performed with adult male Long-Evans rats while electrophysiological recordings were obtained from brain slices of rat pups aged between 14 and 21 days. Results show that bilateral ventral midbrain microinjections of 1.5 and 3 nmol of D-Tyr[11]NT induced a CPP that was respectively attenuated or blocked by co-injection with 1.2 nmol of the NTS1/NTS2 antagonist, SR142948, and the preferred NTS1 antagonist, SR48692. In electrophysiological experiments, D-Tyr[11]NT (0.01-0.5 μM) attenuated glutamatergic EPSC in Ih+ but enhanced it in Ih- neurons. The attenuation effect (Ih+ neurons) was blocked by SR142948 (0.1 μM) while the enhancement effect (Ih- neurons) was blocked by both antagonists (0.1 μM). These findings suggest that (i) NT is acting on ventral midbrain NTS1 receptors to induce a rewarding effect and (ii) that this psychostimulant-like effect could be due to a direct action of NT on dopamine neurons and/or an enhancement of glutamatergic inputs to non-dopamine (Ih-) neurons. PMID:26733785

  1. Basolateral Amygdala Projections to Ventral Hippocampus Modulate the Consolidation of Footshock, but Not Contextual, Learning in Rats

    ERIC Educational Resources Information Center

    Huff, Mary L.; Emmons, Eric B.; Narayanan, Nandakumar S.; LaLumiere, Ryan T.

    2016-01-01

    The basolateral amygdala (BLA) modulates memory consolidation for a variety of types of learning, whereas other brain regions play more selective roles in specific kinds of learning suggesting a role for differential consolidation via distinct BLA pathways. The ventral hippocampus (VH), an efferent target of the BLA, has been suggested to…

  2. Neonatal ventral hippocampus lesion changes nuclear restricted protein/brain (NRP/B) expression in hippocampus, cortex and striatum in developmental periods of rats.

    PubMed

    Tian, Y; Yang, J; Lei, Y; Zhang, Z; Dai, Z; Chen, X; Lui, F; Zhang, J; Ling, S

    2016-04-01

    Schizophrenia is conceptualized as a neurodevelopmental disorder in which developmental alterations in immature brain systems are not clear. Rats with neonatal ventral hippocampal lesions (NVHL) can exhibit schizophrenia-like behaviors, and these rats have been widely used to study the developmental mechanisms of schizophrenia. The nuclear restricted protein/brain (NRP/B) is a nuclear matrix protein that is critical for the normal development of the neuronal system. This study assessed the effect of NVHL induced by the administration of ibotenic acid on the protein expression of NRP/B in the hippocampus, cortex and striatum in pre- and post-pubertal rats. The expressions of NeuN in various developmental periods were assessed accordingly. Sprague-Dawley rat pups were administered ibotenic acid at postnatal day (PD) 7. Western blotting and an immunofluorescence staining analysis showed that the expression of NRP/B was significantly decreased in the hippocampus, cortex and striatum of the NVHL rats at PD14, 28 and 42. The expressions of NeuN were decreased accordingly. In vitro experiment showed the NRP/B knockdown can decrease the Tuj1 expression in cultured cortical neurons. The data suggest that NVHL induces a change in NRP/B expression that affects neurons in the developmental period. PMID:26812035

  3. Activity-based anorexia during adolescence disrupts normal development of the CA1 pyramidal cells in the ventral hippocampus of female rats.

    PubMed

    Chowdhury, Tara G; Ríos, Mariel B; Chan, Thomas E; Cassataro, Daniela S; Barbarich-Marsteller, Nicole C; Aoki, Chiye

    2014-12-01

    Anorexia nervosa (AN) is a psychiatric illness characterized by restricted eating and irrational fears of gaining weight. There is no accepted pharmacological treatment for AN, and AN has the highest mortality rate among psychiatric illnesses. Anorexia nervosa most commonly affects females during adolescence, suggesting an effect of sex and hormones on vulnerability to the disease. Activity-based anorexia (ABA) is a rodent model of AN that shares symptoms with AN, including over-exercise, elevation of stress hormones, and genetic links to anxiety traits. We previously reported that ABA in adolescent female rats results in increased apical dendritic branching in CA1 pyramidal cells of the ventral hippocampus at postnatal day 44 (P44). To examine the long-term effects of adolescent ABA (P44) in female rats, we compared the apical branching in the ventral hippocampal CA1 after recovery from ABA (P51) and after a relapse of ABA (P55) with age-matched controls. To examine the age-dependence of the hippocampal plasticity, we examined the effect of ABA during adulthood (P67). We found that while ABA at P44 resulted in increased branching of ventral hippocampal pyramidal cells, relapse of ABA at P55 resulted in decreased branching. ABA induced during adulthood did not have an effect on dendritic branching, suggesting an age-dependence of the vulnerability to structural plasticity. Cells from control animals were found to exhibit a dramatic increase in branching, more than doubling from P44 to P51, followed by pruning from P51 to P55. The proportion of mature spines on dendrites from the P44-ABA animals is similar to that on dendrites from P55-CON animals. These results suggest that the experience of ABA may cause precocious anatomical development of the ventral hippocampus. Importantly, we found that adolescence is a period of continued development of the hippocampus, and increased vulnerability to mental disorders during adolescence may be due to insults during this

  4. Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions.

    PubMed

    Ouhaz, Zakaria; Ba-M'hamed, Saadia; Bennis, Mohamed

    2014-10-01

    Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition. PMID:25282171

  5. Nicotine Effects in Adolescence and Adulthood on Cognition and α4β2-Nicotinic Receptors in the Neonatal Ventral Hippocampal Lesion Rat Model of Schizophrenia

    PubMed Central

    Berg, Sarah A.; Sentir, Alena M.; Bell, Richard L.; Engleman, Eric A.; Chambers, R. Andrew

    2014-01-01

    Rational Nicotine use in schizophrenia has traditionally been explained as ‘self-medication’ of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. Objectives We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Methods Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. Results NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food–reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p<0.05) but not ventral striatum (<5% changes, p>.40), whereas nicotine history elevated nAChRs across both regions (>30%, p<0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Conclusions Although replicating nicotine-induced up-regulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities. PMID:25388292

  6. Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of Dopamine Neurons and Facilitates Behavioral Effects of Cocaine.

    PubMed

    Glangetas, Christelle; Fois, Giulia R; Jalabert, Marion; Lecca, Salvatore; Valentinova, Kristina; Meye, Frank J; Diana, Marco; Faure, Philippe; Mameli, Manuel; Caille, Stéphanie; Georges, François

    2015-12-15

    The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction. PMID:26628379

  7. Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats

    PubMed Central

    Swerdlow, Neal R.; Powell, Susan B.; Breier, Michelle R.; Hines, Samantha R.; Light, Gregory A.

    2013-01-01

    Background After neonatal ventral hippocampal lesions (NVHLs), adult rats exhibit evidence of neural processing deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI) of acoustic startle and impaired sensory processing. In intact rats, the regulation of PPI by the ventral hippocampus (VH) is mediated via interactions with medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked responses and expression of 7 schizophrenia-related genes in mPFC and NAC, in adult rats after sham- or real NVHLs. Methods Male inbred Buffalo (BUF) rat pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI and auditory-evoked dentate gyrus local field potentials (LFPs) were measured on d56 and d66, respectively. Brains were processed for RT-PCR measures of mPFC and NAC Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Results NVHL rats exhibited significant deficits in PPI (p=0.005) and LFPs (p<0.015) proportional to lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, multiple gene expression levels were highly correlated within- (mean r's≈0.5), but not across-brain regions (mean r's≈0). However, for three genes – Comt, Slc1a2 and Ncam1 – after NVHLs, expression levels became significantly correlated, or “coupled,” across the mPFC and NAC (p's < 0.03, 0.002 and 0.05, respectively), and the degree of “coupling” increased with VH lesion size. Conclusions After NVHLs that disrupt PPI and auditory processing, specific gene expression levels suggest an abnormal functional coupling of the mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs may have implications for understanding the neural basis for PPI- and related sensory processing deficits in schizophrenia patients. PMID:23810830

  8. Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences.

    PubMed

    Czéh, Boldizsár; Varga, Zsófia K Kalangyáné; Henningsen, Kim; Kovács, Gábor L; Miseta, Attila; Wiborg, Ove

    2015-03-01

    Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks. PMID:25331166

  9. Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.

    PubMed

    Vázquez-Roque, Rubén Antonio; Ramos, Brenda; Tecuatl, Carolina; Juárez, Ismael; Adame, Anthony; de la Cruz, Fidel; Zamudio, Sergio; Mena, Raúl; Rockenstein, Edward; Masliah, Eliezer; Flores, Gonzalo

    2012-01-01

    Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms. PMID:21932359

  10. Salicylate-Induced Hearing Loss Trigger Structural Synaptic Modifications in the Ventral Cochlear Nucleus of Rats via Medial Olivocochlear (MOC) Feedback Circuit.

    PubMed

    Fang, Lian; Fu, YaoYao; Zhang, Tian-Yu

    2016-06-01

    Lesion-induced cochlear damage can result in synaptic outgrowth in the ventral cochlear nucleus (VCN). Tinnitus may be associated with the synaptic outgrowth and hyperactivity in the VCN. However, it remains unclear how hearing loss triggers structural synaptic modifications in the VCN of rats subjected to salicylate-induced tinnitus. To address this issue, we evaluated tinnitus-like behavior in rats after salicylate treatment and compared the amplitude of the distortion product evoked otoacoustic emission (DPOAE) and auditory brainstem response (ABR) between control and treated rats. Moreover, we observed the changes in the synaptic ultrastructure and in the expression levels of growth-associated protein (GAP-43), brain-derived neurotrophic factor (BDNF), the microglial marker Iba-1 and glial fibrillary acidic protein (GFAP) in the VCN. After salicylate treatment (300 mg/kg/day for 4 and 8 days), analysis of the gap prepulse inhibition of the acoustic startle showed that the rats were experiencing tinnitus. The changes in the DPOAE and ABR amplitude indicated an improvement in cochlear sensitivity and a reduction in auditory input following salicylate treatment. The treated rats displayed more synaptic vesicles and longer postsynaptic density in the VCN than the control rats. We observed that the GAP-43 expression, predominantly from medial olivocochlear (MOC) neurons, was significantly up-regulated, and that BDNF- and Iba-1-immunoreactive cells were persistently decreased after salicylate administration. Furthermore, GFAP-immunoreactive astrocytes, which is associated with synaptic regrowth, was significantly increased in the treated groups. Our study revealed that reduced auditory nerve activity triggers synaptic outgrowth and hyperactivity in the VCN via a MOC neural feedback circuit. Structural synaptic modifications may be a reflexive process that compensates for the reduced auditory input after salicylate administration. However, massive increases in

  11. COMPARISON OF THE EFFECTS OF TWO AR ANTAGONISTS ON ANDROGEN DEPENDENT TISSUES WEIGHTS AND HORMONE LEVELS IN MALE RATS AND ON EXPRESSION OF THREE ANDROGEN DEPENDENT GENES IN THE VENTRAL PROSTATE

    EPA Science Inventory

    Comparison of the effects of two AR antagonists on tissue weights and hormone levels in male rats and on expression of three androgen dependent genes in the ventral prostate
    VS Wilson, CR Wood, GA Held, CS Lambright, JS Ostby, JR Furr, LE Gray Jr. US EPA, ORD, NHEERL, RTD, ...

  12. Effects of 2,4-dichlorophenoxyacetic acid on the ventral prostate of rats during the peri-pubertal, pubertal and adult stage.

    PubMed

    Pochettino, Arístides A; Hapon, María Belén; Biolatto, Silvana M; Madariaga, María José; Jahn, Graciela A; Konjuh, Cintia N

    2016-10-01

    The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is used on a wide variety of terrestrial and aquatic broadleaf weeds. 2,4-D has been shown to produce a wide range of adverse effects on animal and human health. The aim of the current study was to evaluate the effects of pre- and postnatal exposure to 2,4-D on rat ventral prostate (VP). Pregnant rats were exposed daily to oral doses of 70 mg/kg/day of 2,4-D from 16 days of gestation up to 23 days after delivery. Then, the treated groups (n = 8) were fed with a 2,4-D added diet until sacrificed by decapitation on postnatal day (PND) 45, 60, or 90. Morphometric studies were performed and androgen receptor (AR) protein levels in the VP were determined. AR, insulin-like growth factor-I (IGF-1) and insulin-like growth factor-I receptor (IGF-1R) mRNA expression in the VP along with testosterone (T), dihydroxytestosterone (DHT), growth hormone (GH) and IGF-1 serum levels were also determined to ascertain whether these parameters were differentially affected. Results of this study showed that 2,4-D exposure during gestation and until adulthood altered development of the prostate gland in male rats, delaying it at early ages while increasing its size in adults, indicate that 2,4-D could behave as endocrine disruptors (EDs). PMID:26759115

  13. Peripherally administered tetrahydrobiopterin increases in vivo tryptophan hydroxylase activity in the striatum after transplantation of fetal ventral mesencephalon in six hydroxydopamine lesioned rats.

    PubMed

    Ishida, Y; Todaka, K; Kuwahara, I; Hashiguchi, H; Ishizuka, Y; Nakane, H; Mitsuyama, Y

    1998-08-28

    The intraperitoneal administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4), a natural cofactor for tyrosine hydroxylase and tryptophan hydroxylase (TRH), dose-dependently increased the extracellular concentration of 6R-BH4 itself in rat striatum. The concentration was investigated by in vivo microdialysis and measured simultaneously with 5-hydroxytryptophan (5-HTP), a precursor of serotonin, by high performance liquid chromatography with electrochemical detection. The 6R-BH4 (50 mg/kg, i.p.) administration increased the accumulation of 5-HTP as an index of in vivo TRH activity under the inhibition of aromatic L-amino acid decarboxylase by NSD-1015 in the striatum of both normal control and 6-hydroxydopamine lesioned rats with intrastriatal transplants of fetal ventral mesencephalon (VM). The results suggest that TRH in the striatum of both control and VM-grafted rats is activated by 6R-BH4 penetrating into the brain from the blood. PMID:9754801

  14. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis – effects on anxiety behavior in postpartum and virgin female rats

    PubMed Central

    Smith, Carl D.; Piasecki, Christopher C.; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S.

    2014-01-01

    Emotional hyper-reactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams’ anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine’s anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams’ anxiety, and that BSTv α2-autoreceptor modulation alone has little influence anxiety-related behaviors in postpartum or diestrous rats. PMID:23796237

  15. Sex differences in neurotensin and substance P following nicotine self-administration in rats.

    PubMed

    Pittenger, Steven T; Swalve, Natashia; Chou, Shinnyi; Smith, Misty D; Hoonakker, Amanda J; Pudiak, Cindy M; Fleckenstein, Annette E; Hanson, Glen R; Bevins, Rick A

    2016-08-01

    Investigator-administered nicotine alters neurotensin and substance P levels in Sprague-Dawley rats. This finding suggested a role of the dopamine-related endogenous neuropeptides in nicotine addiction. We sought to extend this observation by determining the responses of neurotensin and substance P systems (assessed using radioimmunoassay) in male and female rats following nicotine self-administration (SA). Male and female Sprague-Dawley were trained to self-administer nicotine, or receive saline infusions yoked to a nicotine-administering rat during daily sessions (1-h; 21 days). Brains were extracted 3 h after the last SA session. Nicotine SA increased tissue levels of neurotensin in the males in the anterior and posterior caudate, globus pallidus, frontal cortex, nucleus accumbens core and shell, and ventral tegmental area. Nicotine SA also increased tissue levels of neurotensin in the females in the anterior caudate, globus pallidus, nucleus accumbens core and shell, but not in the posterior caudate, frontal cortex, or ventral tegmental area. There were fewer sex differences observed in the substance P systems. Nicotine SA increased tissue levels of substance P in both the males and females in the posterior caudate, globus pallidus, frontal cortex, nucleus accumbens shell, and ventral tegmental area. A sex difference was observed in the nucleus accumbens core, where nicotine SA increased tissue levels of substance P in the males, yet decreased levels in the females. The regulation of neuropeptides following nicotine SA may play a role in the susceptibility to nicotine dependence in females and males. Synapse 70:336-346, 2016. © 2016 Wiley Periodicals, Inc. PMID:27074301

  16. Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease.

    PubMed

    Andereggen, Lukas; Meyer, Morten; Guzman, Raphael; Ducray, Angélique D; Widmer, Hans Rudolf

    2009-06-18

    Transplantation of fetal dopaminergic (DA) neurons offers an experimental therapy for Parkinson's disease (PD). The low availability and the poor survival and integration of transplanted cells in the host brain are major obstacles in this approach. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with growth- and survival-promoting capabilities for developing DA neurons. In the present study, we examined whether pretreatment of ventral mesencephalic (VM) free-floating roller tube (FFRT) cultures with GDNF would improve graft survival and function. For that purpose organotypic cultures of E14 rat VM were grown for 2, 4 or 8 days in the absence (control) or presence of GDNF [10 ng/ml] and transplanted into the striatum of 6-hydroxydopamine-lesioned rats. While all groups of rats showed a significant reduction in d-amphetamine-induced rotations at 6 weeks posttransplantation a significantly improved graft function was observed only in the days in vitro (DIV) 4 GDNF pretreated group compared to the control group. In addition, no statistical significant differences between groups were found in the number of surviving tyrosine hydroxylase-immunoreactive (TH-ir) neurons assessed at 9 weeks posttransplantation. However, a tendency for higher TH-ir fiber outgrowth from the transplants in the GDNF pretreated groups as compared to corresponding controls was observed. Furthermore, GDNF pretreatment showed a tendency for a higher number of GIRK2 positive neurons in the grafts. In sum, our findings demonstrate that GDNF pretreatment was not disadvantageous for transplants of embryonic rat VM with the FFRT culture technique but only marginally improved graft survival and function. PMID:19389387

  17. Tegmental defects and cerebrospinal fluid otorrhea.

    PubMed

    Valtonen, H; Geyer, C; Tarlov, E; Heilman, C; Poe, D

    2001-01-01

    Congenital tegmental defects that present as unsuspected cerebrospinal fluid (CSF) otorrhea are diagnostic and therapeutic challenges. We reviewed 5 such patients to determine an optimal strategy for evaluation. Five patients presented with watery otorrhea, 4 of them after ventilation tube placement, and only 1 with rhinorrhea. The preoperative analysis of middle ear effusion for beta(2)-transferrin was positive in 2/4, equivocal in 1/4 and false negative in 1/4. Computerized tomography (CT) revealed nonspecific tegmental defects in all 5 patients. Magnetic resonance imaging (MRI) demonstrated meningoencephalocele in 3/5 and dural irregularity in 1/5. Tegmental defects were confirmed at surgery in all cases, demonstrating meningocele or arachnoid granulations in 2/5 and encephalocele in 2/5 patients. We recommend a combination of beta(2)-transferrin analysis to verify CSF, high resolution CT (axial and coronal planes) to diagnose tegmental defects, and MRI (multiplanar) to evaluate the type of herniation. A combination mastoid and middle fossa approach for definitive repair is suggested. PMID:11174062

  18. The ventral tegmentum and dopamine: A new wave of diversity.

    PubMed

    Barrot, M

    2014-12-12

    Projection systems arising from the ventral tegmental area (VTA) and the substantia nigra (SN) have a critical role in a broad range of functions, as well as in the etiology, symptoms and treatment of neurological and psychiatric diseases. Mostly studied for its dopamine neurons, the ventral tegmentum is in fact heterogeneous at cellular and functional levels. This special issue of Neuroscience gathered some experts in the field to review the connectivity of the ventral mesencephalic dopaminergic complex, its cellular heterogeneity with attention given to glutamate neurons, the D2 autoreceptor and the cholinergic controls of dopamine activity, the influence of neurotrophins, the controls of bursting activity and the heterogeneity of neuronal activity across traits and states, the pedunculopontine tegmental and the sensory controls of dopamine activity, the sex-dependent diversity, the links between circadian and dopamine systems, the functional antero-posterior heterogeneity of the VTA and the role of its GABA tail (tVTA/rostromedial tegmental nucleus (RMTg)), the functional heterogeneity of the VTA outputs, the place of dopamine in cortico-basal ganglia circuitry, the different roles of the D1 and D2 striatal pathways and the role of dopamine in associative learning and memory. Recent progress also highlights the need for molecular markers of functional subpopulations within the ventral tegmentum, for deeper developmental knowledge of this region, and for a single cell level of connectomic. It also raises the question of inter-individual, sex, strain and species heterogeneity, and conversely the question of data generalization in a context of human pathology models, which warrant comparative studies and translational effort. PMID:25453764

  19. Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.

    PubMed

    Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

    2016-06-01

    Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development. PMID:27090561

  20. Blood oxygenation level-dependent response to intragastric load of corn oil emulsion in conscious rats.

    PubMed

    Tsurugizawa, Tomokazu; Uematsu, Akira; Uneyama, Hisayuki; Torii, Kunio

    2009-12-01

    The postingestive actions after intragastric or oronasal stimulation of fat have been well investigated. The blood oxygenation level-dependent (BOLD) signal changes, however, after intragastric load of corn oil emulsion have yet to be elucidated. Here, using functional magnetic resonance imaging, we investigated the BOLD signal response to gut corn oil emulsion in nonanesthetized rats. Intragastrically infused 7% corn oil emulsion induced a BOLD signal increase in several brain regions, including the bilateral amygdala, hippocampus and the ventral tegmental area. These results indicate that the limbic system responds to gut corn oil emulsion and that activation of this system could promote the reinforcing action for food with high fat content. PMID:19918206

  1. Enhanced consumption of salient solutions following pedunculopontine tegmental lesions

    PubMed Central

    MacLaren, Duncan AA; Markovic, Tamara; Daniels, Derek; Clark, Stewart D

    2014-01-01

    Rats with lesions of the pedunculopontine tegmental nucleus (PPTg) reliably overconsume high concentration sucrose solution. This effect is thought to be indicative of response-perseveration or loss of behavioral control in conditions of high excitement. While these theories have anatomical and behavioral support, they have never been explicitly tested. Here, we used a contact lickometer to examine the microstructure of drinking behavior to gain insight into the behavioral changes during overconsumption. Rats received either excitotoxic (ibotenic acid) damage to all PPTg neuronal subpopulations or selective depletion of the cholinergic neuronal sub-population (Dtx-UII lesions). We offered rats a variety of pleasant, neutral and aversive tastants to assess the generalizability and specificity of the overconsumption effect. Ibotenic lesioned rats consumed significantly more 20% sucrose than sham controls, and did so through licking significantly more times. However, the behavioral microstructure during overconsumption was unaffected by the lesion and showed no indications of response-perseveration. Furthermore, the overconsumption effect did not generalize to highly consumed saccharin. In contrast, while only consuming small amounts of quinine solution, ibotenic lesioned rats had significantly more licks and bursts for this tastant. Selective depletion of cholinergic PPTg neurons had no effect on consumption of any tastant. We then assessed whether it is the salience of the solution which determines overconsumption by ibotenic lesioned rats. While maintained on free-food, ibotenic lesioned rats had normal consumption of sucrose and hypertonic saline. After mild food deprivation ibotenic PPTg lesioned rats overconsumed 20% sucrose. Subsequently, after dietary induced sodium deficiency, lesioned rats consumed significantly more saline than controls. These results establish that it is the salience of the solution which is the determining factor leading to

  2. The effect of chronic L-dopa treatment on the recovery of motor function in 6-hydroxydopamine-lesioned rats receiving ventral mesencephalic grafts.

    PubMed

    Blunt, S; Jenner, P; Marsden, C D

    1991-01-01

    The effect of treatment for 5 weeks with L-DOPA (200 mg/kg/24 h) plus carbidopa (25 mg/kg/24 h) on the behavioral recovery produced by rat fetal ventral mesencephalon grafts implanted into the striatum of 6-hydroxydopamine-lesioned rats was assessed. Animals with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway and a sham graft (Group A) showed persistent high rates of rotation in response to the administration of apomorphine (0.5 mg/kg, s.c.) (contralateral rotation) or (+)-amphetamine (5 mg/kg, i.p.) (ipsilateral rotation). Treatment of sham-grafted animals with L-DOPA plus carbidopa had no effect on the rate of rotation to apomorphine or (+)-amphetamine (Group B). The proportion of animals showing marked stereotypy following apomorphine administration was greater in sham-grafted animals receiving L-DOPA and carbidopa than in sham-grafted animals alone. Animals receiving unilateral 6-hydroxydopamine lesions followed by a fetal graft (Group C) showed a reduction in apomorphine-induced contralateral rotation and a complete reversal of (+)-amphetamine-induced ipsilateral rotation when assessed 6 weeks later. The reductions in apomorphine- and (+)-amphetamine-induced rotational behaviour produced by the fetal graft in animals with a 6-hydroxydopamine lesion were not altered by treatment with L-DOPA plus carbidopa (Group D). The proportion of animals showing marked apomorphine-induced stereotypy did not change significantly in either group over time. In rats with a unilateral 6-hydroxydopamine lesion receiving fetal dopamine grafts, treatment with high doses of L-DOPA and carbidopa for 5 weeks does not have a detrimental effect on the functional activity of the grafts as assessed by reduction of apomorphine- and (+)-amphetamine-induced motor asymmetry. The continuation of L-DOPA therapy may not adversely affect fetal graft survival and growth in patients with Parkinson's disease. PMID:1902916

  3. [Organization of the pallidal projections of the rostromedial tegmental nucleus in the dog brain].

    PubMed

    Gorbachevskaya, A I

    2014-01-01

    The method of retrograde and anterograde transport of horse-radish peroxidase was used to study the organization of the projections of the rostromedial tegmental nucleus (RMTN) to functionally distinct regions of pallidal structures of brain in dogs (n = 13). It was found that the fibers formed by the neurons of the limbic medial segments of RMTN rostral and caudal regions projected to the limbic pallidal regions--ventral globus pallidus and ventral pallidum. The reciprocal projections were detected between the ventral pallidum and medial segment of the rostral RMTN. These data indicate the possibility of the segregated conduction of the limbic information in the examined projection systems. However, in the majority of the pallidal structures, the convergence of the projection fibers originating from the neurons of functionally different parts of RMTN was observed. Thus, the projection fibers formed by the neurons of motor lateral and limbic medial parts of RMTN are directed to the limbic ventral segment of the globus pallidus and to the entopeduncular nucleus, which is innervated by the fibers formed by the neurons of functionally diverse structures. The possible pathways for conduction of functionally different information and its integration in the projection systems investigated are discussed. PMID:25823285

  4. [Combined effects of testosterone and estradiol on the ventral lobe of the rat postate in organ culture].

    PubMed

    Feyel-Cabanes, T; Robel, P; Baulieu, E E

    1977-10-31

    After organ culture without hormone, the epithelial gland cells of Rat veantral prostate undergo atrophic changes, whereas the interstitial stroma components tend to increase. Estradiol (1-1,000 nM),added to the culture medium, is ineffective. On the contrary, testosterone (1-100 nM) maintains epithelial cells and prevents the increase of interstitial stroma. When estradiol (1-1,000 nM) is combined with a physiological concentration of testosterone (1-4 nM), the epithelial cells are well maintained, but the inhibitory action of testosterone on the stroma is counteracted so that the glandular epithelium and the interstitial stroma are both stimulated. However, when testosterone is used at supraphysiological (10-100 nM) concentrations, estradiol is completely ineffective and the structure of the prostate is identical to the one given by the androgen alone. PMID:413648

  5. The vasopressinergic innervation of the brain in normal and castrated rats.

    PubMed

    DeVries, G J; Buijs, R M; Van Leeuwen, F W; Caffé, A R; Swaab, D F

    1985-03-01

    A detailed description is given of the distribution of vasopressin-immunoreactive structures in the brain of intact adult male rats. By application of a modified immunocytochemical procedure, vasopressin-immunoreactive fibers were detected in many new areas. In adult male rats which were castrated 15 weeks before death, vasopressin-immunoreactive cell bodies had disappeared from the bed nucleus of the stria terminalis and the medial amygdaloid nucleus. No obvious changes were found in vasopressin-immunoreactive cell bodies in other areas. Furthermore, a very strong reduction was seen in the density of vasopressin-immunoreactive fibers in the olfactory tubercle, nucleus of the diagonal band and its immediate surroundings, ventral pallidum, basal nucleus of Meynert, lateral septum, septofimbrial nucleus, ventral hippocampal formation, amygdaloid area, pre- and supramammillary nucleus, supramammillary decussation, (inter)dorsomedial, parafascicular, and ventral aspect of paraventricular thalamic nuclei, zona incerta, lateral habenular nucleus, ventral tegmental area, substantia nigra, periventricular gray, dorsal and median raphe nucleus, and locus coeruleus. No changes were observed in other areas containing vasopressin-immunoreactive fibers. These changes following gonadectomy were not observed in castrated rats which had been treated with testosterone. The results suggest that vasopressin projections from the bed nucleus of the stria terminalis and possibly from the medial amygdaloid nucleus require the presence of gonadal hormones for their normal appearance. This is in contrast to pathways arising from the hypothalamic vasopressin-producing nuclei, which fail to show obvious changes following castration. PMID:3882778

  6. Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn

    PubMed Central

    Leszczyńska, Anna N.; Majczyński, Henryk; Wilczyński, Grzegorz M.; Sławińska, Urszula; Cabaj, Anna M.

    2015-01-01

    Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3–4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers. PMID

  7. The role of nicotinic acetylcholine and opioid systems of the ventral orbital cortex in modulation of formalin-induced orofacial pain in rats.

    PubMed

    Yousofizadeh, Shahnaz; Tamaddonfard, Esmaeal; Farshid, Amir Abbas

    2015-07-01

    Nicotinic acetylcholine and opioid receptors are involved in modulation of pain. In the present study, we investigated the effects of microinjection of nicotinic acetylcholine and opioid compounds into the ventral orbital cortex (VOC) on the formalin-induced orofacial pain in rats. For this purpose, two guide cannulas were placed into the left and right sides of the VOC of the brain. Orofacial pain was induced by subcutaneous injection of a diluted formalin solution (50μl, 1.5%) into the right vibrissa pad and face rubbing durations were recorded at 3-min blocks for 45min. Formalin produced a marked biphasic pain response (first phase: 0-3min and second phase: 15-33min). Epibatidine (a nicotinic receptor agonist) at doses of 0.05, 0.1 and 0.2μg/site, morphine (an opioid receptor agonist) at doses of 0.5, 1 and 2μg/site and their sub-analgesic doses (0.025μg/site epibatidine with 0.25μg/site morphine) combination treatment suppressed the second phase of pain. The antinociceptive effect induced by 0.2μg/site of epibatidine, but not morphine (2μg/site), was prevented by 2μg/site of mecamylamine (a nicotinic receptor antagonist). Naloxone (an opioid receptor antagonist) at a dose of 2μg/site prevented the antinociceptive effects induced by 2μg/site of morphine and 0.2μg/site of epibatidine. No above-mentioned chemical compounds affected locomotor activity. These results showed that at the VOC level, epibatidine and morphine produced antinociception. In addition, opioid receptor might be involved in epibatidine-induced antinociception, but the antinociception induced by morphine was not mediated through nicotinic acetylcholine receptor. PMID:25864612

  8. Somatostatin 2a receptors are not expressed on functionally identified respiratory neurons in the ventral respiratory column of the rat.

    PubMed

    Le, Sheng; Turner, Anita J; Parker, Lindsay M; Burke, Peter G; Kumar, Natasha N; Goodchild, Ann K; McMullan, Simon

    2016-05-01

    Microinjection of somatostatin (SST) causes site-specific effects on respiratory phase transition, frequency, and amplitude when microinjected into the ventrolateral medulla (VLM) of the anesthetized rat, suggesting selective expression of SST receptors on different functional classes of respiratory neurons. Of the six subtypes of SST receptor, somatostatin 2a (sst2a ) is the most prevalent in the VLM, and other investigators have suggested that glutamatergic neurons in the preBötzinger Complex (preBötC) that coexpress neurokinin-1 receptor (NK1R), SST, and sst2a are critical for the generation of respiratory rhythm. However, quantitative data describing the distribution of sst2a in respiratory compartments other than preBötC, or on functionally identified respiratory neurons, is absent. Here we examine the medullary expression of sst2a with particular reference to glycinergic/expiratory neurons in the Bötzinger Complex (BötC) and NK1R-immunoreactive/inspiratory neurons in the preBötC. We found robust sst2a expression at all rostrocaudal levels of the VLM, including a large proportion of catecholaminergic neurons, but no colocalization of sst2a and glycine transporter 2 mRNA in the BötC. In the preBötC 54% of sst2a -immunoreactive neurons were also positive for NK1R. sst2a was not observed in any of 52 dye-labeled respiratory interneurons, including seven BötC expiratory-decrementing and 11 preBötC preinspiratory neurons. We conclude that sst2a is not expressed on BötC respiratory neurons and that phasic respiratory activity is a poor predictor of sst2a expression in the preBötC. Therefore, sst2a is unlikely to underlie responses to BötC SST injection, and is sparse or absent on respiratory neurons identified by classical functional criteria. J. Comp. Neurol. 524:1384-1398, 2016. © 2015 Wiley Periodicals, Inc. PMID:26470751

  9. Dismantling the Papez circuit for memory in rats

    PubMed Central

    Vann, Seralynne D

    2013-01-01

    Over the last 50 years, anatomical models of memory have repeatedly highlighted the hippocampal inputs to the mammillary bodies via the postcommissural fornix. Such models downplay other projections to the mammillary bodies, leaving them largely ignored. The present study challenged this dominant view by removing, in rats, the two principal inputs reaching the mammillary bodies: the postcommissural fornix from the hippocampal formation and Gudden's ventral tegmental nucleus. The principal mammillary body output pathway, the mammillothalamic tract, was disconnected in a third group. Only mammillothalamic tract and Gudden's ventral tegmental nucleus lesions impaired behavioral tests of spatial working memory and, in particular, disrupted the use of extramaze spatial landmarks. The same lesions also produced widespread reductions in immediate-early gene (c-fos) expression in a network of memory-related regions, not seen after postcommissural fornix lesions. These findings are inconsistent with previous models of mammillary body function (those dominated by hippocampal inputs) and herald a new understanding of why specific diencephalic structures are vital for memory. DOI: http://dx.doi.org/10.7554/eLife.00736.001 PMID:23805381

  10. Pontomesencephalic Tegmental Afferents to VTA Non-dopamine Neurons Are Necessary for Appetitive Pavlovian Learning.

    PubMed

    Yau, Hau-Jie; Wang, Dong V; Tsou, Jen-Hui; Chuang, Yi-Fang; Chen, Billy T; Deisseroth, Karl; Ikemoto, Satoshi; Bonci, Antonello

    2016-09-01

    The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning. PMID:27568569

  11. Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum

    PubMed Central

    Kaag, Anne Marije; Schluter, Renée S.; Karel, Peter; Homberg, Judith; van den Brink, Wim; Reneman, Liesbeth; van Wingen, Guido A.

    2016-01-01

    Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula. PMID:27594829

  12. Brain-wide map of projections from mice ventral subiculum.

    PubMed

    Tang, He; Wu, Gui-Sheng; Xie, Jing; He, Xiaobin; Deng, Ke; Wang, Huadong; Xu, Fuqiang; Luo, Huai-Rong

    2016-08-26

    The hippocampal formation plays a critical role in episodic memory formation and spatial navigation. Within the hippocampus, the subiculum is considered to be a hub connecting the hippocampal formation to the remainder of the brain. There are functional differences between the dorsal and ventral part of subiculum, while the ventral subiculum (vSub) plays a role in anxiety, stress and emotion. In the present study, we examined the projection of the ventral subiculum to the whole brain in mice by using a modified herpes simplex virus 1 strain H129 with an inserted fluorescent protein gene. In our experiments, the modified H129 transits the primary-order, second-order, and third-order neuronal projections at 36-44, 52-60 and 68-76h after inoculation in mice, respectively. Our data revealed that vSub directly projects to the medial entorhinal cortex, amygdalohippocampal area, anterodorsal thalamic nucleus, medial hypothalamus, supramammillary nucleus, medial septal nucleus and adjacent diagonal band, the connections between median raphe nucleus and interpeduncular nucleus in brain stem, while ventral prefrontal cortex, laterodorsal tegmental nucleus and locus coeruleus receives second-order projections from vSub. Our data would help further understanding the functional connections of vSub with other brain regions. PMID:27422730

  13. Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum.

    PubMed

    Kaag, Anne Marije; Schluter, Renée S; Karel, Peter; Homberg, Judith; van den Brink, Wim; Reneman, Liesbeth; van Wingen, Guido A

    2016-01-01

    Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula. PMID:27594829

  14. Laparoscopic Ventral Hernia Repair

    MedlinePlus

    ... the likelihood of a hernia including persistent coughing, difficulty with bowel movements or urination, or frequent need for straining. What are the Advantages of Laparoscopic Ventral Hernia Repair? Keep reading... Page 1 of 2 1 2 » Brought to ...

  15. Impact of prenatal nicotine on the structure of midbrain dopamine regions in the rat.

    PubMed

    Omelchenko, Natalia; Roy, Priya; Balcita-Pedicino, Judith Joyce; Poloyac, Samuel; Sesack, Susan R

    2016-05-01

    In utero exposure of rats to nicotine (NIC) provides a useful animal model for studying the impact of smoking during pregnancy on human offspring. Certain sequelae of prenatal NIC exposure suggest an impact on the development of the midbrain dopamine (DA) system, which receives a robust cholinergic innervation from the mesopontine tegmentum. We therefore investigated whether prenatal NIC induced structural changes in cells and synapses within the midbrain that persisted into adulthood. Osmotic minipumps delivering either sodium bitartrate (vehicle; VEH) or NIC bitartrate at 2 mg/kg/day were implanted into nine timed-pregnant dams at E4. At birth, rat pups were culled to litters of six males each, and the litters were cross-fostered. Plasma levels of NIC and cotinine from killed pups provided evidence of NIC exposure in utero. Pups separated from dams at weaning showed a trend toward reduced locomotor activity at this time point but not when tested again in adulthood. Adult rats were killed for anatomical studies. Estimates of brain size and volume did not vary with NIC treatment. Midbrain sections stained for Nissl or by immunoperoxidase for tyrosine hydroxylase and analyzed using unbiased stereology revealed no changes in volume or cell number in the substantia nigra compacta or ventral tegmental area as a result of NIC exposure. Within the ventral tegmental area, electron microscopic physical disector analysis showed no significant differences in the number of axon terminals or the number of asymmetric (putative excitatory) or symmetric (putative inhibitory) synapses. Although too infrequent to estimate by unbiased stereology, no obvious difference in the proportion of cholinergic axons was noted in NIC- versus VEH-treated animals. These data suggest that activation of nicotinic receptors during prenatal development induces no significant modifications in the structure of cells in the ventral midbrain when assessed in adulthood. PMID:25716298

  16. Gudden's Ventral Tegmental Nucleus Is Vital for Memory: Re-Evaluating Diencephalic Inputs for Amnesia

    ERIC Educational Resources Information Center

    Vann, Seralynne D.

    2009-01-01

    Mammillary body atrophy is present in a number of neurological conditions and recent clinical findings highlight the importance of these nuclei for memory. While most accounts of diencephalic amnesia emphasize the functional importance of the hippocampal projections to the mammillary bodies, the present study tested the importance of the other…

  17. Nicotinic Cholinergic Synaptic Mechanisms in the Ventral Tegmental Area Contribute to Nicotine Addiction

    ERIC Educational Resources Information Center

    Pidoplichko, Volodymyr I.; Noguchi, Jun; Areola, Oluwasanmi O.; Liang, Yong; Peterson, Jayms; Zhang, Tianxiang; Dani, John A.

    2004-01-01

    Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic…

  18. Previous ethanol experience enhances synaptic plasticity of NMDA receptors in the ventral tegmental area.

    PubMed

    Bernier, Brian E; Whitaker, Leslie R; Morikawa, Hitoshi

    2011-04-01

    Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP(3)) in producing facilitation of action potential-evoked Ca(2+) signals, which is critical for LTP induction. This increase in IP(3) effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP(3) effect in ethanol-treated mice. Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons. PMID:21471355

  19. Autoradiographic distribution of /sup 125/I-galanin binding sites in the rat central nervous system

    SciTech Connect

    Skofitsch, G.; Sills, M.A.; Jacobowitz, D.M.

    1986-11-01

    Galanin (GAL) binding sites in coronal sections of the rat brain were demonstrated using autoradiographic methods. Scatchard analysis of /sup 125/I-GAL binding to slide-mounted tissue sections revealed saturable binding to a single class of receptors with a Kd of approximately 0.2 nM. /sup 125/I-GAL binding sites were demonstrated throughout the rat central nervous system. Dense binding was observed in the following areas: prefrontal cortex, the anterior nuclei of the olfactory bulb, several nuclei of the amygdaloid complex, the dorsal septal area, dorsal bed nucleus of the stria terminalis, the ventral pallidum, the internal medullary laminae of the thalamus, medial pretectal nucleus, nucleus of the medial optic tract, borderline area of the caudal spinal trigeminal nucleus adjacent to the spinal trigeminal tract, the substantia gelatinosa and the superficial layers of the dorsal spinal cord. Moderate binding was observed in the piriform, periamygdaloid, entorhinal, insular cortex and the subiculum, the nucleus accumbens, medial forebrain bundle, anterior hypothalamic, ventromedial, dorsal premamillary, lateral and periventricular thalamic nuclei, the subzona incerta, Forel's field H1 and H2, periventricular gray matter, medial and superficial gray strata of the superior colliculus, dorsal parts of the central gray, peripeduncular area, the interpeduncular nucleus, substantia nigra zona compacta, ventral tegmental area, the dorsal and ventral parabrachial and parvocellular reticular nuclei. The preponderance of GAL-binding in somatosensory as well as in limbic areas suggests a possible involvement of GAL in a variety of brain functions.

  20. Lesions in Guddesn's tegmental nuclei produce behavioral and 5-HT effects similar to those after raphe lesions.

    PubMed

    Lorens, S A; Köhler, C; Guldberg, H C

    1975-01-01

    Lesions largely restricted to the dorsal and ventral tegmental nuclei of Gudden (GTN) produced several effects similar to those seen after midbrain raphe lesions. GTN lesions significantly reduced the 5-hydroxytryptamine (5-HT) concentration of the diencephalon (31 percent), hippocampus (59 percent), and remaining portion of the telencephalon (29 percent). Striatal 5-HT, however, was not affected. GTN lesions enhanced activity in an enclosed field and facilitated two-way avoidance acquisition. Pain sensitivity as measured by the flinch-jump method was not affected. These results suggest that the GTN may be the origin of ascending 5-HT fides and may be involved in the regulation of activity level and the adaptation of an animal to aversive situations. Thus, some of the behavioral and 5-HT effects of lesions in the midbrain raphe nuclei may be due to their involvement of the GTN and associated pathways. PMID:1187729

  1. Projections from the mesopontine tegmental anesthesia area to regions involved in pain modulation.

    PubMed

    Sukhotinsky, I; Reiner, K; Govrin-Lippmann, R; Belenky, M; Lu, J; Hopkins, D A; Saper, C B; Devor, M

    2006-12-01

    Pentobarbital microinjected into a restricted locus in the upper brainstem induces a general anesthesia-like state characterized by atonia, loss of consciousness, and pain suppression as assessed by loss of nocifensive response to noxious stimuli. This locus is the mesopontine tegmental anesthesia area (MPTA). Although anesthetic agents directly influence spinal cord nociceptive processing, antinociception during intracerebral microinjection indicates that they can also act supraspinally. Using neuroanatomical tracing methods we show that the MPTA has multiple descending projections to brainstem and spinal areas associated with pain modulation. Most prominent is a massive projection to the rostromedial medulla, a nodal region for descending pain modulation. Together with the periaqueductal gray (PAG), the MPTA is the major mesopontine input to this region. Less dense projections target the PAG, the locus coeruleus and pericoerulear areas, and dorsal and ventral reticular nuclei of the caudal medulla. The MPTA also has modest direct projections to the trigeminal nuclear complex and to superficial layers of the dorsal horn. Double anterograde and retrograde labeling at the light and electron microscopic levels shows that MPTA neurons with descending projections synapse directly on spinally projecting cells of rostromedial medulla. The prominence of the MPTA's projection to the rostromedial medulla suggests that, like the PAG, it may exert antinociceptive actions via this bulbospinal relay. PMID:17049433

  2. Dextromethorphan increases tyrosine hydroxylase mRNA in the mesencephalon of adolescent rats.

    PubMed

    Zhang, T Y; Jahng, J W; Kim, D G

    2001-08-24

    Dextromethorphan (DM), an antitussive widely available in over-the-counter, has been abused mostly in teenage groups at high doses. To examine effects of DM on the reward pathway, we injected a high dose of DM (40 mg/kg; intraperitoneally) into the adolescent rat and measured tyrosine hydroxylase (TH) mRNA by in situ hybridization in the ventral tegmental area (VTA) and the substantia nigra (SN). Remarkable increases in the level of TH mRNA were observed in the VTA and SN 2 h after DM injection. Stereotyped behavior and ataxia increased, and rearing decreased by DM administration. These results suggest that DM-induced increase in TH mRNA expression in mesencephalon contribute to the reinforcing property and the behavioral effects of DM. PMID:11502351

  3. Cholinergic projections to the substantia nigra from the pedunculopontine and laterodorsal tegmental nuclei.

    PubMed

    Gould, E; Woolf, N J; Butcher, L L

    1989-01-01

    The cholinergic innervation of the compact and reticular parts of the substantia nigra in the rat was investigated by use of highly sensitive retrograde and anterograde tract-tracing methods in combination with choline acetyltransferase immunohistochemistry. The fluorescent tracers True Blue, propidium iodide, or fluorogold were infused preferentially into either nigral subnucleus. Cells positive for choline acetyltransferase and retrograde tracer were found in both the pedunculopontine and laterodorsal tegmental nuclei, although considerably more double-labeled somata were observed in the former than in the latter component of the pontomesencephalotegmental cholinergic complex. Approximately 2-3 times more cholinergic cells were labeled in the peduculopontine and laterodorsal tegmental nuclei when tracer injections were centered in the compact nigral subdivision than when infusions of about the same size were confined totally to the reticular part. Infusions of the anterogradely transported tracer Phaseolus vulgaris leucoagglutinin into the pontomesencephalotegmental cholinergic complex resulted in uptake and transport of that label to both nigral subnuclei, and some of the Phaseolus vulgaris leucoagglutinin-accumulating somata and proximal processes also demonstrated choline acetyltransferase-like immunoreactivity. The Phaseolus vulgaris agglutinin-labeled entities in the substantia nigra exhibited terminal-like profiles that were reminiscent of the pattern of nigral choline acetyltransferase-positive puncta demonstrated immunohistochemically by use of nickel ammonium sulfate enhancement of the final reaction product in the avidin-biotin procedure. These observations strongly support the contention that the pontomesencephalotegmental cholinergic complex is the major source of cholinergic projections to both the compact and reticular portions of the rat substantia nigra. PMID:2710334

  4. Functional redundancy of ventral spinal locomotor pathways.

    PubMed

    Loy, David N; Magnuson, David S K; Zhang, Y Ping; Onifer, Stephen M; Mills, Michael D; Cao, Qi-lin; Darnall, Jessica B; Fajardo, Lily C; Burke, Darlene A; Whittemore, Scott R

    2002-01-01

    Identification of long tracts responsible for the initiation of spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. Pathways derived from the mesencephalic locomotor region and pontomedullary medial reticular formation responsible for fictive locomotion in decerebrate preparations project to the thoracolumbar levels of the spinal cord via reticulospinal axons in the ventrolateral funiculus (VLF). However, white matter regions critical for spontaneous over-ground locomotion remain unclear because cats, monkeys, and humans display varying degrees of locomotor recovery after ventral SCIs. We studied the contributions of myelinated tracts in the VLF and ventral columns (VC) to spontaneous over-ground locomotion in the adult rat using demyelinating lesions. Animals received ethidium bromide plus photon irradiation producing discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, VC, VLF-VC, or complete ventral white matter (CV). Behavior [open-field Basso, Beattie, and Bresnahan (BBB) scores and grid walking] and transcranial magnetic motor-evoked potentials (tcMMEP) were studied at 1, 2, and 4 weeks after lesion. VLF lesions resulted in complete loss or severe attenuation of tcMMEPs, with mean BBB scores of 18.0, and no grid walking deficits. VC lesions produced behavior similar to VLF-lesioned animals but did not significantly affect tcMMEPs. VC-VLF and CV lesions resulted in complete loss of tcMMEP signals with mean BBB scores of 12.7 and 6.5, respectively. Our data support a diffuse arrangement of axons within the ventral white matter that may comprise a system of multiple descending pathways subserving spontaneous over-ground locomotion in the intact animal. PMID:11756515

  5. Ventral horn cell responses to spaceflight and hindlimb suspension

    NASA Technical Reports Server (NTRS)

    Jiang, Bian; Roy, Roland R.; Poliakov, I. V.; Krasnov, I. B.; Edgerton, V. R.

    1992-01-01

    Ventral horn cells of the lumbosacral enlargement of the spinal cord were studied focusing on the succinate dehydrogenase (SDH) activity and cross-sectional area of the soma of ventral horn cells which were measured using a computer-aided image-processing system. The relationships between the soma size and SDH activities of lumber ventral horn cells after 14 days of spaceflight (Cosmos 2044) or of hindlimb suspension are considered. Three groups of rats under consideration include control, 14-day spaceflight, and 14-day hindlimb suspension. Data obtained indicate that, compared to the control group, the population distribution of SDH activities in the flight rats shifted toward higher activities, whereas in the suspended rats the distribution shifted toward lower activities. The interactive effects within individual cells showed that there was a higher percentage of small cells with high SDH activities in the flight than in the control or suspended rats. It is suggested that changes in ventral horn cells were due to factors other than simply the absence of weight support.

  6. [Neurochemical mechanisms of depression-like behavior in WAG/Rij rats].

    PubMed

    Sarkisova, K Iu; Kulikov, M A; Kudrin, V S; Narkevich, V B; Midzianovskaia, I S; Biriukova, L M; Folomkina, A A; Basian, A S

    2013-01-01

    Behavior in the light-dark choice, open-field, sucrose consumption/preference and forced swimming tests, monoamines and their metabolites level in 6 brain structures (prefrontal cortex, nucleus accumbens, striatum, hypothalamus, hippocampus, amygdala), and density of D2-like dopamine receptors in 21 brain regions were studied in WAG/Rij and Wistar rats. WAG/Rij rats exhibited symptoms of depression-like behavior such as increased immobility in the forced swim test and decreased sucrose consumption/preference (anhedonia). Substantial changes in behavior indicating increased anxiety in WAG/Rij rats were not revealed. Neurochemical abnormalities suggesting hypofunction of the mesolimbic dopaminergic brain system were found in "depressive" WAG/Rij rats compared with "normal" Wistar rats: decreased levels of noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine in the nucleus accumbens, and increased density of D2-like dopamine receptors in the nucleus accumbens and ventral tegmental area. Reduced levels of dopamine were also observed in the prefrontal cortex and striatum. No substantial changes in the content of monoamines and their metabolites have been revealed in the hypothalamus, hippocampus and amygdala as well as in the content ofserotonin and its metabolite 5-hydroxyindolacetic acid in all studied brain structures with the exception of increased level ofserotonin in the amygdala. Results suggest that hypofunction of the mesolimbic dopaminergic brain system (nucleus accumbens) is a neurochemical mechanism of depression-like behavior in WAG/Rij rats. PMID:24450162

  7. Differential Effects of Dopaminergic Therapies on Dorsal and Ventral Striatum in Parkinson's Disease: Implications for Cognitive Function

    PubMed Central

    MacDonald, Penny A.; Monchi, Oury

    2011-01-01

    Cognitive abnormalities are a feature of Parkinson's disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment. PMID:21437185

  8. Peripheral vagus nerve stimulation significantly affects lipid composition and protein secondary structure within dopamine-related brain regions in rats.

    PubMed

    Surowka, Artur Dawid; Krygowska-Wajs, Anna; Ziomber, Agata; Thor, Piotr; Chrobak, Adrian Andrzej; Szczerbowska-Boruchowska, Magdalena

    2015-06-01

    Recent immunohistochemical studies point to the dorsal motor nucleus of the vagus nerve as the point of departure of initial changes which are related to the gradual pathological developments in the dopaminergic system. In the light of current investigations, it is likely that biochemical changes within the peripheral nervous system may influence the physiology of the dopaminergic system, suggesting a putative role for it in the development of neurodegenerative disorders. By using Fourier transform infrared microspectroscopy, coupled with statistical analysis, we examined the effect of chronic, unilateral electrical vagus nerve stimulation on changes in lipid composition and in protein secondary structure within dopamine-related brain structures in rats. It was found that the chronic vagal nerve stimulation strongly affects the chain length of fatty acids within the ventral tegmental area, nucleus accumbens, substantia nigra, striatum, dorsal motor nucleus of vagus and the motor cortex. In particular, the level of lipid unsaturation was found significantly increasing in the ventral tegmental area, substantia nigra and motor cortex as a result of vagal nerve stimulation. When it comes to changes in protein secondary structure, we could see that the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways are particularly affected by vagus nerve stimulation. This is due to the co-occurrence of statistically significant changes in the content of non-ordered structure components, alpha helices, beta sheets, and the total area of Amide I. Macromolecular changes caused by peripheral vagus nerve stimulation may highlight a potential connection between the gastrointestinal system and the central nervous system in rat during the development of neurodegenerative disorders. PMID:25893743

  9. Fast transmission from the dopaminergic ventral midbrain to the sensory cortex of awake primates.

    PubMed

    Mylius, Judith; Happel, Max F K; Gorkin, Alexander G; Huang, Ying; Scheich, Henning; Brosch, Michael

    2015-11-01

    Motivated by the increasing evidence that auditory cortex is under control of dopaminergic cell structures of the ventral midbrain, we studied how the ventral tegmental area and substantia nigra affect neuronal activity in auditory cortex. We electrically stimulated 567 deep brain sites in total within and in the vicinity of the two dopaminergic ventral midbrain structures and at the same time, recorded local field potentials and neuronal discharges in cortex. In experiments conducted on three awake macaque monkeys, we found that electrical stimulation of the dopaminergic ventral midbrain resulted in short-latency (~35 ms) phasic activations in all cortical layers of auditory cortex. We were also able to demonstrate similar activations in secondary somatosensory cortex and superior temporal polysensory cortex. The electrically evoked responses in these parts of sensory cortex were similar to those previously described for prefrontal cortex. Moreover, these phasic responses could be reversibly altered by the dopamine D1-receptor antagonist SCH23390 for several tens of minutes. Thus, we speculate that the dopaminergic ventral midbrain exerts a temporally precise, phasic influence on sensory cortex using fast-acting non-dopaminergic transmitters and that their effects are modulated by dopamine on a longer timescale. Our findings suggest that some of the information carried by the neuronal discharges in the dopaminergic ventral midbrain, such as the motivational value or the motivational salience, is transmitted to auditory cortex and other parts of sensory cortex. The mesocortical pathway may thus contribute to the representation of non-auditory events in the auditory cortex and to its associative functions. PMID:25084746

  10. Ecto-nucleoside triphosphate diphosphohydrolase 3 in the ventral and lateral hypothalamic area of female rats: morphological characterization and functional implications

    PubMed Central

    Kiss, David S; Zsarnovszky, Attila; Horvath, Krisztina; Gyorffy, Andrea; Bartha, Tibor; Hazai, Diana; Sotonyi, Peter; Somogyi, Virag; Frenyo, Laszlo V; Diano, Sabrina

    2009-01-01

    Background Based on its distribution in the brain, ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3) may play a role in the hypothalamic regulation of homeostatic systems, including feeding, sleep-wake behavior and reproduction. To further characterize the morphological attributes of NTPDase3-immunoreactive (IR) hypothalamic structures in the rat brain, here we investigated: 1.) The cellular and subcellular localization of NTPDase3; 2.) The effects of 17β-estradiol on the expression level of hypothalamic NTPDase3; and 3.) The effects of NTPDase inhibition in hypothalamic synaptosomal preparations. Methods Combined light- and electron microscopic analyses were carried out to characterize the cellular and subcellular localization of NTPDase3-immunoreactivity. The effects of estrogen on hypothalamic NTPDase3 expression was studied by western blot technique. Finally, the effects of NTPDase inhibition on mitochondrial respiration were investigated using a Clark-type oxygen electrode. Results Combined light- and electron microscopic analysis of immunostained hypothalamic slices revealed that NTPDase3-IR is linked to ribosomes and mitochondria, is predominantly present in excitatory axon terminals and in distinct segments of the perikaryal plasma membrane. Immunohistochemical labeling of NTPDase3 and glutamic acid decarboxylase (GAD) indicated that γ-amino-butyric-acid- (GABA) ergic hypothalamic neurons do not express NTPDase3, further suggesting that in the hypothalamus, NTPDase3 is predominantly present in excitatory neurons. We also investigated whether estrogen influences the expression level of NTPDase3 in the ventrobasal and lateral hypothalamus. A single subcutaneous injection of estrogen differentially increased NTPDase3 expression in the medial and lateral parts of the hypothalamus, indicating that this enzyme likely plays region-specific roles in estrogen-dependent hypothalamic regulatory mechanisms. Determination of mitochondrial respiration rates

  11. Metamers of the ventral stream

    PubMed Central

    Freeman, Jeremy; Simoncelli, Eero P.

    2011-01-01

    The human capacity to recognize complex visual patterns emerges in a sequence of brain areas known as the ventral stream, beginning with primary visual cortex (V1). We develop a population model for mid-ventral processing, in which non-linear combinations of V1 responses are averaged within receptive fields that grow with eccentricity. To test the model, we generate novel forms of visual metamers — stimuli that differ physically, but look the same. We develop a behavioral protocol that uses metameric stimuli to estimate the receptive field sizes in which the model features are represented. Because receptive field sizes change along the ventral stream, the behavioral results can identify the visual area corresponding to the representation. Measurements in human observers implicate V2, providing a new functional account of this area. The model explains deficits of peripheral vision known as “crowding”, and provides a quantitative framework for assessing the capabilities of everyday vision. PMID:21841776

  12. Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.

    PubMed

    Bendre, M; Comasco, E; Nylander, I; Nilsson, K W

    2015-01-01

    Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse. PMID:26645625

  13. Pedunculopontine tegmental nucleus lesions impair probabilistic reversal learning by reducing sensitivity to positive reward feedback.

    PubMed

    Syed, Anam; Baker, Phillip M; Ragozzino, Michael E

    2016-05-01

    Recent findings indicate that pedunculopontine tegmental nucleus (PPTg) neurons encode reward-related information that is context-dependent. This information is critical for behavioral flexibility when reward outcomes change signaling a shift in response patterns should occur. The present experiment investigated whether NMDA lesions of the PPTg affects the acquisition and/or reversal learning of a spatial discrimination using probabilistic reinforcement. Male Long-Evans rats received a bilateral infusion of NMDA (30nmoles/side) or saline into the PPTg. Subsequently, rats were tested in a spatial discrimination test using a probabilistic learning procedure. One spatial location was rewarded with an 80% probability and the other spatial location rewarded with a 20% probability. After reaching acquisition criterion of 10 consecutive correct trials, the spatial location - reward contingencies were reversed in the following test session. Bilateral and unilateral PPTg-lesioned rats acquired the spatial discrimination test comparable to that as sham controls. In contrast, bilateral PPTg lesions, but not unilateral PPTg lesions, impaired reversal learning. The reversal learning deficit occurred because of increased regressions to the previously 'correct' spatial location after initially selecting the new, 'correct' choice. PPTg lesions also reduced the frequency of win-stay behavior early in the reversal learning session, but did not modify the frequency of lose-shift behavior during reversal learning. The present results suggest that the PPTg contributes to behavioral flexibility under conditions in which outcomes are uncertain, e.g. probabilistic reinforcement, by facilitating sensitivity to positive reward outcomes that allows the reliable execution of a new choice pattern. PMID:26976089

  14. Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats.

    PubMed

    Haile, C N; Hiroi, N; Nestler, E J; Kosten, T A

    2001-09-01

    Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine. PMID:11391778

  15. Laparoscopic Repair of Ventral Hernias

    PubMed Central

    Heniford, B Todd; Park, Adrian; Ramshaw, Bruce J.; Voeller, Guy

    2003-01-01

    Objective: To evaluate the efficacy and safety of laparoscopic repair of ventral hernias. Summary Background Data: The recurrence rate after standard repair of ventral hernias may be as high as 12-52%, and the wide surgical dissection required often results in wound complications. Use of a laparoscopic approach may decrease rates of complications and recurrence after ventral hernia repair. Methods: Data on all patients who underwent laparoscopic ventral hernia repair (LVHR) performed by 4 surgeons using a standardized procedure between November 1993 and October 2002 were collected prospectively (85% of patients) or retrospectively. Results: LVHR was completed in 819 of the 850 patients (422 men; 428 women) in whom it was attempted. Thirty-four percent of completed LVHRs were for recurrent hernias. The patient mean body mass index was 32; the mean defect size was 118 cm2. Mesh, averaging 344 cm2, was used in all cases. Mean operating time was 120 min, mean estimated blood loss was 49 mL, and hospital stay averaged 2.3 days. There were 128 complications in 112 patients (13.2%). One patient died of a myocardial infarction. The most common complications were ileus (3%) and prolonged seroma (2.6%). During a mean follow-up time of 20.2 months (range, 1-94 months), the hernia recurrence rate was 4.7%. Recurrence was associated with large defects, obesity, previous open repairs, and perioperative complications. Conclusion: In this large series, LVHR had a low rate of conversion to open surgery, a short hospital stay, a moderate complication rate, and a low risk of recurrence. PMID:14501505

  16. Mephedrone (4-methylmethcathinone, 'meow'): acute behavioural effects and distribution of Fos expression in adolescent rats.

    PubMed

    Motbey, Craig P; Hunt, Glenn E; Bowen, Michael T; Artiss, Suzanne; McGregor, Iain S

    2012-03-01

    Mephedrone (4-methylmethcathinone) is a novel recreational drug that has rapidly increased in popularity in recent years. Users report mephedrone as having the stimulant-like qualities of methamphetamine and cocaine, combined with the prosocial, entactogenic effects of 3,4-methylenedioxymethamphetamine (MDMA). Anecdotal and case study reports indicate that mephedrone may have the potential to engender compulsive patterns of use as well as toxicity in overdose. However, there have been almost no neuropharmacological investigations of the drug up to this point. Here we examined the effects of two different mephedrone doses [15 and 30 mg/kg, intraperitoneal (IP)] relative to the well-known stimulant methamphetamine (2 mg/kg IP) in adolescent rats. Rats were injected, assessed for locomotor activity for 60 minutes and then tested in a 10-minute social preference test (measuring time spent in close proximity to a real rat versus a dummy rat). Their brains were then processed using Fos immunohistochemistry to determine patterns of brain activation. Results showed that mephedrone caused profound locomotor hyperactivity at both dose levels while tending to reduce social preference. Patterns of Fos expression with mephedrone resembled a combination of those observed with methamphetamine and MDMA, with particularly strong Fos expression in the cortex, dorsal and ventral striatum, ventral tegmental area (typical of both MDMA and methamphetamine) and supraoptic nucleus (typical of MDMA). These results demonstrate for the first time the powerful stimulant effects of mephedrone in animal models and its capacity to activate mesolimbic regions. These results also provide some empirical basis to user reports that mephedrone subjectively resembles a MDMA/methamphetamine hybrid. PMID:21995495

  17. Ventral Pallidum Roles in Reward and Motivation

    PubMed Central

    Smith, Kyle S.; Tindell, Amy J.; Aldridge, J. Wayne; Berridge, Kent C.

    2008-01-01

    In recent years the ventral pallidum has become a focus of great research interest as a mechanism of reward and incentive motivation. As a major output for limbic signals, the ventral pallidum was once associated primarily with motor functions rather than regarded as a reward structure in its own right. However, ample evidence now suggests that ventral pallidum function is a major mechanism of reward in the brain. We review data indicating that 1) an intact ventral pallidum is necessary for normal reward and motivation, 2) stimulated activation of ventral pallidum is sufficient to cause reward and motivation enhancements, and 3) activation patterns in ventral pallidum neurons specifically encode reward and motivation signals via phasic bursts of excitation to incentive and hedonic stimuli. We conclude that the ventral pallidum may serve as an important ‘limbic final common pathway’ for mesocorticolimbic processing of many rewards. PMID:18955088

  18. Autoradiographic localization of nicotinic receptor binding in rat brain using (/sup 3/H)methylcarbamylcholine, a novel radioligand

    SciTech Connect

    Yamada, S.; Gehlert, D.R.; Hawkins, K.N.; Nakayama, K.; Roeske, W.R.; Yamamura, H.I.

    1987-12-28

    Light microscopic autoradiography was used to visualize the neuroanatomical distribution of nicotinic receptors in rat brain using a novel radioligand, (/sup 3/H)methylcarbamylcholine (MCC). Specific (/sup 3/H)MCC binding to slide-mounted tissue sections of rat brain was saturable, reversible and of high affinity. Data analysis revealed a single population of (/sup 3/H)MCC binding sites with a K/sub d/ value or 1.8 nM and B/sub max/ of 20.1 fmol/mg protein. Nicotinic agonists and antagonists competed for (/sup 3/H)MCC binding sites in slide-mounted brain sections with much greater potency than muscarinic drugs. The rat brain areas containing the highest densities of (/sup 3/H)MCC binding were in thalamic regions, the medial habenular nucleus and the superior colliculus. Moderate densities of (/sup 3/H)MCC binding were seen over the anterior cingulate cortex, the nucleus accumbens, the zona compacta of substantia nigra and ventral tegmental area. Low densities of (/sup 3/H)MCC binding were found in most other brain regions. These data suggest that (/sup 3/H)MCC selectively labels central nicotinic receptors and that these receptors are concentrated in the thalamus, the medial habenular nucleus and the superior colliculus of the rat brain. 29 references, 6 figures, 2 tables.

  19. Ginkgo biloba extract enhances noncontact erection in rats: the role of dopamine in the paraventricular nucleus and the mesolimbic system.

    PubMed

    Yeh, K-Y; Wu, C-H; Tai, M-Y; Tsai, Y-F

    2011-08-25

    Penile erection is essential for successful copulation in males. Dopaminergic projections from the paraventricular nucleus (PVN) to the ventral tegmental area (VTA) and from the VTA to the nucleus accumbens (NAc) are thought to exert a facilitatory effect on penile erection. Our previous study showed that treatment with an extract of Ginkgo biloba leaves (EGb 761) enhances noncontact erection (NCE) in male rats. However, the relationship between NCE and dopaminergic activity in the PVN, VTA, and NAc remains unknown. The present study examined the relationship between NCE and central dopaminergic activity following EGb 761 treatment. We report here that, in comparison with the controls, there was a significant increase in the number of NCEs in rats after treatment with 50 mg/kg of EGb 761 for 14 days. EGb 761-treated rats also showed more NCEs than the same group before EGb 761 treatment. A significant increase in the expression of catecholaminergic neurons in the PVN and the VTA was seen by means of tyrosine hydroxylase immunohistochemistry, and tissue levels of dopamine and 3,4-dihydroxyphenylacetic acid in the NAc were also markedly increased in the EGb 761-treated animals. However, the norepinephrine tissue levels in the PVN and the NAc in the EGb 761-treated group were not significantly different from those in the controls. Together, these results suggest that administration of EGb 761 increases dopaminergic activity in the PVN and the mesolimbic system to facilitate NCE in male rats. PMID:21640798

  20. Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: An in vivo electrophysiological study on monoaminergic and glutamatergic neurons

    PubMed Central

    El Iskandrani, Kareem S; Oosterhof, Chris A; Blier, Pierre

    2015-01-01

    The rapid antidepressant action of a subanesthetic dose of ketamine in treatment-resistant patients represents the most striking recent breakthrough in the understanding of the antidepressant response. Evidence demonstrates tight interactions between the glutamatergic and monoaminergic systems. It is thus hypothesized that monoamine systems may play a role in the immediate/rapid effects of ketamine. In vivo electrophysiological recordings were carried in male rats following ketamine administration (10 and 25 mg/kg, i.p.) to first assess its effects on monoaminergic neuron firing. In a second series of experiments, the effects of ketamine administration on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate receptor (NMDA)-evoked responses in hippocampus CA3 pyramidal neurons were also investigated using micro-iontophoretic applications. Although acute (~2 hours) ketamine administration did not affect the mean firing activity of dorsal raphe serotonin and ventral tegmental area dopamine neurons, it did increase that of locus coeruleus norepinephrine neurons. In the latter brain region, while ketamine also enhanced bursting activity, it did increase population activity of dopamine neurons in the ventral tegmental area. These effects of ketamine were prevented by the prior administration of the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide. An increase in AMPA-evoked response of CA3 pyramidal neurons was also observed 30 minutes following acute ketamine administration. The present findings suggest that acute ketamine administration produces a rapid enhancement of catecholaminergic neurons firing activity through an amplification of AMPA transmission. These effects may play a crucial role in the antidepressant effects of ketamine observed shortly following its infusion in depressed patients. PMID:25759403

  1. Time-dependent co-relation of BDNF and CREB mRNAs in adult rat brains following acute psychological stress in the communication box paradigm.

    PubMed

    Li, Gongying; Wang, Yanmei; Yan, Min; Ma, Hongxia; Gao, Yanjie; Li, Zexuan; Li, Changqi; Tian, Hongjun; Zhuo, Chuanjun

    2016-06-15

    Psychological stress affects human health, and chronic stress leads to life-threatening diseases, such as depression and post-traumatic stress disorder. Psychological stress coping mechanisms involve the brain-derived neurotrophic factor (BDNF) and downstream cAMP response element binding protein (CREB), which are targets of the adverse effects of stress paradigms. Fourty-seven adult male Sprague-Dawley rats were divided into control, physical stress and six psychological stress groups which were assayed at 0h, 0.5h, 1h, 2h, 6h and 24h after communication box (CB) stress induction. Behavioral assessment using open field and elevated plus maze tests determined that CB stress significantly increased anxiety. After CB stress, the alternation of mRNA levels of BDNF and CREB were assessed at different time points by in situ hybridization. The mRNA levels of BDNF and CREB were significantly decreased, then gradually recovered over 24h to maximum levels in the hippocampus (CA1 region), prefrontal cortex (PFC), central amygdaloid nuclei (AG), shell of accumbens nucleus (NAC), periaqueductal gray (PAG) and ventral tegmental area, except for the ventral tegmental area (VTA). Moreover, mRNA levels of BDNF and CREB were positively correlated in all examined brain regions, except for the VTA region at 0 and 24h after CB stress induction. These findings suggest that BDNF and CREB may belong to the same pathway and be involved in psychological stress response mechanisms, and protect the organism from stress induced, aversive processes leading to disease. PMID:27132084

  2. Glucocorticoid receptor expression and sub-cellular localization in dopamine neurons of the rat midbrain.

    PubMed

    Hensleigh, E; Pritchard, L M

    2013-11-27

    Stress plays an important role in the development of addiction. Animals subjected to stress exhibit sensitized responses to psychostimulant drugs, and this sensitized response is associated with functional adaptations of the mesolimbic dopamine system. These adaptations likely arise from direct or indirect effects of glucocorticoids on dopaminergic neurons. Though glucocorticoid receptor expression in midbrain dopaminergic neurons has been examined in previous studies, results have been somewhat equivocal. We sought to clarify this issue by analyzing tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) co-localization in the rat midbrain by dual fluorescence immunohistochemistry. We also examined sub-cellular localization of the GR in rat midbrain neurons after acute restraint stress. Adult Long-Evans rats were sacrificed 0, 30, 60 or 120min after 30min of restraint stress. A control group did not undergo restraint. Blood samples were collected immediately before and after restraint for measurement of plasma corticosterone by enzyme immunoassay. Glucocorticoid receptors were observed in dopaminergic neurons in both the substantia nigra (SN) and ventral tegmental area (VTA). The degree of co-localization of TH and GR did not differ between the VTA and the SN. All animals subjected to stress exhibited significant increases in plasma corticosterone. Significant translocation of GR signal to cell nuclei was observed after restraint in the SN, but not in the VTA. These results suggest that stress-induced glucocorticoid secretion could trigger functional changes in the mesolimbic dopamine system by direct activation of glucocorticoid receptors in dopaminergic neurons. PMID:24121048

  3. The effects of morphine treatment on the NCAM and its signaling in the MLDS of rats.

    PubMed

    Cao, Jun Ping; Wang, Hong Jun; Li, Li; Zhang, Su Ming

    2016-10-01

    Prolonged exposure to opiates induces a constellation of neuroadaptations, especially in the mesolimbic dopamine system (MLDS), which leads to alteration in the function of motivational circuitry. The neural cell adhesion molecule (NCAM) mediates cell-cell interactions and plays an important role in processes associated with neural plasticity. Moreover, it has been shown that NCAM were related to risk of alcoholism in human populations. Here, coimmunoprecipitation and western blotting were used to investigate whether morphine treatment induced alteration of the expression of NCAM or its signaling level in MLDS. The rats receiving escalating dose of morphine treatment were divided into three groups: morphine 1d, 3d and 5d group, which were injected subcutaneously with morphine hydrochloride for 1 day, 3 days and 5 days, respectively. Twelve hours after the last injection, animals were sacrificed and the tissues of ventral tegmental area (VTA), prefrontal cortex (PFC) and nucleus accumbens (NAc) were punched out to examine the expression of NCAM or its signaling level. The results showed that morphine treatment had no significant effect on the expression of NCAM, but downregulated the phosphorylation of NCAM-associated focal adhesion kinase (FAK) in the VTA and PFC of rats. In the NAc of rats, however, the expression of NCAM and its signaling were not altered significantly by morphine treatment. These results indicated that the downregulation of NCAM signaling in the VTA and PFC might be involved in the formation of morphine addiction. PMID:26821693

  4. Perinatal ethanol exposure alters met-enkephalin levels of male and female rats.

    PubMed

    Lugo, Joaquin N; Wilson, Marlene A; Kelly, Sandra J

    2006-01-01

    This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long-Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors. PMID:16457985

  5. Preferential Reactivation of Motivationally Relevant Information in the Ventral Striatum

    PubMed Central

    Lansink, Carien S.; Goltstein, Pieter M.; Lankelma, Jan V.; Joosten, Ruud N. J. M. A.; McNaughton, Bruce L.

    2008-01-01

    Spontaneous “off-line” reactivation of neuronal activity patterns may contribute to the consolidation of memory traces. The ventral striatum exhibits reactivation and has been implicated in the processing of motivational information. It is unknown, however, whether reactivating neuronal ensembles specifically recapitulate information relating to rewards that were encountered during wakefulness. We demonstrate a prolonged reactivation in rat ventral striatum during quiet wakefulness and slow-wave but not rapid eye movement sleep. Reactivation of reward-related information processed in this structure was particularly prominent, and this was primarily attributable to spike trains temporally linked to reward sites. It was accounted for by small, strongly correlated subgroups in recorded cell assemblies and can thus be characterized as a sparse phenomenon. Our results indicate that reactivated memory traces may not only comprise feature- and context-specific information but also contain a value component. PMID:18562607

  6. Role for the rostromedial tegmental nucleus in signaling the aversive properties of alcohol

    PubMed Central

    Glover, Elizabeth J.; McDougle, Molly J.; Siegel, Griffin S.; Jhou, Thomas C.; Chandler, L. Judson

    2016-01-01

    Background While the rewarding effects of alcohol contribute significantly to its addictive potential, it is becoming increasingly appreciated that alcohol’s aversive properties also play an important role in the propensity to drink. Despite this, the neurobiological mechanism for alcohol’s aversive actions is not well understood. The rostromedial tegmental nucleus (RMTg) was recently characterized for its involvement in aversive signaling and has been shown to encode the aversive properties of cocaine, yet its involvement in alcohol’s aversive actions have not been elucidated. Methods Adult male and female Long-Evans rats underwent conditioned taste aversion (CTA) procedures where exposure to a novel saccharin solution was paired with i.p. administration of saline, lithium chloride (LiCl), or ethanol (EtOH). Control rats underwent the same paradigm except that drug and saccharin exposure were explicitly unpaired. Saccharin consumption was measured on test day in the absence of drug administration and rats were sacrificed 90–105 min following access to saccharin. Brains were subsequently harvested and processed for cFos immunohistochemistry. The number of cFos labeled neurons was counted in the RMTg and the lateral habenula (LHb) – a region that sends prominent glutamatergic input to the RMTg. Results In rats that received paired drug and saccharin exposure, EtOH and LiCl induced significant CTA compared to saline to a similar degree in males and females. Both EtOH- and LiCl-induced CTA significantly enhanced cFos expression in the RMTg and LHb but not the hippocampus. Similar to behavioral measures, no significant effect of sex on CTA-induced cFos expression was observed. cFos expression in both the RMTg and LHb was significantly correlated to CTA magnitude with greater cFos being associated with more pronounced CTA. In addition, cFos expression in the RMTg was positively correlated with LHb cFos. Conclusions These data suggest that the RMTg and LHb are

  7. Reward cues in space: commonalities and differences in neural coding by hippocampal and ventral striatal ensembles

    PubMed Central

    Lansink, Carien S.; Jackson, Jadin; Lankelma, Jan V.; Ito, Rutsuko; Robbins, Trevor W.; Everitt, Barry J.; Pennartz, Cyriel M.A.

    2012-01-01

    Forming place-reward associations critically depends on the integrity of the hippocampal-ventral striatal system. The ventral striatum receives a strong hippocampal input conveying spatial-contextual information, but it is unclear how this structure integrates this information to invigorate reward-directed behavior. Neuronal ensembles in rat hippocampus and ventral striatum were simultaneously recorded during a conditioning task in which navigation depended on path integration. In contrast to hippocampus, ventral striatal neurons showed low spatial selectivity, but rather coded behavioral task phases towards reaching goal sites. Outcome-predicting cues induced a remapping of firing patterns in the hippocampus, consistent with its role in episodic memory. Ventral striatum remapped in conjunction with the hippocampus, indicating that remapping can take place in multiple brain regions engaged in the same task. Subsets of ventral striatal neurons showed a “flip” from high activity when cue lights were illuminated to low activity in intertrial intervals, or vice versa. The cues induced an increase in spatial information transmission and sparsity in both structures. These effects were paralleled by an enhanced temporal specificity of ensemble coding and a more accurate reconstruction of the animal’s position from population firing patterns. Altogether, the results reveal strong differences in spatial processing between hippocampal area CA1 and ventral striatum, but indicate similarities in how discrete cues impact on this processing. PMID:22956836

  8. A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits

    PubMed Central

    Pomrenze, Matthew B.; Millan, E. Zayra; Hopf, F. Woodward; Keiflin, Ronald; Maiya, Rajani; Blasio, Angelo; Dadgar, Jahan; Kharazia, Viktor; De Guglielmo, Giordano; Crawford, Elena; Janak, Patricia H.; George, Olivier; Rice, Kenner C.; Messing, Robert O.

    2015-01-01

    Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons. PMID:26733798

  9. Mesopontine tegmental anesthesia area projects independently to the rostromedial medulla and to the spinal cord.

    PubMed

    Reiner, K; Sukhotinsky, I; Devor, M

    2007-05-25

    General anesthetics are presumed to act in a distributed manner throughout the CNS. However, we found that microinjection of GABAA-receptor (GABAA-R) active anesthetics into a restricted locus in the rat brainstem, the mesopontine tegmental anesthesia area (MPTA), rapidly induces a reversible anesthesia-like state characterized by suppressed locomotion, atonia, anti-nociception and loss of consciousness. GABA-sensitive neurons in the MPTA may therefore have powerful control over major aspects of brain and spinal function. Tracer studies have shown that the MPTA projects to the rostromedial medulla, an important reticulospinal relay for pain modulation and motor control. It also projects directly to the spinal cord. But do individual MPTA neurons project to one or to both targets? We microinjected fluorogold into the rostromedial medulla and cholera toxin b-subunit into the spinal cord, or vice versa. Neurons that were double-labeled, and hence project to both targets, were intermingled with single-labeled neurons within the MPTA, and comprised only 11.5% of the total. MPTA neurons that project directly to the spinal cord were larger, on average, than those projecting to the rostromedial medulla, differed in shape, and were much more likely to express GABAA-alpha1Rs as assessed by receptor alpha-1 subunit immunoreactivity (51.4% vs. 18.9%). Thus, for the most part, separate and morphologically distinct populations of MPTA neurons project to the rostromedial medulla and to the spinal cord. Either or both may be involved in the modulation of nociception and the generation of atonia during the MPTA-induced anesthesia-like state. PMID:17395384

  10. The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors

    PubMed Central

    Root, David H.; Melendez, Roberto I.; Zaborszky, Laszlo; Napier, T. Celeste

    2015-01-01

    The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally-relevant stimuli and coherent adaptive behaviors. PMID:25857550

  11. The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors.

    PubMed

    Root, David H; Melendez, Roberto I; Zaborszky, Laszlo; Napier, T Celeste

    2015-07-01

    The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally relevant stimuli and coherent adaptive behaviors. PMID:25857550

  12. Gestational treatment with cocaine and fluoxetine alters oxytocin receptor number and binding affinity in lactating rat dams.

    PubMed

    Johns, Josephine M; Lubin, Deborah A; Walker, Cheryl H; Joyner, Paul; Middleton, Christopher; Hofler, Vivian; McMurray, Matthew

    2004-01-01

    Cocaine administered chronically throughout gestation has been correlated with deficits in maternal behavior, increased maternal aggressive behavior and decreased oxytocin levels in rats. In addition to its effects on oxytocin levels, cocaine is a potent serotonergic, dopaminergic and noradrenergic reuptake inhibitor. Alterations in the dopaminergic and serotonergic systems have been suggested as possibly having a role in cocaine-induced maternal aggression. This study was in part, an attempt to understand some of the mechanisms by which cocaine increases postpartum aggression, particularly as they relate to changes in the oxytocin system. Oxytocin receptor number and binding affinity in the medial preoptic area of the hypothalamus, ventral tegmental area, hippocampus and amygdala were determined for lactating rat dams on postpartum day 6 (PPD 6) that were gestationally treated with cocaine, fluoxetine, saline or an amfonelic acid/fluoxetine drug combination. Cocaine and fluoxetine treatment both resulted in a significant up-regulation of oxytocin receptor number and lower receptor affinity in the amygdala of lactating rat dams compared to saline controls and the amfonelic acid/fluoxetine combination treatment group. Cocaine treatment also resulted in a significant down-regulation of oxytocin receptors in the medial preoptic area and both cocaine and fluoxetine treated dams had the highest affinity for oxytocin receptors in this brain region. Results of the present study support previous data indicating that alterations in oxytocinergic and perhaps serotonergic system dynamics in the amygdala may play a role in cocaine-induced postpartum aggression. PMID:15380831

  13. Heteropterys tomentosa (A. Juss.) infusion counteracts Cyclosporin a side effects on the ventral prostate

    PubMed Central

    2013-01-01

    Background Cyclosporin A (CsA) is an immunosuppressive drug widely used in treatment of auto-immune diseases or after organ transplants. However, several side effects are commonly associated with CsA long term intake, some regarding to loss of reproductive organ function due to oxidative damage. Considering that phytotherapy is an important tool often used against oxidative stress, we would like to describe the beneficial effects of Heteropterys tomentosa intake to minimize the damage caused by CsA to the ventral prostate tissue of Wistar rats under laboratorial conditions. Methods Thirty adult Wistar rats (Rattus norvegicus albinus) were divided into: control group (water); CsA group (Cyclosporin A); Ht group (H. tomentosa infusion) and CsA + Ht group (CsA and H. tomentosa infusion). Plasmic levels of hepatotoxicity markers, triglycerides, cholesterol and glucose were quantified. The ventral prostate tissue was analyzed under light microscopy, using stereological, morphometrical and immunohistochemical techniques. Results H. tomentosa did not cause any alterations either of the plasmic parameters or of the ventral prostate structure. CsA caused alterations of GOT, total and indirect bilirubin, cholesterol, triglycerides and glucose levels in the plasma; CsA-treated rats showed alterations of the ventral prostate tissue. There were no alterations regarding the plasma levels of GOT, triglycerides and glucose of CsA + Ht animals. The same group also showed normalization of most of the parameters analyzed on the ventral prostate tissue when compared to the CsA group. The treatments did not alter the pattern of AR expression or the apoptotic index of the ventral prostate epithelium. Conclusions The results suggest a protective action of the H. tomentosa infusion against the side effects of CsA on the ventral prostate tissue, which could also be observed with plasmic biochemical parameters. PMID:23406403

  14. Androgen Decreases Dopamine Neurone Survival in Rat Midbrain

    PubMed Central

    Johnson, M. L.; Day, A. E.; Ho, C. C.; Walker, Q. D.; Francis, R.; Kuhn, C. M.

    2011-01-01

    Clinical studies show that men are more likely to develop disorders affecting midbrain dopaminergic pathways, such as drug addiction and Parkinson’s disease (PD). Although a great deal of focus has been given to the role of oestrogen in the maintenance of midbrain dopaminergic pathways, little is known about how testosterone influences these pathways. In the present study, we used stereological analysis of tyrosine hydroxylase-immunoreactive (TH-IR) cell bodies to determine how testosterone influences the dopaminergic cell bodies of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Rats and mice were castrated at post-natal day (PN) 60, and these midbrain cell populations were counted on PN 90. One month after castration, TH-IR cell number had increased in the SNpc and VTA of rats and mice. Replacement with testosterone or the non-aromatisable analogue dihydrotestosterone (DHT) in castrated animals reduced TH-IR cell number in the SNpc and VTA in rats. In mice, the decrease of TH-IR cell number with testosterone or DHT replacement was observed only in the SNpc. The apparent increase in TH-IR neurone number after castration is not explained by an increase in TH expression because the number of nondopaminergic cells (TH-immunonegative, TH-IN) did not decrease proportionally after castration. TH-IN cell number did not change after castration or hormone replacement in rat or mouse SNpc or VTA. These findings suggest that testosterone may play a suppressive role in midbrain dopaminergic pathways. PMID:20136692

  15. Oestrogen Receptors Enhance Dopamine Neurone Survival in Rat Midbrain

    PubMed Central

    Johnson, M. L.; Ho, C. C.; Day, A. E.; Walker, Q. D.; Francis, R.; Kuhn, C. M.

    2011-01-01

    Previous findings in our laboratory and elsewhere have shown that ovariectomy of rats in adulthood attenuates cocaine-stimulated locomotor behaviour. Ovarian hormones enhance both cocaine-stimulated behaviour and increase dopamine overflow after psychomotor stimulants. The present study aimed to determine whether ovarian hormones have these effects in part by maintaining dopamine neurone number in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) and to investigate the roles of specific oestrogen receptors (ERs) in the maintenance of mesencephalic dopamine neurones. To accomplish this goal, we used unbiased stereological techniques to estimate the number of tyrosine hydroxylase-immunoreactive (TH-IR) cell bodies in midbrain regions of intact, ovariectomised and hormone-replaced female rats and mice. Animals received active or sham gonadectomy on postnatal day 60 and received vehicle, 17β-oestradiol (E2) or selective ER agonists propyl-pyrazole-triol (PPT, ERα) or diarylpropionitrile (DPN, ERβ) for 1 month post-surgery. In both rats and mice, ovariectomy reduced the number of TH-IR cells in the SNpc and VTA. Replacement with E2, PPT or DPN prevented or attenuated the loss observed with ovariectomy in both rats and mice. An additional study using ER knockout mice revealed that adult female mice lacking ERα had fewer TH-IR cells in midbrain regions than wild-type mice, whereas mice lacking ERβ had TH-IR cell counts comparable to wild-type. These findings suggest that, although both ER subtypes play a role in the maintenance of TH-IR cell number in the SNpc and VTA, ERα may play a more significant role. PMID:20136693

  16. Central control of penile erection: a re-visitation of the role of oxytocin and its interaction with dopamine and glutamic acid in male rats.

    PubMed

    Melis, Maria Rosaria; Argiolas, Antonio

    2011-01-01

    Oxytocin is a potent inducer of penile erection when injected into the central nervous system. In male rats, the most sensitive brain area for the pro-erectile effect of oxytocin is the paraventricular nucleus of the hypothalamus. This nucleus and surrounding regions contain the cell bodies of all oxytocinergic neurons projecting to extra-hypothalamic brain areas and the spinal cord. This review shows that oxytocin induces penile erection also when injected in some of these areas (e.g., ventral tegmental area, ventral subiculum of the hippocampus, posteromedial cortical nucleus of the amygdala and thoraco-lumbar spinal cord). Microinjection studies combined with intra-cerebral microdialysis and double immuno-fluorescence studies suggest that oxytocin in these areas activates directly or indirectly (mainly through glutamic acid) mesolimbic dopaminergic neurons. Dopamine released in the nucleus accumbens in turn activates neural pathways leading to the activation of incerto-hypothalamic dopaminergic neurons in the paraventricular nucleus. This activates not only oxytocinergic neurons projecting to the spinal cord and mediating penile erection, but also those projecting to the above extra-hypothalamic areas, modulating directly or indirectly (through glutamic acid) the activity of mesolimbic dopaminergic neurons controlling motivation and reward. Together these neural pathways may constitute a complex hypothetical circuit, which plays a role not only in the consummatory phase of sexual activity (erectile function and copulation), but also in the motivational and rewarding aspects of the anticipatory phase of sexual behaviour. PMID:21050872

  17. Combined MSC-Secreted Factors and Neural Stem Cell Transplantation Promote Functional Recovery of PD Rats.

    PubMed

    Yao, Yuan; Huang, Chen; Gu, Ping; Wen, Tieqiao

    2016-01-01

    Stem cell transplantation has enormous potential for the treatment of neurodegenerative disorders like Parkinson's disease (PD). Mesenchymal stem cells (MSCs) have attracted much attention because they can secrete a wide variety of cellular factors that promote cell growth. In this study, we prepared a conditioned medium (CM) using lyophilized MSC culture medium that contained the secretome of MSCs and applied this CM to the culture of neural stem cells (CM-NSCs) for the transplantation of PD model rats. Quantitative real-time PCR, Western blot, and immunocytochemistry were used to identify cell differentiation and expression of dopaminergic neuron-specific genes in vitro. Behavioral tests including rotational behavior and MWM training tests were also performed to assess the recovery. Our results indicated that combined treatment of CM and neural stem cell transplantation can significantly reduce apomorphine-induced rotational asymmetry and improve spatial learning ability. The CM-NSCs were able to differentiate into dopaminergic neurons in the ventral tegmental area (VTA) and medial forebrain bundle (MFB), and migrated around the lesion site. They showed a higher activity than untreated NSCs in cell survival, migration, and behavior improvement in the dopa-deficit rat model. These findings suggest that the neural stem cells treated with conditioned medium possess a great potential as a graft candidate for the treatment of Parkinson's disease. PMID:26607204

  18. The effect of different durations of morphine exposure on mesencephalic dopaminergic neurons in morphine dependent rats.

    PubMed

    Shi, Weibo; Ma, Chunling; Qi, Qian; Liu, Lizhe; Bi, Haitao; Cong, Bin; Li, Yingmin

    2015-12-01

    Mesencephalic dopaminergic neurons are heavily involved in the development of drug dependence. Thyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, plays an important role in the survival of dopaminergic neurons. Therefore, this study investigated TH changes in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN), as well as the morphine effects on dopaminergic neurons induced by different durations of morphine dependence. Models of morphine dependence were established in rats, and paraffin-embedded sections, immunohistochemistry and western blotting were used to observe the changes in the expression of TH protein. Fluoro-Jade B staining was used to detect degeneration and necrosis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) detected the apoptosis of mesencephalic dopaminergic nerve cells. Immunohistochemistry and western blotting showed that the number of TH positive cells and the protein levels in the VTA and SN were significantly decreased in the rats with a long period of morphine dependency. With prolonged morphine exposure, the dopaminergic nerve cells in the VTA and SN showed degeneration and necrosis, while apoptotic cells were not observed. The number of VTA and SN dopaminergic nerve cells decreased with increasing periods of morphine dependence, which was most likely attributable to the degeneration and necrosis of nerve cells induced by morphine toxicity. PMID:26386147

  19. Cellular activation in limbic brain systems during social play behaviour in rats

    PubMed Central

    van Kerkhof, Linda W.M.; Trezza, Viviana; Mulder, Tessa; Gao, Ping; Voorn, Pieter; Vanderschuren, Louk J.M.J.

    2013-01-01

    Positive social interactions during the juvenile and adolescent phases of life are essential for proper social and cognitive development in mammals, including humans. During this developmental period, there is a marked increase in peer-peer interactions, signified by the abundance of social play behaviour. Despite its importance for behavioural development, our knowledge of the neural underpinnings of social play behaviour is limited. Therefore, the purpose of this study was to map the neural circuits involved in social play behaviour in rats. This was achieved by examining cellular activity after social play using the immediate early gene c-fos as a marker. After a session of social play behaviour, pronounced increases in c-fos expression were observed in the medial prefrontal cortex, medial and ventral orbitofrontal cortex, dorsal striatum, nucleus accumbens core and shell, lateral amygdala, several thalamic nuclei, dorsal raphe and the pedunculopontine tegmental nucleus. Importantly, the cellular activity patterns after social play were topographically organised in this network, as indicated by play-specific correlations in c-fos activity between regions with known direct connections. These correlations suggest involvement in social play behaviour of the projections from the medial prefrontal cortex to the striatum, and of amygdala and monoaminergic inputs to frontal cortex and striatum. The analyses presented here outline a topographically organised neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats. PMID:23670540

  20. Differences in BOLD responses to intragastrically infused glucose and saccharin in rats.

    PubMed

    Tsurugizawa, Tomokazu; Uneyama, Hisayuki

    2014-10-01

    The postingestive effect is different between caloric and noncaloric sweeteners. The gut administration of glucose induces a preference for flavored water which is paired with the intragastric infusion of glucose. However, a comparison of the brain response to the gut glucose and saccharin stimuli still remains to be demonstrated. Here, using functional magnetic resonance imaging, we investigated the blood oxygenation level-dependent signal response to gut glucose and saccharin in the brain of conscious rats. Glucose induced a positive signal increase in the amygdala and nucleus accumben, both of which receive dopaminergic input from the ventral tegmental area. In contrast, saccharin administration did not activate these areas. Both glucose and saccharin increased the blood oxygenation level-dependent signal intensity in the insular cortex and the nucleus of the solitary tract. These results show that there were significant differences between postingestive glucose and saccharin-induced increases in the blood oxygenation level-dependent signal in rats. Together with previous findings, these results suggest distinct activation patterns in the brain for both glucose and saccharin, which is partially due to different changes of internal signals, including the blood glucose and insulin levels. PMID:25179231

  1. Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats

    PubMed Central

    Sun, Min; Wang, Ke; Yu, Yan; Su, Wen-Ting; Jiang, Xin-Xin

    2016-01-01

    Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD. PMID:27525025

  2. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  3. Propofol Produces Immobility via Action in the Ventral Horn of the Spinal Cord by a GABAergic Mechanism

    PubMed Central

    Kungys, Gudrun; Kim, JongBun; Jinks, Steven L.; Atherley, Richard J.; Antognini, Joseph F.

    2011-01-01

    Background We investigated the actions of propofol and isoflurane on nociceptive responses of neurons in the spinal cord. Methods We determined nociceptive responses of lumbar neurons in the dorsal horn (<1200 μm) and ventral horn (>1200 μm) of decerebrate rats before and during propofol (1 effective dose, ED50) or isoflurane (1 minimum alveolar concentration) anesthesia. During recording of ventral horn neurons, we administered picrotoxin by infusion to determine whether isoflurane and propofol differed in their effects at the gamma amminobutyric acid (GABA) Type A receptors. We also determined whether decerebration altered propofol requirements to produce immobility. Results Decerebration did not affect propofol requirements. The ED50 for propofol was 497 ± 58 μg/kg/min in intact rats and 420 ± 65 μg/kg/min in decerebrated rats (p>0.05), with corresponding propofol blood concentrations of 8.1 ± 1.1 μg/ml and 7.3 ± 1.1 μg/ml, respectively (p>0.05). Propofol did not significantly depress dorsal horn neurons, but isoflurane depressed the responses to 56% of control (p<0.05). Propofol depressed ventral horn neurons to 47% of control, whereas isoflurane depressed ventral horn neurons to 20% of control. Picrotoxin significantly reversed the depressant effect of propofol on ventral horn neuronal responses (79% of control, not significantly different from control). Picrotoxin, however, had no effect on isoflurane’s depression of ventral horn neuronal responses (26% of control). Conclusions Propofol acts in the spinal cord to produce immobility. This depressive effect occurs in the ventral horn and is mediated mainly by GABAA receptors. Isoflurane also depresses neurons in the ventral horn; however, isoflurane actions at the GABAA receptor are either weak or overridden by other effects in the ventral horn. PMID:19372332

  4. Modulation Effect of HIV-1 Viral Proteins and Nicotine on Expression of the Immune-Related Genes in Brain of the HIV-1 Transgenic Rats.

    PubMed

    Yang, Zhongli; Nesil, Tanseli; Connaghan, Kaitlyn P; Li, Ming D; Chang, Sulie L

    2016-09-01

    The human immunodeficiency virus-1 transgenic (HIV-1Tg) rat is a non-infectious rodent model for HIV-1 infection which develops altered immune-responses similar to those in persons infected with HIV-1. HIV-1Tg and F344 rats respond significantly different to morphine, ethanol, nicotine and other psychostimulants, although the molecular mechanisms underlying these differences remain largely undetermined. Here, we compared expression of 52 immune-related genes in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) of HIV-1Tg and F344 rats treated with either nicotine (0.4 mg/kg nicotine, base, s.c.) or saline for 27 days, to identify differentially expressed genes in the presence of HIV-1 with and without nicotine treatment. Using quantitative RT-PCR array, we measured RNA expression levels. Results showed that RNA expression of CASP3, CCL5, CX3CL1, CX3CR1, IL1α, LRF4, LFR7, TGFβ1 and TLR4 in NAc, CCL2, CCL5, TGFβ1 and TLR4 in PFC, and CASP3, CX3CR1, IFNα1, IL1β and IL6 in VTA was significantly modulated in HIV-1Tg rats compared with F344 rats. IL1α showed a 58 % (P = 0.000072) decrease and IRF6 showed a 93.7 % increase (P = 0.000227) in the NAc of HIV-1Tg compared with F344 rats; results remained significant after correction for multiple testing. We also found that several genes were significantly modulated by nicotine in HIV-1Tg rats while only a small number of immune-related genes were altered by nicotine in F344 rats. These findings imply that HIV-1 viral proteins greatly impact immune function and alter responsiveness to nicotine in certain immune-related genes. PMID:27147085

  5. Maternal care differentially affects neuronal excitability and synaptic plasticity in the dorsal and ventral hippocampus.

    PubMed

    Nguyen, Huy-Binh; Bagot, Rosemary C; Diorio, Josie; Wong, Tak Pan; Meaney, Michael J

    2015-06-01

    Variations in early life maternal care modulate hippocampal development to program distinct emotional-cognitive phenotypes that persist into adulthood. Adult rat offspring that received low compared with high levels of maternal licking and grooming (low LG offspring) in early postnatal life show reduced long term potentiation (LTP) and impaired hippocampal-dependent memory, suggesting a 'detrimental' maternal effect on neural development. However, these studies focused uniquely on the dorsal hippocampus. Emerging evidence suggests a distinct role of the ventral hippocampus in mediating aggression, anxiety, and fear-memory formation, which are enhanced in low LG offspring. We report that variations in maternal care in the rat associate with opposing effects on hippocampal function in the dorsal and ventral hippocampus. Reduced pup licking associated with suppressed LTP formation in the dorsal hippocampus, but enhanced ventral hippocampal LTP. Ventral hippocampal neurons in low LG offspring fired action potentials at lower threshold voltages that were of larger amplitude and faster rise rate in comparison with those in high LG offspring. Furthermore, recordings of excitatory postsynaptic potential-to-spike coupling (E-S coupling) revealed an increase in excitability of ventral hippocampal CA1 neurons in low LG offspring. These effects do not associate with changes in miniature excitatory postsynaptic currents or paired-pulse facilitation, suggesting a specific effect of maternal care on intrinsic excitability. These findings suggest region-specific influences of maternal care in shaping neural development and synaptic plasticity. PMID:25598429

  6. Maternal Care Differentially Affects Neuronal Excitability and Synaptic Plasticity in the Dorsal and Ventral Hippocampus

    PubMed Central

    Nguyen, Huy-Binh; Bagot, Rosemary C; Diorio, Josie; Wong, Tak Pan; Meaney, Michael J

    2015-01-01

    Variations in early life maternal care modulate hippocampal development to program distinct emotional–cognitive phenotypes that persist into adulthood. Adult rat offspring that received low compared with high levels of maternal licking and grooming (low LG offspring) in early postnatal life show reduced long term potentiation (LTP) and impaired hippocampal-dependent memory, suggesting a ‘detrimental' maternal effect on neural development. However, these studies focused uniquely on the dorsal hippocampus. Emerging evidence suggests a distinct role of the ventral hippocampus in mediating aggression, anxiety, and fear-memory formation, which are enhanced in low LG offspring. We report that variations in maternal care in the rat associate with opposing effects on hippocampal function in the dorsal and ventral hippocampus. Reduced pup licking associated with suppressed LTP formation in the dorsal hippocampus, but enhanced ventral hippocampal LTP. Ventral hippocampal neurons in low LG offspring fired action potentials at lower threshold voltages that were of larger amplitude and faster rise rate in comparison with those in high LG offspring. Furthermore, recordings of excitatory postsynaptic potential-to-spike coupling (E-S coupling) revealed an increase in excitability of ventral hippocampal CA1 neurons in low LG offspring. These effects do not associate with changes in miniature excitatory postsynaptic currents or paired-pulse facilitation, suggesting a specific effect of maternal care on intrinsic excitability. These findings suggest region-specific influences of maternal care in shaping neural development and synaptic plasticity. PMID:25598429

  7. Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum

    PubMed Central

    Oleson, Erik B.; Beckert, Michael V.; Morra, Joshua T.; Lansink, Carien S.; Cachope, Roger; Abdullah, Rehab A.; Loriaux, Amy L.; Schetters, Dustin; Pattij, Tommy; Roitman, Mitchell F.; Lichtman, Aron H.; Cheer, Joseph F.

    2012-01-01

    SUMMARY Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior. PMID:22284189

  8. Current Trends in Laparoscopic Ventral Hernia Repair

    PubMed Central

    Patapis, Paul; Zavras, Nick; Tzanetis, Panagiotis; Machairas, Anastasios

    2015-01-01

    Background and Objectives: The purpose of this study was to analyze the surgical technique, postoperative complications, and possible recurrence after laparoscopic ventral hernia repair (LVHR) in comparison with open ventral hernia repair (OVHR), based on the international literature. Database: A Medline search of the current English literature was performed using the terms laparoscopic ventral hernia repair and incisional hernia repair. Conclusions: LVHR is a safe alternative to the open method, with the main advantages being minimal postoperative pain, shorter recovery, and decreased wound and mesh infections. Incidental enterotomy can be avoided by using a meticulous technique and sharp dissection to avoid thermal injury. PMID:26273186

  9. Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus.

    PubMed

    Bongiovanni, Rodolfo; Kyser, Abby N; Jaskiw, George E

    2012-12-01

    In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus. A tyrosine- and phenylalanine-free neutral amino acid mixture was used to lower brain tyrosine levels in rats undergoing in vivo microdialysis. In one group, NSD-1015 was included in perfusate to permit measurement of DOPA levels. In a second group, NSD-1015 was not included in perfusate so that catecholamine levels could be assayed. Tyrosine depletion significantly lowered DOPA levels in the NSD-1015 treated group and lowered DOPAC but not dopamine or noradrenaline levels in the group not exposed to NSD-1015. We conclude that while catecholamine synthesis in the ventral hippocampus declines when tyrosine availability is lowered, under basal conditions, compensatory mechanisms are able to maintain stable extracellular catecholamine levels. PMID:23022716

  10. Ketamine Suppresses the Ventral Striatal Response to Reward Anticipation: A Cross-Species Translational Neuroimaging Study.

    PubMed

    Francois, Jennifer; Grimm, Oliver; Schwarz, Adam J; Schweiger, Janina; Haller, Leila; Risterucci, Celine; Böhringer, Andreas; Zang, Zhenxiang; Tost, Heike; Gilmour, Gary; Meyer-Lindenberg, Andreas

    2016-04-01

    Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and

  11. CART modulates the effects of levodopa in rat model of Parkinson's disease.

    PubMed

    Upadhya, Manoj A; Shelkar, Gajanan P; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2016-03-15

    Parkinson's disease (PD) is an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of substantia nigra (SN). The neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to closely interact with the dopamine system and regulate psychomotor activity. We screened the effectiveness of CART in reversing the symptoms of PD in a rat model. PD like condition was induced by administering 6-hydroxydopamine (6-OHDA) directly in the SN of the right side. Fifteen days later, intraperitoneal (IP) treatment with apomorphine hydrochloride to these rats, resulted in contralateral rotations in the rotation test chamber suggesting induction of PD-like symptoms. This action of apomorphine was significantly attenuated by intracerebroventricular (ICV) treatment with CART and potentiated by CART antibody. IP treatment with levodopa also produced contralateral rotation in PD induced rats, and showed anti-Parkinson-like action. Prior treatment with CART via ICV route potentiated the anti-Parkinsonian effects of levodopa, while CART antibody produced opposite effects. CART treatment per se, to PD induced rats produced ipsilateral rotations, suggesting that the peptide may promote the endogenous release of dopamine from intact neurons. While CART-immunoreactivity in arcuate nucleus, paraventricular nucleus, striatum, substantia nigra, ventral tegmental area and locus coeruleus was reduced in the PD induced rats, levodopa treatment restored the expression of CART-immunoreactivity in these nuclei. These results suggest that endogenous CART might closely interact with the dopamine containing SN-striatal pathway which is known to profoundly influence the motor system. The study underscores the importance of CART as a potential therapeutic agent in the treatment of PD. PMID:26771081

  12. The effects of morphine and morphine conditioned context on 50 kHz ultrasonic vocalisation in rats.

    PubMed

    Hamed, Adam; Taracha, Ewa; Szyndler, Janusz; Krząścik, Paweł; Lehner, Małgorzata; Maciejak, Piotr; Skórzewska, Anna; Płaźnik, Adam

    2012-04-15

    The 50 kHz ultrasonic vocalisations (USVs) that are emitted by rats are dependent on activity of dopaminergic neurons projecting from the ventral tegmental area to the limbic and cortical structures. According to many experimental data, emission of the 50 kHz USV reflects a positive emotional state. The appetitive calls are also emitted in response to the administration of drugs of abuse, e.g., cocaine or amphetamine (AMPH), or in a reply to a positively conditioned context. However, there is no strong evidence in the literature that morphine can also modulate 50 kHz USVs. The aim of this paper is to study the effects of morphine and morphine-conditioned context on 50 kHz USVs, using spontaneously or drug-modulated 50 kHz USVs. Our results showed that acute administration of morphine to rats after withdrawal period inhibited the emission of 50 kHz USVs. The stimulating effect of morphine-conditioned context on 50 kHz USVs appeared on the post-withdrawal challenge day immediately before drug injection, 14 days after the last episode of morphine-induced context conditioning. The context-induced 50 kHz USVs can be used as a sensitive test for drug dependency. The current study also shows that 50 kHz USVs can be useful tool for studying the mechanisms of long lasting central effects of morphine. PMID:22326697

  13. ADOLESCENT INTERMITTENT ETHANOL EXPOSURE ENHANCES ETHANOL ACTIVATION OF THE NUCLEUS ACCUMBENS WHILE BLUNTING THE PREFRONTAL CORTEX RESPONSES IN ADULT RAT

    PubMed Central

    LIU, W.; CREWS, F. T.

    2016-01-01

    The brain continues to develop through adolescence when excessive alcohol consumption is prevalent in humans. We hypothesized that binge drinking doses of ethanol during adolescence will cause changes in brain ethanol responses that persist into adulthood. To test this hypothesis Wistar rats were treated with an adolescent intermittent ethanol (AIE; 5 g/kg, i.g. 2 days on–2 days off; P25–P54) model of underage drinking followed by 25 days of abstinence during maturation to young adulthood (P80). Using markers of neuronal activation c-Fos, EGR1, and phophorylated extracellar signal regulated kinase (pERK1/2), adult responses to a moderate and binge drinking ethanol challenge, e.g., 2 or 4 g/kg, were determined. Adult rats showed dose dependent increases in neuronal activation markers in multiple brain regions during ethanol challenge. Brain regional responses correlated are consistent with anatomical connections. AIE led to marked decreases in adult ethanol PFC (prefrontal cortex) and blunted responses in the amygdala. Binge drinking doses led to the nucleus accumbens (NAc) activation that correlated with the ventral tegmental area (VTA) activation. In contrast to other brain regions, AIE enhanced the adult NAc response to binge drinking doses. These studies suggest that adolescent alcohol exposure causes long-lasting changes in brain responses to alcohol that persist into adulthood. PMID:25727639

  14. Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

    PubMed Central

    Natividad, Luis A.; Buczynski, Matthew W.; Parsons, Loren H.; Torres, Oscar; O'Dell, Laura E.

    2012-01-01

    Adolescent smokers report enhanced positive responses to tobacco and fewer negative effects of withdrawal from this drug than adults, and this is believed to propel higher tobacco use during adolescence. Differential dopaminergic responses to nicotine are thought to underlie these age-related effects, since adolescent rats experience lower withdrawal-related deficits in nucleus accumbens (NAcc) dopamine versus adults. This study examined whether age differences in NAcc dopamine during withdrawal are mediated by excitatory or inhibitory transmission in the ventral tegmental area (VTA) dopamine cell body region. In vivo microdialysis was used to monitor extracellular levels of glutamate and gamma-aminobutyric acid (GABA) in the VTA of adolescent and adult rats experiencing nicotine withdrawal. In adults, nicotine withdrawal produced decreases in VTA glutamate levels (44% decrease) and increases in VTA GABA levels (38% increase). In contrast, adolescents did not exhibit changes in either of these measures. Naïve controls of both ages did not display changes in NAcc dopamine, VTA glutamate or VTA GABA following mecamylamine. These results indicate that adolescents display resistance to withdrawal-related neurochemical processes that inhibit mesolimbic dopamine function in adults experiencing nicotine withdrawal. Our findings provide a potential mechanism involving VTA amino acid neurotransmission that modulates age differences during withdrawal. PMID:22905672

  15. Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats.

    PubMed

    Sakashita, Yuichi; Abe, Kenji; Katagiri, Nobuyuki; Kambe, Toshie; Saitoh, Toshiaki; Utsunomiya, Iku; Horiguchi, Yoshie; Taguchi, Kyoji

    2015-01-01

    Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate). In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway. PMID:25342005

  16. Separate neural substrates for skill learning and performance in the ventral and dorsal striatum.

    PubMed

    Atallah, Hisham E; Lopez-Paniagua, Dan; Rudy, Jerry W; O'Reilly, Randall C

    2007-01-01

    It is widely accepted that the striatum of the basal ganglia is a primary substrate for the learning and performance of skills. We provide evidence that two regions of the rat striatum, ventral and dorsal, play distinct roles in instrumental conditioning (skill learning), with the ventral striatum being critical for learning and the dorsal striatum being important for performance but, notably, not for learning. This implies an actor (dorsal) versus director (ventral) division of labor, which is a new variant of the widely discussed actor-critic architecture. Our results also imply that the successful performance of a skill can ultimately result in its establishment as a habit outside the basal ganglia. PMID:17187065

  17. Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats.

    PubMed

    Simmons, Steven J; Gentile, Taylor A; Mo, Lili; Tran, Fionya H; Ma, Sisi; Muschamp, John W

    2016-11-01

    Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated

  18. Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy

    PubMed Central

    Walker, Q. David; Johnson, Misha L.; Van Swearingen, Amanda E.D.; Arrant, Andrew E.; Caster, Joseph M.; Kuhn, Cynthia M.

    2012-01-01

    Ovarian hormones modulate the pharmacological effects of psychostimulants and may enhance vulnerability to drug addiction. Female rats have more midbrain dopamine neurons than males and greater dopamine uptake and release rates. Cocaine stimulates motor behavior and dopamine efflux more in female than male rats, but the mediating mechanisms are unknown. This study investigated individual differences in anatomic, neurochemical, and behavioral measures in female rats to understand how ovarian hormones affect the relatedness of these endpoints. Ovarian hormone effects were assessed by comparing individual responses in ovariectomized (OVX) and sham adult female rats. Locomotion was determined before and following 10 mg/kg cocaine. Electrically-stimulated dopamine efflux was assessed using fast cyclic voltammetry in vivo. Dopamine neuron number and density in substantia nigra (SN) and ventral tegmental area (VTA) were determined in the same animals using tyrosine-hydroxylase immunohistochemistry and unbiased stereology. Locomotor behavior and dopamine efflux did not differ at baseline but were greater in sham than OVX following cocaine. Cocaine increased dopamine release rates in both groups but uptake inhibition (Km) was greater in sham than OVX. Dopamine neuron number and density in SN and VTA were greater in shams. Sham females with the largest uterine weights exhibited the highest density of dopamine neurons in the SN, and the most cocaine-stimulated behavior and dopamine efflux. Ovariectomy eliminated these relationships. We postulate that SN density could link ovarian hormones and high-psychostimulant responses in females. Similar mechanisms may be involved in individual differences in the addiction vulnerability of women. PMID:22342988

  19. Decomposition of abnormal free locomotor behavior in a rat model of Parkinson's disease

    PubMed Central

    Grieb, Benjamin; von Nicolai, Constantin; Engler, Gerhard; Sharott, Andrew; Papageorgiou, Ismini; Hamel, Wolfgang; Engel, Andreas K.; Moll, Christian K.

    2013-01-01

    Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video-monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a “first” and “second gear” of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease. PMID:24348346

  20. ANI inactivation: unconditioned anxiolytic effects of anisomycin in the ventral hippocampus.

    PubMed

    Greenberg, Anastasia; Ward-Flanagan, Rachel; Dickson, Clayton T; Treit, Dallas

    2014-11-01

    Although hippocampal function is typically described in terms of memory, recent evidence suggests a differentiation along its dorsal/ventral axis, with dorsal regions serving memory and ventral regions serving emotion. While long-term memory is thought to be dependent on de novo protein synthesis because it is blocked by translational inhibitors such as anisomycin (ANI), online (moment-to-moment) functions of the hippocampus (such as unconditioned emotional responding) should not be sensitive to such manipulations since they are unlikely to involve neuroplasticity. However, ANI has recently been shown to suppress neural activity which suggests (1) that protein synthesis is critical for neural function and (2) that paradigms using ANI are confounded by its inactivating effects. We tested this idea using a neurobehavioral assay which compared the influence of intrahippocampal infusions of ANI at dorsal and ventral sites on unconditioned emotional behavior of rats. We show that ANI infusions in ventral, but not dorsal, hippocampus produced a suppression of anxiety-related responses in two well-established rodent tests: the elevated plus maze and shock-probe burying tests. These results are similar to those previously observed when ventral hippocampal activity is directly suppressed (e.g., by using sodium channel blockers). The present study offers compelling behavioral evidence for the proposal that ANI adversely affects ongoing neural function and therefore its influence is not simply limited to impairing the consolidation of long-term memories PMID:24910137

  1. Rats showing low and high sensitization of frequency-modulated 50-kHz vocalization response to amphetamine differ in amphetamine-induced brain Fos expression.

    PubMed

    Kaniuga, Ewelina; Taracha, Ewa; Stępień, Tomasz; Wierzba-Bobrowicz, Teresa; Płaźnik, Adam; Chrapusta, Stanisław J

    2016-10-01

    Individuals predisposed to addiction constitute a minority of drug users, in both humans and animal models of the disorder, but there are no established characteristics that would allow identifying them beforehand. Our studies demonstrate that sensitization of rat 50-kHz ultrasonic vocalization (USV) response to amphetamine shows marked inter-individual diversity but substantial intra-individual stability. Low sensitization of the response shows relevance to the acquisition of self-administration of this drug and hence might be of predictive value regarding the risk of addiction. We compared amphetamine-induced Fos expression in 16 brain regions considered important for the development of addiction between rats preselected for low and high sensitization of the response and next given nine daily amphetamine doses followed by a 2-week withdrawal and final amphetamine challenge. Ventral tegmental area and nucleus accumbens shell Fos-positive nuclei counts correlated positively with 50-kHz USV response to the challenge in high-sensitized rats. Compared to those in amphetamine-untreated controls, Fos-positive nuclei counts were significantly and markedly (2-6 times) higher in 12 regions in high-sensitized rats, whereas in low-sensitized rats they were significantly higher in the cingulate cortex and dorsomedial striatum only. The difference in the counts between the latter two subsets reached statistical significance in dorsomedial and dorsolateral striatum and three out of four cortical regions studied. The fact that the diversification was most distinct in dorsal striatum that plays a critical role in the transition from controlled to compulsive drug intake suggests that the USV-based categorization may be related to divergent vulnerability of rats to AMPH addiction. PMID:27507424

  2. Sub-chronic treatment with classical but not atypical antipsychotics produces morphological changes in rat nigro-striatal dopaminergic neurons directly related to "early onset" vacuous chewing.

    PubMed

    Marchese, Giorgio; Casu, Maria Antonietta; Bartholini, Francesco; Ruiu, Stefania; Saba, Pierluigi; Gessa, Gian Luigi; Pani, Luca

    2002-04-01

    In the present work, we investigated if an impairment of dopaminergic neurons after subchronic haloperidol treatment might be a possible physiopathologic substrate of the "early onset" vacuous chewing movements (VCMs) in rats. For this purpose, different antipsychotics were used to analyse a possible relationship between VCMs development and morphological alterations of tyrosine-hydroxylase-immunostained (TH-IM) neurons. Rats treated twice a day with haloperidol displayed a significant increase of VCMs that was both time- (2-4 weeks) and dose (0.1-1 mg/kg) dependent. Immunocytochemical analysis showed a shrinkage of TH-IM cell bodies in substantia nigra pars compacta and reticulata and a reduction of TH-immunostaining in the striatum of haloperidol treated rats with the arising of VCMs. No differences were observed in TH-IM neurons of ventral tegmental area and nucleus accumbens vs. control rats. The atypical antipsychotics risperidone (2 mg/kg, twice a day), amisulpride (20 mg/kg, twice a day) and clozapine (10 mg/kg, twice a day) did not produce any nigro-striatal morphological changes or VCMs. TH-IM nigro-striatal neuron morphological alterations and VCMs were still present after three days of withdrawal in rats treated for four weeks with haloperidol (1 mg/kg). Both the main morphological changes and the behavioural correlate disappeared after three weeks of withdrawal. These results suggest that haloperidol induces a morphological impairment of the dopaminergic nigro-striatal neurons which is directly associated with the arising, permanency and disappearance of VCMs in rats. PMID:11982629

  3. Differential roles of ventral pallidum subregions during cocaine self-administration behaviors

    PubMed Central

    Root, David H.; Ma, Sisi; Barker, David J.; Megehee, Laura; Striano, Brendan M.; Ralston, Carla M.; Fabbricatore, Anthony T.; West, Mark O.

    2012-01-01

    The ventral pallidum (VP) is necessary for drug-seeking behavior. VP contains ventromedial (VPvm) and dorsolateral (VPdl) subregions which receive projections from the nucleus accumbens shell and core, respectively. To date, no study has investigated the behavioral functions of the VPdl and VPvm subregions. To address this issue, we investigated whether changes in firing rate (FR) differed between VP subregions during four events: approaching toward, responding on, or retreating away from a cocaine-reinforced operandum, and a cocaine-associated cue. Baseline FR and waveform characteristics did not differ between subregions. VPdl neurons exhibited a greater change in FR compared to VPvm neurons during approaches toward, as well as responses on, the cocaine-reinforced operandum. VPdl neurons were more likely to exhibit a similar change in FR (direction and magnitude) during approach and response than VPvm neurons. In contrast, VPvm firing patterns were heterogeneous, changing FRs during approach or response alone, or both. VP neurons did not discriminate cued behaviors from uncued behaviors. No differences were found between subregions during the retreat and no VP neurons exhibited patterned changes in FR in response to the cocaine-associated cue. The stronger, sustained FR changes of VPdl neurons during approach and response may implicate VPdl in the processing of drug-seeking and drug-taking behavior via projections to subthalamic nucleus and substantia nigra pars reticulata. In contrast, heterogeneous firing patterns of VPvm neurons may implicate VPvm in facilitating mesocortical structures with information related to the sequence of behaviors predicting cocaine self-infusions via projections to mediodorsal thalamus and ventral tegmental area. PMID:22806483

  4. Parkinson's disease duration determines effect of dopaminergic therapy on ventral striatum function.

    PubMed

    MacDonald, Alex A; Monchi, Oury; Seergobin, Ken N; Ganjavi, Hooman; Tamjeedi, Ruzbeh; MacDonald, Penny A

    2013-02-01

    We investigated the hypothesis that variation in endogenous dopamine (DA) across brain regions explains dissimilar effects of dopaminergic therapy on aspects of cognition in early Parkinson's disease (PD). Extensive degeneration of DA-producing cells in the substantia nigra cause dorsal striatum (DS) DA deficiency and movement abnormalities. Particularly in early PD, this contrasts with relative sparing of the dopaminergic cells of the ventral tegmental area (VTA). The hypothesis predicts that DS-mediated cognitive functions are deficient at baseline and improved by DA replacement, whereas functions depending upon VTA-innervated brain regions are normal off medication and worsen with treatment. The latter pattern presumably owes to overdose of relatively DA-replete VTA-supplied brain regions with medication levels titrated to DS-mediated motor symptoms. As PD progresses, however, VTA degeneration increases. Impairment in cognitive operations performed by VTA-innervated brain regions, such as the ventral striatum (VS), is expected. We compared the performance of early and late PD patients, on and off dopaminergic medication, relative to age-matched controls, on reward learning, previously shown to implicate the VS. As expected, in early PD, stimulus-reward learning was normal off medication, but worsened with DA replacement. At more advanced disease stages, PD patients learned stimulus-reward contingencies more poorly than controls and early PD patients off medication. Furthermore, dopaminergic medication did not worsen reward learning in late PD patients, in line with the dopamine overdose hypothesis. Unlike its effect on DS-mediated functions, however, DA-replacement therapy did not improve reward learning in late PD patients. PMID:23165957

  5. Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking.

    PubMed

    Venkiteswaran, Kala; Alexander, Danielle N; Puhl, Matthew D; Rao, Anand; Piquet, Amanda L; Nyland, Jennifer E; Subramanian, Megha P; Iyer, Puja; Boisvert, Matthew M; Handly, Erin; Subramanian, Thyagarajan; Grigson, Patricia Sue

    2016-05-01

    Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the 'reward pathway' that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that the RPEC graft provides beneficial effects to prevent drug seeking in drug addiction via its effects directly on the NAc and its neural network with the VTA. PMID:26562520

  6. Quantitative autoradiography of /sup 3/H-nomifensine binding sites in rat brain

    SciTech Connect

    Scatton, B.; Dubois, A.; Dubocovich, M.L.; Zahniser, N.R.; Fage, D.

    1985-03-04

    The distribution of /sup 3/H-nomifensine binding sites in the rat brain has been studied by quantitative autoradiography. The binding of /sup 3/H-nomifensine to caudate putamen sections was saturable, specific, of a highly affinity (Kd = 56 nM) and sodium-dependent. The dopamine uptake inhibitors benztropine, nomifensine, cocaine, bupropion and amfonelic acid were the most potent competitors of /sup 3/H-nomifensine binding to striatal sections. The highest levels of (benztropine-displaceable) /sup 3/H-nomifensine binding sites were found in the caudate-putamen, the olfactory tubercle and the nucleus accumbens. 6-Hydroxy-dopamine-induced lesion of the ascending dopaminergic bundle resulted in a marked decrease in the /sup 3/H-ligand binding in these areas. Moderately high concentrations of the /sup 3/H-ligand were observed in the bed nucleus of the stria terminalis, the anteroventral thalamic nucleus, the cingulate cortex, the lateral septum, the hippocampus, the amygdala, the zona incerta and some hypothalamic nuclei. There were low levels of binding sites in the habenula, the dorsolateral geniculate body, the substantia nigra, the ventral tegmental area and the periaqueductal gray matter. These autoradiographic data are consistent with the hypothesis that /sup 3/H-nomifensine binds primarily to the presynaptic uptake site for dopamine but also labels the norepinephrine uptake site. 33 references, 2 figures, 1 table.

  7. Oxytocin-Dopamine Interactions Mediate Variations in Maternal Behavior in the Rat

    PubMed Central

    Shahrokh, Dara K.; Zhang, Tie-Yuan; Diorio, Josie; Gratton, Alain; Meaney, Michael J.

    2010-01-01

    Variations in maternal behavior among lactating rats associate with differences in estrogen-oxytocin interactions in the medial preoptic area (mPOA) and in dopamine levels in the nucleus accumbens (nAcc). Thus, stable, individual differences in pup licking/grooming (LG) are abolished by oxytocin receptor blockade or treatments that eliminate differences in the nAcc dopamine signal. We provide novel evidence for a direct effect of oxytocin at the level of the ventral tegmental area (VTA) in the regulation of nAcc dopamine levels. Mothers that exhibit consistently increased pup LG (i.e. high LG mothers) by comparison with low LG mothers show increased oxytocin expression in the mPOA and the paraventricular nucleus of the hypothalamus and increased projections of oxytocin-positive cells from both mPOA and paraventricular nucleus of the hypothalamus to the VTA. Direct infusion of oxytocin into the VTA increased the dopamine signal in the nAcc. Finally, high compared with low LG mothers show greater increases in dopamine signal in the nAcc during bouts of pup LG, and this difference is abolished with infusions of an oxytocin receptor antagonist directly into the VTA. These studies reveal a direct effect of oxytocin on dopamine release within the mesocorticolimbic dopamine system and are consistent with previous reports of oxytocin-dopamine interactions in the establishment and maintenance of social bonds. PMID:20228171

  8. Differential activation of dopaminergic systems in rat brain basal ganglia by morphine and methamphetamine.

    PubMed

    Mori, T; Iwase, Y; Saeki, T; Iwata, N; Murata, A; Masukawa, D; Suzuki, T

    2016-05-13

    Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system. PMID:26820597

  9. An update on the connections of the ventral mesencephalic dopaminergic complex

    PubMed Central

    Yetnikoff, Leora; Lavezzi, Heather N.; Reichard, Rhett A.; Zahm, Daniel S.

    2014-01-01

    This review covers the intrinsic organization and afferent and efferent connections of the midbrain dopaminergic complex, comprising the substantia nigra, ventral tegmental area and retrorubral field, which house, respectively, the A9, A10 and A8 groups of nigrostriatal, mesolimbic and mesocortical dopaminergic neurons. In addition, A10dc (dorsal, caudal) and A10rv (rostroventral) extensions into, respectively, the ventrolateral periaqueductal gray and supramammillary nucleus are discussed. Associated intrinsic and extrinsic connections of the midbrain dopaminergic complex that utilize gamma-aminobutyric acid (GABA), glutamate and neuropeptides and various co-expressed combinations of these compounds are considered in conjunction with the dopamine-containing systems. A framework is provided for understanding the organization of masssive afferent systems descending and ascending to the midbrain dopaminergic complex from the telencephalon and brainstem, respectively. Within the context of this framework, the basal ganglia direct and indirect output pathways are treated in some detail. Findings from rodent brain are briefly compared with those from primates, including human. Recent literature is emphasized, including traditional experimental neuroanatomical and modern gene transfer and optogenetic studies. An attempt was made to provide sufficient background and cite a representative sampling of earlier primary papers and reviews so that people new to the field may find this to be a relatively comprehensive treatment of the subject. PMID:24735820

  10. An update on the connections of the ventral mesencephalic dopaminergic complex.

    PubMed

    Yetnikoff, L; Lavezzi, H N; Reichard, R A; Zahm, D S

    2014-12-12

    This review covers the intrinsic organization and afferent and efferent connections of the midbrain dopaminergic complex, comprising the substantia nigra, ventral tegmental area and retrorubral field, which house, respectively, the A9, A10 and A8 groups of nigrostriatal, mesolimbic and mesocortical dopaminergic neurons. In addition, A10dc (dorsal, caudal) and A10rv (rostroventral) extensions into, respectively, the ventrolateral periaqueductal gray and supramammillary nucleus are discussed. Associated intrinsic and extrinsic connections of the midbrain dopaminergic complex that utilize gamma-aminobutyric acid (GABA), glutamate and neuropeptides and various co-expressed combinations of these compounds are considered in conjunction with the dopamine-containing systems. A framework is provided for understanding the organization of massive afferent systems descending and ascending to the midbrain dopaminergic complex from the telencephalon and brainstem, respectively. Within the context of this framework, the basal ganglia direct and indirect output pathways are treated in some detail. Findings from rodent brain are briefly compared with those from primates, including humans. Recent literature is emphasized, including traditional experimental neuroanatomical and modern gene transfer and optogenetic studies. An attempt was made to provide sufficient background and cite a representative sampling of earlier primary papers and reviews so that people new to the field may find this to be a relatively comprehensive treatment of the subject. PMID:24735820

  11. Illustrated Review of the Ventral Striatum's Olfactory Tubercle.

    PubMed

    Xiong, Angeline; Wesson, Daniel W

    2016-09-01

    Modern neuroscience often relies upon artistic renderings to illustrate key aspects of anatomy. These renderings can be in 2 or even 3 dimensions. Three-dimensional renderings are especially helpful in conceptualizing highly complex aspects of neuroanatomy which otherwise are not visually apparent in 2 dimensions or even intact biological samples themselves. Here, we provide 3 dimensional renderings of the gross- and cellular-anatomy of the rodent olfactory tubercle. Based upon standing literature and detailed investigations into rat brain specimens, we created biologically inspired illustrations of the olfactory tubercle in 3 dimensions as well as its connectivity with olfactory bulb projection neurons, the piriform cortex association fiber system, and ventral pallidum medium spiny neurons. Together, we intend for these illustrations to serve as a resource to the neuroscience community in conceptualizing and discussing this highly complex and interconnected brain system with established roles in sensory processing and motivated behaviors. PMID:27340137

  12. Dopaminergic projections to the medial preoptic area of postpartum rats

    PubMed Central

    Miller, Stephanie M.; Lonstein, Joseph S.

    2010-01-01

    Dopamine receptor activity in the rodent medial preoptic area (mPOA) is crucial for the display of maternal behaviors, as well as numerous other physiological and behavioral functions. However, the origin of dopaminergic input to the mPOA has not been identified through neuroanatomical tracing. To accomplish this, the retrograde tracer Fluorogold was iontophoretically applied to the mPOA of postpartum laboratory rats, and dual-label immunocytochemistry for Fluorogold and tyrosine hydroxylase later performed to identify dopaminergic cells of the forebrain and midbrain projecting to the mPOA. Results indicate that the number of dopaminergic cells projecting to the mPOA is moderate (~90 cells to one hemisphere), and that these cells have an unexpectedly wide distribution. Even so, more than half of the dual-labeled cells were found in what has been considered extensions of the A10 dopamine group (particularly the ventrocaudal posterior hypothalamus and adjacent medial supramammillary nucleus), or in the A10 cells of the ventral tegmental area. The rostral hypothalamus and surrounding region also contained numerous dual-labeled cells, with the greatest number found within the mPOA itself (including in the AVPV and PVpo). Notably, dual-labeled cells were rare in the zona incerta (A13), a site previously suggested to provide dopaminergic input to the mPOA. This study is the first to use anatomical tracing to detail the dopaminergic projections to the mPOA in the laboratory rat, and indicates that much of this projection originates more caudally than previously suggested. PMID:19409227

  13. Ventral-clap modes of hovering passerines

    NASA Astrophysics Data System (ADS)

    Chang, Yu-Hung; Ting, Shang-Chieh; Su, Jian-Yuan; Soong, Chyi-Yeou; Yang, Jing-Tang

    2013-02-01

    Some small birds typically clap their wings ventrally, particularly during hovering. To investigate this phenomenon, we analyzed the kinematic motion and wake flow field of two passerine species that hover with the same flapping frequency. For these two birds, the ventral clap is classified as direct and cupping. Japanese White-eyes undertake a direct clap via their hand wings, whereas Gouldian Finches undertake a cupping clap with one wing overlaying the other. As a result of their morphological limitation, birds of both greater size and wing span cup their wings to increase the wing speed during a ventral clap because of the larger wing loading. This morphological limitation leads also to a structural discrepancy of the wake flow fields between these two passerine species. At the instant of clapping, the direct clap induces a downward air velocity 1.68 times and generates a weight-normalized lift force 1.14 times that for the cupping clap. The direct clap produces a small upward jet and a pair of counter-rotating vortices, both of which abate the transient lift at the instant of clapping, but they are not engendered by the cupping clap. The aerodynamic mechanisms generated with a ventral clap help the small birds to avoid abrupt body swinging at the instant of clapping so as to maintain their visual stability during hovering.

  14. Dorsal and Ventral Pathways for Prosody.

    PubMed

    Sammler, Daniela; Grosbras, Marie-Hélène; Anwander, Alfred; Bestelmeyer, Patricia E G; Belin, Pascal

    2015-12-01

    Our vocal tone--the prosody--contributes a lot to the meaning of speech beyond the actual words. Indeed, the hesitant tone of a "yes" may be more telling than its affirmative lexical meaning. The human brain contains dorsal and ventral processing streams in the left hemisphere that underlie core linguistic abilities such as phonology, syntax, and semantics. Whether or not prosody--a reportedly right-hemispheric faculty--involves analogous processing streams is a matter of debate. Functional connectivity studies on prosody leave no doubt about the existence of such streams, but opinions diverge on whether information travels along dorsal or ventral pathways. Here we show, with a novel paradigm using audio morphing combined with multimodal neuroimaging and brain stimulation, that prosody perception takes dual routes along dorsal and ventral pathways in the right hemisphere. In experiment 1, categorization of speech stimuli that gradually varied in their prosodic pitch contour (between statement and question) involved (1) an auditory ventral pathway along the superior temporal lobe and (2) auditory-motor dorsal pathways connecting posterior temporal and inferior frontal/premotor areas. In experiment 2, inhibitory stimulation of right premotor cortex as a key node of the dorsal stream decreased participants' performance in prosody categorization, arguing for a motor involvement in prosody perception. These data draw a dual-stream picture of prosodic processing that parallels the established left-hemispheric multi-stream architecture of language, but with relative rightward asymmetry. PMID:26549262

  15. Ventral vs. dorsal chick dermal progenitor specification.

    PubMed

    Fliniaux, Ingrid; Viallet, Jean P; Dhouailly, Danielle

    2004-01-01

    The dorsal and the ventral trunk integuments of the chick differ in their dermal cell lineage (originating from the somatic and somatopleural mesoderm respectively) and in the distribution of their feather fields. The dorsal macropattern has a large spinal pteryla surrounded by semi-apteria, whereas the ventral skin has a true medial apterium surrounded by the ventral pterylae. Comparison of the results of heterotopic transplantations of distal somatopleure in place of somatic mesoderm (Mauger 1972) or in place of proximal somatopleure (our data), leads to two conclusions. These are that the fate of the midventral apterium is not committed at day 2 of incubation and that the signals from the environment which specify the ventral and dorsal featherforming dermal progenitors are different. Effectively, Shh, but not Wnt -1 signalling can induce the formation of feather forming dermis from the embryonic somatopleure. Shh is not able, however, to trigger the formation of a feather forming dermis from the extra embryonic somatopleure. This brief report constitutes the first attempt, by comparing old and new preliminary results, to understand whether dermal progenitors at different sites are specified by different signalling pathways. PMID:15272375

  16. National results after ventral hernia repair.

    PubMed

    Helgstrand, Frederik

    2016-07-01

    Ventral hernia repairs are among the most frequently performed surgical procedures. The variations of repair techniques are multiple and outcome has been unacceptable. Despite the high volume, it has been difficult to obtain sufficient data to provide evidence for best practice. In order to monitor national surgical quality and provide the warranted high volume data, the first national ventral hernia register (The Danish Ventral Hernia Database) was established in 2007 in Denmark. The present study series show that data from a well-established database supported by clinical examinations, patient files, questionnaires, and administrative data makes it possible to obtain nationwide high volume data and to achieve evidence for better outcome in a complex surgical condition as ventral hernia. Due to the high volume and included variables on surgical technique, it is now possible to make analyses adjusting for a variety of surgical techniques and different hernia specifications. We documented high 30-day complications and recurrence rates for both primary and secondary ventral hernias in a nationwide cohort. Furthermore, recurrence found by clinical examination was shown to exceed the number of patients undergoing reoperation for recurrence by a factor 4-5. The nationwide adjusted analyses proved that open mesh and laparoscopic repair for umbilical and epigastric hernias does not differ in 30-day outcome or in risk of recurrence. There is a minor risk reduction in early complications after open sutured repairs. However, the risk for a later recurrence repair is significantly higher after sutured repairs compared with mesh repairs. The study series showed that large hernia defects and open re-pairs were independent predictors for 30-day complications after an incisional hernia repair. Open procedures and large hernia defects were independent risk factors for a later recurrence re-pair. However, patients with large defects (> 15 cm) seemed to benefit from an open mesh

  17. Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.

    PubMed

    Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Panlilio, Leigh V; Fattore, Liana; Goldberg, Steven R; Fratta, Walter; Fadda, Paola

    2016-04-01

    Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans. PMID:26388146

  18. Autoradiographic localization of /sup 3/H-paroxetine-labeled serotonin uptake sites in rat brain

    SciTech Connect

    De Souza, E.B.; Kuyatt, B.L.

    1987-01-01

    Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.

  19. Norepinephrine Activates Dopamine D4 Receptors in the Rat Lateral Habenula

    PubMed Central

    Root, David H.; Hoffman, Alexander F.; Good, Cameron H.; Zhang, Shiliang; Gigante, Eduardo

    2015-01-01

    The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function. PMID:25716845

  20. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms

    PubMed Central

    Lim, L W; Prickaerts, J; Huguet, G; Kadar, E; Hartung, H; Sharp, T; Temel, Y

    2015-01-01

    Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN. PMID:25826110

  1. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms.

    PubMed

    Lim, L W; Prickaerts, J; Huguet, G; Kadar, E; Hartung, H; Sharp, T; Temel, Y

    2015-01-01

    Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN. PMID:25826110

  2. Brain activation by an olfactory stimulus paired with juvenile play in female rats.

    PubMed

    Paredes-Ramos, P; McCarthy, M M; Bowers, J M; Miquel, M; Manzo, J; Coria-Avila, G A

    2014-06-22

    We have previously shown that reward experienced during social play at juvenile age can be paired with artificial odors, and later in adulthood facilitate olfactory conditioned partner preferences (PP) in female rats. Herein, we examined the expression of FOS immunoreactivity (FOS-IR) following exposure to the odor paired with juvenile play (CS+). Starting at day P31 females received daily 30-min periods of social play with lemon-scented (paired group) or unscented females (unpaired group). At day P42, they were tested for play-PP with two juvenile males, one bearing the CS+ (lemon) and one bearing a novel odor (almond). Females were ovariectomized, hormone-primed and at day P55 tested for sexual-PP between two adult stud males scented with lemon or almond. In both tests, females from the paired group displayed conditioned PP (play or sexual) toward males bearing the CS+. In the present experiments females were exposed at day P59 to the CS+ during 60 min and their brains processed for FOS-IR. One group of female rats (Play+Sex) underwent play-PP and sexual-PP, whereas a second group of females (Play-only) underwent exclusively play-PP but not sexual-PP. Results showed that in the Play-only experiment exposure to the CS+ induced more FOS-IR in the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, and ventral tegmental area as compared to females from the unpaired group. In the Play+Sex experiment, more FOS-IR was observed in the piriform cortex, dorsal striatum, lateral septum, nucleus accumbens shell, bed nucleus of the stria terminalis and medial amygdala as compared to females from the unpaired group. Taken together, these results indicate mesocorticolimbic brain areas direct the expectation and/or choice of conditioned partners in female rats. In addition, transferring the meaning of play to sex preference requires different brain areas. PMID:24835545

  3. Differential regional responsiveness of astroglia in mild hepatic encephalopathy: An Immunohistochemical approach in bile duct ligated rat.

    PubMed

    Hiba, Omar El; Elgot, Abdeljalil; Ahboucha, Samir; Gamrani, Halima

    2016-05-01

    Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. However, the pathomechanisms of the disease remains obscure. Neuropathological studies have demonstrated a primary gliopathy in humans as well as in animal models of chronic and acute liver failure. Here, we have investigated in an animal model of mild HE: the bile duct ligated rat (BDL) at the cirrhotic stage (4 weeks after surgery), the expression of the key marker of mature astrocytes; the glial fibrillary acidic protein (GFAP) in different brain areas such as: Substantia nigra pars compacta (SNc), Ventral tegmental area (VTA), hippocampus, dorsal striatum and brain cortex by means of immunohistochemistry. The immunohistochemical study showed, in BDL compared to the operated controls (shams), a diminished astrocyte reactivity corresponding to a loss of GFAP expression within SNc, VTA, hippocampus and dorsal striatum (p<0.05),whereas in the brain cortex astrocytes appeared strongly immunoreactive with increased GFAP expression (p<0.05) as compared to shams. Our finding demonstrated differential astroglial responses which depend to the specificity of the area investigated and its particular neuronal neighboring environment, and could have possible outcomes on the diverse neuronal functions especially those observed during the different episodes of hepatic encephalopathy. PMID:26995310

  4. Nicotine mediates expression of genes related to antioxidant capacity and oxidative stress response in HIV-1 transgenic rat brain.

    PubMed

    Song, Guohua; Nesil, Tanseli; Cao, Junran; Yang, Zhongli; Chang, Sulie L; Li, Ming D

    2016-02-01

    Oxidative stress plays an important role in the progression of HIV-1 infection. Nicotine can either protect neurons from neurodegeneration or induce oxidative stress, depending on its dose and degree of oxidative stress impairment. However, the relationship between nicotine and oxidative stress in the HIV-1-infected individuals remains largely unknown. The purpose of this study was to determine the effect of nicotine on expression of genes related to the glutathione (GSH)-centered antioxidant system and oxidative stress in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of HIV-1 transgenic (HIV-1Tg) and F344 control rats. Adult HIV-1Tg and F344 rats received nicotine (0.4 mg/kg, base, s.c.) or saline injections once per day for 27 days. At the end of treatment, various brain regions including the NAc and VTA were collected from each rat. Following total RNA extraction and complementary DNA (cDNA) synthesis of each sample, quantitative reverse transcription PCR (RT-PCR) analysis was performed for 43 oxidative-stress-related genes. Compared with F344 control rats, HIV-1Tg rats showed a significant downregulation of genes involved in ATPase and cyctochrome oxidase at the messenger RNA (mRNA) level in both regions. Further, we found a significant downregulation of Gstm5 in the NAc and upregulation of Cox1, Cox3, and Gsta6 in the VTA of HIV-1Tg rats. HIV-1Tg rats showed brain-region-specific responses to chronic nicotine treatment. This response resulted in a change in the expression of genes involved in antioxidant mechanisms including the downregulation of genes such as Atp5h, Calml1, Gpx7, Gstm5, Gsr, and Gsta6 and upregulation of Sod1 in the NAc, as well as downregulation of genes like Cox5a, Gpx4, Gpx6, Gpx7, Gstm5, and Sod1 in the VTA of HIV-1Tg rats. Together, we conclude that chronic nicotine treatment has a dual effect on the antioxidant defense system and oxidative-stress-induced apoptosis signaling in HIV-1Tg rats. These findings suggest that

  5. Distinct effect of stress on 11beta-hydroxysteroid dehydrogenase type 1 and corticosteroid receptors in dorsal and ventral hippocampus.

    PubMed

    Ergang, P; Kuželová, A; Soták, M; Klusoňová, P; Makal, J; Pácha, J

    2014-01-01

    Multiple lines of evidence suggest the participation of the hippocampus in the feedback inhibition of the hypothalamus-pituitary-adrenal axis during stress response. This inhibition is mediated by glucocorticoid feedback due to the sensitivity of the hippocampus to these hormones. The sensitivity is determined by the expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors and 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that regulates the conversion of glucocorticoids from inactive to active form. The goal of our study was to assess the effect of stress on the expression of 11HSD1, GR and MR in the ventral and dorsal region of the CA1 hippocampus in three different rat strains with diverse responses to stress: Fisher 344, Lewis and Wistar. Stress stimulated 11HSD1 in the ventral but not dorsal CA1 hippocampus of Fisher 344 but not Lewis or Wistar rats. In contrast, GR expression following stress was decreased in the dorsal but not ventral CA1 hippocampus of all three strains. MR expression was not changed in either the dorsal or ventral CA1 region. These results indicate that (1) depending on the strain, stress stimulates 11HSD1 in the ventral hippocampus, which is known to be involved in stress and emotion reactions whereas (2) independent of strain, stress inhibits GR in the dorsal hippocampus, which is predominantly involved in cognitive functions. PMID:24397806

  6. The role of alpha-synuclein in the development of the dopaminergic neurons in the substantia nigra and ventral tegmental area.

    PubMed

    Tarasova, T V; Lytkina, O A; Roman, A Yu; Bachurin, S O; Ustyugov, A A

    2016-01-01

    Alpha-synuclein is a presynaptic protein of vertebrates that belongs to the family of synucleins. Normal functions of synucleins remain unknown. Alpha-synuclein is one of the causative factors of the familial and idiopathic forms of Parkinson's disease (PD). The progressive loss of dopaminergic (DA) neurons is characteristic of PD and the most severe damage occurs in the substantia nigra (SN). This leads to an erraticism of the synthesis and synaptic secretion of the neurotransmitters, subsequently resulting in the loss of the connections between brain areas. This work shows that alpha-synuclein is directly involved in the formation of the mature DA neurons of the midbrain at different stages of the ontogenesis and these findings are consistent with data obtained in other studies. Thus, alpha-synuclein may have a varying modulating effect on the growth dynamics and the fate of populations of DA neurons. PMID:27021360

  7. Ventral Schwannoma of the Thoracolumbar Spine

    PubMed Central

    Yamaguchi, Satoshi; Mori, Masanao; Kubo, Fumikatsu; Tokimura, Hiroshi; Arita, Kazunori

    2013-01-01

    We report two patients with ventral schwannoma in the thoracolumbar region manifesting as low back pain with or without paraparesis. In both patients magnetic resonance imaging (MRI) revealed a heterogeneously-enhanced intradural extramedullary mass in the thoracolumbar region. The tumors were successfully removed via the posterior approach. Their histology was consistent with schwannoma. Postoperative MRI showed no evidence of a tumor in either patient. Spinal schwannomas are common benign intradural extramedullary spinal neoplasms; most arise from the dorsal- and very few from the anterior roots. A literature review revealed that ventral schwannomas, including giant tumors as in the one from case 2 in our study, affect mainly the cervical region, and most are surgically addressed via the posterior approach. Careful handling of the spinal cord is mandatory for satisfactory surgical results. PMID:24353852

  8. Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit.

    PubMed

    Do-Monte, Fabricio H; Rodriguez-Romaguera, Jose; Rosas-Vidal, Luis E; Quirk, Gregory J

    2013-01-01

    Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression. PMID:23964215

  9. Comparison of the locomotor activating effects of bicuculline infusions into the preoptic area and ventral pallidum

    PubMed Central

    Zahm, Daniel S.; Schwartz, Zachary M.; Lavezzi, Heather N.; Yetnikoff, Leora; Parsley, Kenneth P.

    2013-01-01

    Ambulatory locomotion in the rodent is robustly activated by unilateral infusions into the basal forebrain of type A gamma-aminobutyric acid (GABAA) receptor antagonists, such as bicuculline and picrotoxin. The present study was carried out to better localize the neuroanatomical substrate(s) underlying this effect. To accomplish this, differences in total locomotion accumulated during a 20 minute test period following bicuculline versus saline infusions in male Sprague-Dawley rats were calculated, rank ordered and mapped on a diagram of basal forebrain transposed from immunoprocessed sections. The most robust locomotor activation was elicited by bicuculline infusions clustered in rostral parts of the preoptic area. Unilateral infusions of bicuculline into the ventral pallidum produced an unanticipatedly diminutive activation of locomotion, which led us to evaluate bilateral ventral pallidal infusions, and these also produced only a small activation of locomotion, and, interestingly, a non-significant trend toward suppression of rearing. Subjects with bicuculline infused bilaterally into the ventral pallidum also exhibited persistent bouts of abnormal movements. Bicuculline infused unilaterally into other forebrain structures, including the bed nucleus of stria terminalis, caudate-putamen, globus pallidus, sublenticular extended amygdala and sublenticular substantia innominata, did not produce significant locomotor activation. Our data identify the rostral preoptic area as the main substrate for the locomotor activating effects of basal forebrain bicuculline infusions. In contrast, slight activation of locomotion and no effect on rearing accompanied unilateral and bilateral ventral pallidal infusions. Implications of these findings for forebrain processing of reward are discussed. PMID:23423460

  10. Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats.

    PubMed

    Sárvári, Miklós; Deli, Levente; Kocsis, Pál; Márk, László; Maász, Gábor; Hrabovszky, Erik; Kalló, Imre; Gajári, Dávid; Vastagh, Csaba; Sümegi, Balázs; Tihanyi, Károly; Liposits, Zsolt

    2014-10-01

    The mesocortical dopaminergic pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) contributes to the processing of reward signals. This pathway is regulated by gonadal steroids including estradiol. To address the putative role of estradiol and isotype-selective estrogen receptor (ER) agonists in the regulation of the rodent mesocortical system, we combined fMRI, HPLC-MS and qRT-PCR techniques. In fMRI experiments adult, chronically ovariectomized rats, treated with either vehicle, estradiol, ERα agonist 16α-lactone-estradiol (LE2) or ERβ agonist diarylpropionitrile (DPN), received a single dose of d-amphetamine-sulphate (10mg/kg, i.p.) and BOLD responses were monitored in the VTA and the PFC. Ovariectomized rats showed no significant response to amphetamine. In contrast, the VTA of ER agonist-substituted ovariectomized rats showed robust amphetamine-evoked BOLD increases. The PFC of estradiol-replaced animals was also responsive to amphetamine. Mass spectroscopic analysis of dopamine and its metabolites revealed a two-fold increase in both dopamine and 3,4-dihydroxyphenylacetic acid content of the PFC in estradiol-replaced animals compared to ovariectomized controls. qRT-PCR studies revealed upregulation of dopamine transporter and dopamine receptor in the VTA and PFC, respectively, of ER agonist-treated ovariectomized animals. Collectively, the results indicate that E2 and isotype-selective ER agonists can powerfully modulate the responsiveness of the mesocortical dopaminergic system, increase the expression of key genes related to dopaminergic neurotransmission and augment the dopamine content of the PFC. In a broader sense, the findings support the concept that the manifestation of reward signals in the PFC is dependent on the actual estrogen milieu of the brain. PMID:24976584

  11. Ethanol reduces evoked dopamine release and slows clearance in the rat medial prefrontal cortex

    PubMed Central

    Shnitko, Tatiana A.; Kennerly, Laura C.; Spear, Linda P.; Robinson, Donita L.

    2014-01-01

    Background Ethanol intoxication affects cognitive performance, contributing to attentional deficits and poor decision making, which may occur via actions in the medial prefrontal cortex (mPFC). mPFC function is modulated by the catecholamines dopamine and norepinephrine. In this study, we examine the acute effects of ethanol on electrically-evoked dopamine release and clearance in the mPFC of anaesthetized rats naïve to alcohol or chronically exposed to alcohol during adolescence. Methods Dopamine release and clearance was evoked by electrical stimulation of the VTA and measured in the mPFC of anaesthetized rats with fast-scan cyclic voltammetry. In Experiments 1 and 2, effects of a high dose of ethanol (4g/kg, i.p.) on dopamine neurotransmission in the mPFC of ethanol-naïve rats and rats given ethanol exposure during adolescence were investigated. Effects of cumulative dosing of ethanol (0.5–4g/kg) on the dopamine release and clearance were investigated in Experiment 3. Experiment 4 studied effects of ethanol locally applied to the ventral tegmental area (VTA) on the dopamine neurotransmission in the mPFC of ethanol-naïve rats. Results A high dose of ethanol decreased evoked dopamine release within 10 min of administration in ethanol-naïve rats. When tested via cumulative dosing from 0.5–4g/kg, both 2 and 4g/kg ethanol inhibited evoked dopamine release in the mPFC of ethanol-naïve rats, while 4g/kg ethanol also slowed dopamine clearance. A similar effect on electrically-evoked dopamine release in the mPFC was observed after infusion of ethanol into the VTA. Interestingly, intermittent ethanol exposure during adolescence had no effect on observed changes in mPFC dopamine release and clearance induced by acute ethanol administration. Conclusions Taken together, these data describe ethanol-induced reductions in the dynamics of VTA-evoked mPFC dopamine release and clearance, with the VTA contributing to the attenuation of evoked mPFC dopamine release induced

  12. mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts.

    PubMed

    Caruso, Vanni; Sreedharan, Smitha; Carlini, Valeria P; Jacobsson, Josefin A; Haitina, Tatjana; Hammer, Joanna; Stephansson, Olga; Crona, Filip; Sommer, Wolfgang H; Risérus, Ulf; Lannfelt, Lars; Marcus, Claude; Heilig, Markus; de Barioglio, Susana R; Fredriksson, Robert; Schiöth, Helgi B

    2016-05-01

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis. PMID:26827797

  13. Activation of matrix metalloproteinase in dorsal hippocampus drives improvement in spatial working memory after intra-VTA nicotine infusion in rats.

    PubMed

    Shu, Hui; Zheng, Guo-qing; Wang, Xiaona; Sun, Yanyun; Liu, Yushan; Weaver, John Michael; Shen, Xianzhi; Liu, Wenlan; Jin, Xinchun

    2015-10-01

    The hippocampus receives dopaminergic projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences hippocampus-dependent behaviors. Enhancements in working memory performance have been previously reported following acute smoking/nicotine exposure. However, the underlying mechanism remains unclear. This study investigated the effects of nicotine on spatial working memory (SWM) and the mechanisms involved. Delayed alternation T-maze task was used to assess SWM. In situ and gel gelatin zymography were used to detect matrix metalloproteinase-9 (MMP-9) in SWM. Systemic or local (intra-VTA) administration of nicotine significantly improves SWM, which was accompanied by increased MMP-9 activity in dorsal hippocampus (dHPC). Intra-dHPC administration of MMP inhibitor FN-439 abolished the memory enhancement induced by intra-VTA nicotine infusion. FN-439 had no effect on locomotor behavior. Our data suggest that intra-VTA nicotine infusion activates MMP-9 in dHPC to improve SWM in rats. PMID:26263395

  14. Expression and colocalization of NMDA receptor and FosB/ΔFosB in sensitive brain regions in rats after chronic morphine exposure.

    PubMed

    Zhang, Qiang; Liu, Qi; Li, Tongzhou; Liu, You; Wang, Lei; Zhang, Zhonghai; Liu, Hongzhi; Hu, Min; Qiao, Yuehua; Niu, Haichen

    2016-02-12

    Research in the last decade demonstrated that the NMDA receptor (NMDAR) has an important role in opiate-induced neural and behavioral plasticity. In addition, increased levels of FosB-like proteins (FosB/ΔFosB) were found to be related to morphine withdrawal behaviors. However, the relationship between NMDAR and FosB/ΔFosB in sensitive brain regions during morphine withdrawal is largely unknown. In this study, we aimed to investigate NMDAR dynamics and FosB/ΔFosB levels in multiple brain regions and whether they are related in sensitive brain regions during morphine abstinence. Quantitative immunohistochemistry was adopted to test NMDAR and FosB/ΔfosB levels during morphine withdrawal in rats. Increased NMDAR and FosB/ΔFosB levels were found in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), central amygdaloid nucleuscapsular part (CeC), ventral tegmental area (VTA) and cingulate cortex (Cg). Double-immunofluorescence labeling indicated that NMDAR colocalized with Fos/ΔFosB in these five regions. These results suggest that multiple phenotypic regions are mediated by NMDAR and Fos/ΔFosB during morphine withdrawal, such as the motivational (AcbC, AcbSh), limbic (CeC, VTA) and executive (Cg) system pathways, and may be the primary targets of NMDAR and Fos/ΔfosB that impact morphine withdrawal behaviors. PMID:26655477

  15. AAV-Mediated Gene Transfer of the Obesity-Associated Gene Etv5 in Rat Midbrain Does Not Affect Energy Balance or Motivated Behavior

    PubMed Central

    Boender, Arjen J.; Koning, Nivard A.; van den Heuvel, José K.; Luijendijk, Mieneke C. M.; van Rozen, Andrea J.; la Fleur, Susanne E.; Adan, Roger A. H.

    2014-01-01

    Several genome-wide association studies have implicated the transcription factor E-twenty- six version 5 (Etv5) in the regulation of body mass index. Further substantiating the role of Etv5 in feeding behavior are the findings that targeted disruption of Etv5 in mice leads to decreased body weight gain and that expression of Etv5 is decreased in the ventral tegmental area and substantia nigra pars compacta (VTA/SNpc) after food restriction. As Etv5 has been suggested to influence dopaminergic neurotransmission by driving the expression of genes that are responsible for the synthesis and release of dopamine, we investigated if expression levels of Etv5 are dependent on nutritional state and subsequently influence the expression levels of tyrosine hydroxylase. While it was shown that Etv5 expression in the VTA/SNpc increases after central administration of leptin and that Etv5 was able to drive expression of tyrosine hydroxylase in vitro, AAV-mediated gene transfer of Etv5 into the VTA/SNpc of rats did not alter expression of tyrosine hydroxylase in vivo. Moreover, AAV-mediated gene transfer of Etv5 in the VTA/SNpc did not affect measures of energy balance or performances in a progressive ratio schedule. Thus, these data do not support a role for increased expression of Etv5 in the VTA/SNpc in the regulation of feeding behavior. PMID:24710089

  16. Brainstem tegmental lesions in neonates with hypoxic-ischemic encephalopathy: Magnetic resonance diagnosis and clinical outcome

    PubMed Central

    Quattrocchi, Carlo Cosimo; Fariello, Giuseppe; Longo, Daniela

    2016-01-01

    Lesions of the brainstem have been reported in the clinical scenarios of hypoxic-ischemic encephalopathy (HIE), although the prevalence of these lesions is probably underestimated. Neuropathologic studies have demonstrated brainstem involvement in severely asphyxiated infants as an indicator of poor outcome. Among survivors to HIE, the most frequent clinical complaints that may be predicted by brainstem lesions include feeding problems, speech, language and communication problems and visual impairments. Clinical series, including vascular and metabolic etiologies, have found selective involvement of the brainstem with the demonstration of symmetric bilateral columnar lesions of the tegmentum. The role of brainstem lesions in HIE is currently a matter of debate, especially when tegmental lesions are present in the absence of supra-tentorial lesions. Differential diagnosis of tegmental lesions in neonates and infants include congenital metabolic syndromes and drug-related processes. Brainstem injury with the presence of supratentorial lesions is a predictor of poor outcome and high rates of mortality and morbidity. Further investigation will be conducted to identify specific sites of the brainstem that are vulnerable to hypoxic-ischemic and toxic-metabolic insults. PMID:26981220

  17. A Method to Make a Craniotomy on the Ventral Skull of Neonate Rodents

    PubMed Central

    Rodríguez-Contreras, Adrián; Shi, Lingyan; Fu, Bingmei M.

    2014-01-01

    The use of a craniotomy for in vivo experiments provides an opportunity to investigate the dynamics of diverse cellular processes in the mammalian brain in adulthood and during development. Although most in vivo approaches use a craniotomy to study brain regions located on the dorsal side, brainstem regions such as the pons, located on the ventral side remain relatively understudied. The main goal of this protocol is to facilitate access to ventral brainstem structures so that they can be studied in vivo using electrophysiological and imaging methods. This approach allows study of structural changes in long-range axons, patterns of electrical activity in single and ensembles of cells, and changes in blood brain barrier permeability in neonate animals. Although this protocol has been used mostly to study the auditory brainstem in neonate rats, it can easily be adapted for studies in other rodent species such as neonate mice, adult rodents and other brainstem regions. PMID:24894439

  18. [Neurochemical features of the ventral pallidum in realization of the antiaversive effects of anxiolytics in different models of anxiety].

    PubMed

    Talalaenko, A N; Pankrat'ev, D V; Bulgakova, N P

    2006-01-01

    Preliminary intraperitoneal injections of some combinations of adreno- and dopaminomimetics, monoamines, and mediator amino acids (as well as of their agonists and antagonists) followed by microinjections of the same combinations into the ventral pallidum reveal differences in the functional significance of the neurochemical profile of this paleostriatum formation in realization of the anxiety states of different genesis, as manifested in the "illuminated site avoidance" and the "threatening situation" tests in rats. The pharmacological analysis based on the local injection of anxiosedative and anxioselective agents into the ventral paleostriatum showed that the antiaversive action of campirone is revealed under the conditions of dominating fear motivation, while that analogous action of chlordiazepoxide, phenibut and indoter is revealed under negative stressful zoosocial impacts and is realized by serotonin- and GABA-ergic (rather than by cathecholamine- and glutaminergic) aversive systems of the ventral pallidum. PMID:16579051

  19. Ventral lamina terminalis mediates enhanced cardiovascular responses of rostral ventrolateral medulla neurons during increased dietary salt.

    PubMed

    Adams, Julye M; Bardgett, Megan E; Stocker, Sean D

    2009-08-01

    Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the rostral ventrolateral medulla (RVLM). The purpose of the present study was to determine whether neurons of the forebrain lamina terminalis (LT) mediated these changes in the RVLM. Male Sprague-Dawley rats with and without LT lesions were fed normal chow and given access to water or 0.9% NaCl for 14 to 15 days. Unilateral injection of l-glutamate into the RVLM produced significantly larger increases in renal sympathetic nerve activity and arterial blood pressure of sham rats ingesting 0.9% NaCl versus water. However, these differences were not observed between ventral LT-lesioned rats drinking 0.9% NaCl versus water. Similar findings were observed when angiotensin II or gamma-aminobutyric acid was injected into the RVLM. Interestingly, a subset of animals drinking 0.9% but with damage restricted to the organum vasculosum of the lamina terminalis did not show enhanced responses to l-glutamate or gamma-aminobutyric acid. In marked contrast, RVLM injection of l-glutamate or gamma-aminobutyric acid produced exaggerated sympathetic nerve activity and arterial blood pressure responses in animals drinking 0.9% NaCl versus water after an acute ventral LT lesion or chronic lesion of the subfornical organ. Additional experiments demonstrated that plasma sodium concentration and osmolality were increased at night in rats ingesting 0.9% NaCl. These findings suggest that neurons of the ventral LT mediate the ability of increased dietary salt to enhance the responsiveness of RVLM sympathetic neurons. PMID:19506102

  20. Korean Red Ginseng attenuates anxiety-like behavior during ethanol withdrawal in rats

    PubMed Central

    Zhao, ZhengLin; Kim, Young Woo; Wu, YiYan; Zhang, Jie; Lee, Ju-Hee; Li, XiaoHua; Cho, Il Je; Park, Sang Mi; Jung, Dae Hwa; Yang, Chae Ha; Kim, Sang Chan; Zhao, RongJie

    2014-01-01

    Background Korean Red Ginseng (KRG) is known to have antianxiety properties. This study was conducted to investigate the anxiolytic effects of KRG extract (KRGE) during ethanol withdrawal (EW) and the involvement of the mesoamygdaloid dopamine (DA) system in it. Methods Rats were treated with 3 g/kg/d of ethanol for 28 d, and subjected to 3 d of withdrawal. During EW, KRGE (20 mg/kg/d or 60 mg/kg/d, p.o.) was given to rats once/d for 3 d. Thirty min after the final dose of KRGE, anxiety-like behavior was evaluated in an elevated plus maze (EPM), and plasma corticosterone (CORT) levels were determined by a radioimmunoassay (RIA). In addition, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the central nucleus of the amygdala (CeA) were also measured by high performance liquid chromatography (HPLC). Results The EPM test and RIA revealed KRGE inhibited anxiety-like behavior and the over secretion of plasma CORT during EW. Furthermore, the behavioral effect was blocked by a selective DA D2 receptor (D2R) antagonist (eticlopride) but not by a selective DA D1 receptor (D1R) antagonist (SCH23390). HPLC analyses showed KRGE reversed EW-induced decreases of DA and DOPAC in a dose-dependent way. Additionally, Western blotting and real-time polymerase chain reaction (PCR) assays showed that KRGE prevented the EW-induced reductions in tyrosine hydroxylase (TH) protein expression in the CeA and TH mRNA expression in the ventral tegmental area (VTA). Conclusion These results suggest that KRGE has anxiolytic effects during EW by improving the mesoamygdaloid DA system. PMID:25379005

  1. Application of fast-scan cyclic voltammetry for the in vivo characterization of optically evoked dopamine in the olfactory tubercle of the rat brain.

    PubMed

    Wakabayashi, Ken T; Bruno, Michael J; Bass, Caroline E; Park, Jinwoo

    2016-06-21

    The olfactory tubercle (OT), as a component of the ventral striatum, serves as an important multisensory integration center for reward-related processes in the brain. Recent studies show that dense dopaminergic innervation from the ventral tegmental area (VTA) into the OT may play an outsized role in disorders such as psychostimulant addiction and disorders of motivation, increasing recent scientific interest in this brain region. However, due to its anatomical inaccessibility, relative small size, and proximity to other dopamine-rich structures, neurochemical assessments using conventional methods cannot be readily employed. Here, we investigated dopamine (DA) regulation in the OT of urethane-anesthetized rats using in vivo fast-scan voltammetry (FSCV) coupled with carbon-fiber microelectrodes, following optogenetic stimulation of the VTA. The results were compared with DA regulation in the nucleus accumbens (NAc), a structure located adjacent to the OT and which also receives dense DA innervation from the VTA. FSCV coupled with optically evoked release allowed us to investigate the spatial distribution of DA in the OT and characterize OT DA dynamics (release and clearance) with subsecond temporal and micrometer spatial resolution for the first time. In this study, we demonstrated that DA transporters play an important role in regulating DA in the OT. However, the control of extracellular DA by uptake in the OT was less than in the NAc. The difference in DA transmission in the terminal fields of the OT and NAc may be involved in region-specific responses to drugs of abuse and contrasting roles in mediating reward-related behavior. PMID:27063845

  2. Oxytocin induces penile erection when injected into the ventral subiculum: role of nitric oxide and glutamic acid.

    PubMed

    Melis, Maria Rosaria; Succu, Salvatora; Cocco, Cristina; Caboni, Emanuela; Sanna, Fabrizio; Boi, Antonio; Ferri, Gian Luca; Argiolas, Antonio

    2010-06-01

    Oxytocin (100 ng) induces penile erection when injected unilaterally into the ventral subiculum of the hippocampus of male rats. The pro-erectile effect started mostly 30 min after treatment and occurred 15 min after an increase in both nitric oxide (NO) production, measured by the concentration of NO(2)(-) and NO(3)(-), the main metabolites of newly formed NO, and extra-cellular glutamic acid concentration in the dialysate obtained from the ventral subiculum by intracerebral microdialysis. These responses were abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (2 microg), an oxytocin receptor antagonist, S-methyl-L-thiocitrulline (SMTC), a selective inhibitor of neuronal NO-synthase (25 microg), and haemoglobin, a NO scavenger (25 microg), given into the ventral subiculum before oxytocin. Unlike d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin, SMTC and haemoglobin, (+)MK-801 (5 microg), a noncompetitive antagonist of NMDA receptors abolished oxytocin-induced penile erection, but reduced only partially the increase in NO production and extra-cellular glutamic acid. As NMDA (0.25-1 microg) injected into the ventral subiculum induces penile erection episodes, which also occurred with an increase of NO production and extra-cellular glutamic acid, and NMDA responses were abolished by (+)MK-801 (5 microg), but not by SMTC (25 microg) or haemoglobin (25 microg), injected into the ventral subiculum, these results show that oxytocin injected into the ventral subiculum increases NO production by activating its own receptors. NO in turn increases glutamic acid neurotransmission, leading to penile erection, possibly through neural (glutamatergic) efferent projections from the ventral subiculum to extra-hippocampal brain areas (e.g., prefrontal cortex) modulating the activity of mesolimbic dopaminergic neurons. PMID:20156463

  3. Regulation of dorsal-ventral patterning: the ventralizing effects of the novel Xenopus homeobox gene Vox.

    PubMed

    Schmidt, J E; von Dassow, G; Kimelman, D

    1996-06-01

    The formation of the dorsal-ventral axis in Xenopus laevis is elicited by a signaling cascade on the dorsal side of the embryo initiated by cortical rotation. These early developmental events impart an initial axial polarity to the embryo. By the time gastrulation occurs, the embryo has established opposing dorsal and ventral regulatory regions. Through a dynamic process, the embryo acquires a definitive pattern that reflects the distribution of future cell fates. Here we present a novel homeobox gene, Vox, whose expression reflects this dynamic process. Vox is first expressed throughout the embryo and subsequently eliminated from the notochord and neural plate. Ectopic expression of Vox demonstrates that the normal function of this gene may be to suppress dorsal genes such as Xnot and chordin, and induce ventral and paraxial genes such as Bmp-4 and MyoD. Ectopic expression of BMP-4 ventralizes embryos and positively regulates the expression of Vox, suggesting that these genes are components of a reciprocal regulatory network. PMID:8674411

  4. Stereotactic ventral pallidotomy for Parkinson's disease.

    PubMed

    Dogali, M; Fazzini, E; Kolodny, E; Eidelberg, D; Sterio, D; Devinsky, O; Berić, A

    1995-04-01

    Eighteen patients with medically intractable Parkinson's disease that was characterized by bradykinesia, rigidity, and marked "on-off" fluctuations underwent stereotactic ventral pallidotomy under local anesthesia. Targeting was aided by anatomic coordinates derived from the MRI, intraoperative cell recordings, and electrical stimulation prior to lesioning. A nonsurgically treated group of seven similarly affected individuals was also followed. Assessment of motor function was made at baseline and at 3-month intervals for 1 year. Following the lesioning, patients improved in bradykinesia, rigidity, resting tremor, and balance with resolution of medication-induced contralateral dyskinesia. When compared with preoperative baseline, all quantifiable test scores after surgery improved significantly with the patients off medications for 12 hours: UPDRS by 65%, and CAPIT subtest scores on the contralateral limb by 38.2% and the ipsilateral limb by 24.2%. Walk scores improved by 45%. Medication requirements were unchanged, but the patients who had had surgery were able to tolerate larger doses because of reduced dyskinesia. Ventral pallidotomy produces statistically significant reduction in parkinsonism and contralateral "on" dyskinesia without morbidity or mortality and with a short hospitalization in Parkinson's disease patients for whom medical therapy has failed. PMID:7723966

  5. Conceptual size representation in ventral visual cortex.

    PubMed

    Gabay, Shai; Kalanthroff, Eyal; Henik, Avishai; Gronau, Nurit

    2016-01-29

    Recent findings suggest that visual objects may be mapped along the ventral occipitotemporal cortex according to their real-world size (Konkle and Oliva, 2012). It has been argued that such mapping does not reflect an abstract, conceptual size representation, but rather the visual or functional properties associated with small versus big real-world objects. To determine whether a more abstract conceptual size representation may affect visual cortical activation we used meaningless geometrical shapes, devoid of semantic or functional associations, which were associated with specific size representations by virtue of extensive training. Following training, participants underwent functional magnetic resonance imaging (fMRI) scanning while performing a conceptual size comparison task on the geometrical shapes. In addition, a size comparison task was conducted for numeral digits denoting small and big numbers. A region-of-interest analysis revealed larger blood oxygenation level dependent (BOLD) responses for conceptually 'big' than for conceptually 'small' shapes, as well as for big versus small numbers, within medial (parahippocampal place area, PPA) and lateral (occipital place area, OPA) place-selective regions. Processing of the 'big' visual shapes further elicited enhanced activation in early visual cortex, possibly reflecting top-down projections from PPA. By using arbitrary shapes and numbers we minimized visual, categorical, or functional influences on fMRI measurement, providing evidence for a possible neural mechanism underlying the representation of abstract conceptual size within the ventral visual stream. PMID:26731198

  6. Partial kindling of the ventral hippocampus: identification of changes in limbic physiology which accompany changes in feline aggression and defense.

    PubMed

    Adamec, R E

    1991-03-01

    This study examined the interictal consequences of partial kindling of the ventral perforant path on attack and defensive behavior in the domestic cat. Partial kindling produced a lasting increase in defense response of cats to both rats and conspecific threat howls. In addition, there was a lasting suppression of approach-attack behaviors directed toward rats. The suppression of some components of approach-attack were shown to be independent of the increases in defensive response. The effects of partial kindling of the ventral perforant path on spread of seizure activity into the amygdala, and on the output of the amygdala to both the ventromedial hypothalamus (VMH) and bed nucleus of the stria terminalis (BNST) were also examined. In addition, the effects of repeated hippocampal seizures on recurrent inhibition in the trisynaptic circuit (areas CA1 and CA3) were investigated. Growth of seizure activity in the amygdala and VMH as partial kindling progressed was essential for behavioral change. In addition, interictal long-term potentiation of potentials evoked in the VMH and in the BNST by pulsed stimulation of the amygdala followed partial kindling or afterdischarge threshold determination in the ventral perforant path. A lasting interictal increase in inhibition in area CA3 and a lasting interictal failure of inhibition in area CA1 of the ventral hippocampus also followed partial kindling. These changes in limbic physiology were related to the behavioral changes produced by partial kindling. The analysis revealed the importance of the amygdalo-VMH pathway in increased defensive response to rats. The amygdalo-BNST pathway is not important in mediating defensive response to prey, but it is implicated in suppression of some types of predatory aggression. Finally, changes in neural inhibition in the ventral hippocampus in areas CA1 and CA3 are associated with changes in both defensiveness and predatory aggression. PMID:1648239

  7. Activation of σ-Receptors Induces Binge-like Drinking in Sardinian Alcohol-Preferring Rats

    PubMed Central

    Sabino, Valentina; Cottone, Pietro; Blasio, Angelo; Iyer, Malliga R; Steardo, Luca; Rice, Kenner C; Conti, Bruno; Koob, George F; Zorrilla, Eric P

    2011-01-01

    RNA expression of μ- and δ-opioid receptors in the ventral tegmental area. These results suggest a key facilitatory role for σ-receptors in the reinforcing effects of alcohol and identify a potential mechanism that contributes to binge-like and excessive drinking. PMID:21346735

  8. A Framework for Understanding the Emerging Role of Corticolimbic-Ventral Striatal Networks in OCD-Associated Repetitive Behaviors

    PubMed Central

    Wood, Jesse; Ahmari, Susanne E.

    2015-01-01

    Significant interest in the mechanistic underpinnings of obsessive-compulsive disorder (OCD) has fueled research on the neural origins of compulsive behaviors. Converging clinical and preclinical evidence suggests that abnormal repetitive behaviors are driven by dysfunction in cortico-striatal-thalamic-cortical (CSTC) circuits. These findings suggest that compulsive behaviors arise, in part, from aberrant communication between lateral orbitofrontal cortex (OFC) and dorsal striatum. An important body of work focused on the role of this network in OCD has been instrumental to progress in the field. Disease models focused primarily on these regions, however, fail to capture an important aspect of the disorder: affective dysregulation. High levels of anxiety are extremely prevalent in OCD, as is comorbidity with major depressive disorder. Furthermore, deficits in processing rewards and abnormalities in processing emotional stimuli are suggestive of aberrant encoding of affective information. Accordingly, OCD can be partially characterized as a disease in which behavioral selection is corrupted by exaggerated or dysregulated emotional states. This suggests that the networks producing OCD symptoms likely expand beyond traditional lateral OFC and dorsal striatum circuit models, and highlights the need to cast a wider net in our investigation of the circuits involved in generating and sustaining OCD symptoms. Here, we address the emerging role of medial OFC, amygdala, and ventral tegmental area projections to the ventral striatum (VS) in OCD pathophysiology. The VS receives strong innervation from these affect and reward processing regions, and is therefore poised to integrate information crucial to the generation of compulsive behaviors. Though it complements functions of dorsal striatum and lateral OFC, this corticolimbic-VS network is less commonly explored as a potential source of the pathology underlying OCD. In this review, we discuss this network’s potential role

  9. Dopamine receptor signaling in the medial orbital frontal cortex and the acquisition and expression of fructose-conditioned flavor preferences in rats

    PubMed Central

    Malkusz, Danielle C.; Yenko, Ira; Rotella, Francis M.; Banakos, Theodore; Olsson, Kerstin; Dindyal, Trisha; Vig, Vishal; Bodnar, Richard J.

    2014-01-01

    Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked fructose-conditioned flavor preference (CFP) acquisition and expression. Fructose-CFP acquisition was eliminated by medial prefrontal cortex (mPFC) SCH and mPFC or amygdala (AMY) RAC. Fructose-CFP expression was reduced following SCH or RAC in AMY or nucleus accumbens (NAc). The present study examined fructose-CFP acquisition and expression following SCH and RAC in the medial orbital frontal cortex (MOFC), another ventral tegmental area DA target. For fructose-CFP acquisition, five groups of rats received vehicle, SCH (24 or 48 nmol) or RAC (24 or 48 nmol) in the MOFC 0.5 h prior to 8 training sessions with one flavor (CS+/Fs) mixed in 8% fructose and 0.2% saccharin, and another flavor (CS-/s) mixed in 0.2% saccharin. In six 2-bottle choice tests in 0.2% saccharin, similar fructose-CFP preferences occurred in groups trained with vehicle (76–77%), SCH24 (69–78%), SCH48(70–74%) and RAC48 (85–92%). RAC24-trained rats displayed significant CS+ preferences during the first (79%) and third (71%), but not second (58%) test pair. For fructose-CFP expression, rats similarly trained with CS+/Fs and CS- solutions received 2-bottle choice tests following MOFC injections of SCH or RAC (12–48 nmol). CS+ preference expression was significantly reduced by RAC (48 nmol: 58%), but not SCH relative to vehicle (78%). A control group receiving RAC in the dorsolateral prefrontal cortex displayed fructose-CFP expression similar to vehicle. These data demonstrate differential frontal cortical DA mediation of fructose-CFP with mPFC D1 and D2 signaling exclusively mediating acquisition, and MOFC D2 signaling primarily mediating expression. PMID:25446441

  10. Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder--lack of effect of methylphenidate.

    PubMed

    Warton, Fleur L; Howells, Fleur M; Russell, Vivienne A

    2009-12-01

    Attention-deficit/hyperactivity disorder (ADHD) is a behavioural disorder that has been associated with dysfunction of the dopaminergic system. Abnormal dopamine function could be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transporter, synthesis, receptor function) or an indirect result of impaired glutamate and/or noradrenergic regulation of dopamine neurons. There is considerable evidence to suggest that dopamine release is impaired at mesolimbic and nigrostriatal dopaminergic terminals. However, it is not known whether dysregulation occurs at the level of the cell bodies in the ventral tegmental area of the midbrain (VTA) and substantia nigra (SN). An in vitro superfusion technique was used to measure dopamine release in a widely used model of ADHD, the spontaneously hypertensive rat (SHR), and its normotensive Wistar-Kyoto (WKY) control. At approximately 30 days of age, rats were analysed for behavioural differences in the open field in response to acute treatment with methylphenidate (0.5 to 2 mg/kg in condensed milk, oral self-administration). In addition, rats were treated chronically with methylphenidate (2 mg/kg, oral self-administration, twice daily for 14 days from postnatal day 21 to 34) before the VTA and the SN were analysed for glutamate-stimulated and depolarization-evoked release of dopamine in these areas. In support of its use as an animal model for ADHD, SHR were more active in the open field and displayed less anxiety-like behaviour than WKY. Neither strain showed any effect of treatment with methylphenidate. A significant difference was observed in glutamate-stimulated release of dopamine in the SN of SHR and WKY, with SHR releasing more dopamine, consistent with the hypothesis of altered glutamate regulation of dopamine neurons in SHR. PMID:19821016

  11. Neural activation patterns underlying basolateral amygdala influence on intra-accumbens opioid-driven consummatory versus appetitive high-fat feeding behaviors in the rat.

    PubMed

    Parker, Kyle E; McCabe, Matt P; Johns, Howard W; Lund, Dane K; Odu, Fiona; Sharma, Rishi; Thakkar, Mahesh M; Cornelison, D D W; Will, Matthew J

    2015-12-01

    The present study explored the role of the amygdala in mediating a unique pattern of feeding behavior driven by intra-accumbens (intra-Acb) opioid activation in the rat. Temporary inactivation of the basolateral amygdala (BLA), via GABAA agonist muscimol administration prevents increased consumption following intra-Acb opioid administration of the selective μ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), yet leaves food approach behaviors intact, particularly after consumption has ended. One interpretation is that inactivation of the BLA selectively blocks neural activity underlying DAMGO-driven consummatory (consumption) but not appetitive (approach) behaviors. The present experiments take advantage of this temporal dissociation of consumption and approach behaviors to investigate their associated neural activity. Following either intra-Acb saline or DAMGO administration, with or without BLA muscimol administration, rats were given 2-hr access to a limited amount of high-fat diet. Immediately following the feeding session, rats were sacrificed and brains assayed for neural activity patterns across critical brain regions known to regulate both appetitive and consummatory feeding behaviors. The results show that intra-Acb DAMGO administration increased c-Fos activation in orexin neurons within the perifornical area of the hypothalamus and that this increase in activation is blocked by BLA muscimol inactivation. Intra-Acb DAMGO administration significantly increased c-Fos activation within dopaminergic neurons of the ventral tegmental area, compared to saline controls, and BLA inactivation had no effect on this increase. Overall, these data provide underlying circuitry that may mediate the selective influence of the BLA on driving consummatory, but not appetitive, feeding behaviors in a model of hedonically driven feeding behavior. PMID:26501175

  12. Neural activation patterns underlying basolateral amygdala influence on intra-accumbens opioid-driven consummatory vs. appetitive high-fat feeding behaviors in the rat

    PubMed Central

    Parker, Kyle E.; McCabe, Matt P.; Johns, Howard W.; Lund, Dane K.; Odu, Fiona; Sharma, Rishi; Thakkar, Mahesh M.; Cornelison, DDW; Will, Matthew J.

    2015-01-01

    The present study explored the role of the amygdala in mediating a unique pattern of feeding behavior driven by intra-accumbens (Acb) opioid activation in the rat. Temporary inactivation of the basolateral amygdala (BLA), via GABAA agonist muscimol administration prevents increased consumption following intra-Acb opioid administration of the selective µ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), yet leaves food approach behaviors intact, particularly after consumption has ended. One interpretation is that inactivation of the BLA selectively blocks neural activity underlying DAMGO-driven consummatory (consumption), but not appetitive (approach) behaviors. The present experiments take advantage of this temporal dissociation of consumption and approach behaviors to investigate their associated neural activity. Following either intra-Acb saline or DAMGO administration, with or without BLA muscimol administration, rats were given 2hr access to a limited amount of high-fat diet. Immediately following the feeding session, rats were sacrificed and brains assayed for neural activity patterns across critical brain regions known to regulate both appetitive and consummatory feeding behaviors. The results show that intra-Acb DAMGO administration increased c-Fos activation in orexin neurons within the perifornical area of the hypothalamus and that this increase in activation is blocked by BLA muscimol inactivation. Intra-Acb DAMGO administration significantly increased c-Fos activation within dopaminergic neurons of the ventral tegmental area, compared to saline controls, and BLA inactivation had no effect on this increase. Overall, these data provide underlying circuitry that may mediate the selective influence of the BLA on driving consummatory, but not appetitive, feeding behaviors in a model of hedonically-driven feeding behavior. PMID:26501175

  13. Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.

    PubMed

    Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y

    2006-02-15

    We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of opiate-treated rats that received low doses of naltrexone in their drinking water. No significant difference in PKA or pCREB was detected in these regions following drug treatment. To examine further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a significant increase in muOR expression in the NTS of morphine-dependent rats that received low doses of naltrexone in their drinking water, and increases in muOR expression were also found to be dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition of NTS neurons resulting from increased muOR expression in this region. PMID:16385558

  14. Sex and age-dependent effects of a maternal junk food diet on the mu-opioid receptor in rat offspring.

    PubMed

    Gugusheff, Jessica R; Bae, Sung Eun; Rao, Alexandra; Clarke, Iain J; Poston, Lucilla; Taylor, Paul D; Coen, Clive W; Muhlhausler, Beverly S

    2016-03-15

    Perinatal junk food exposure increases the preference for palatable diets in juvenile and adult rat offspring. Previous studies have implicated reduced sensitivity of the opioid pathway in the programming of food preferences; however it is not known when during development these changes in opioid signalling first emerge. This study aimed to determine the impact of a maternal junk food (JF) diet on mu-opioid receptor (MuR) expression and ligand binding in two key regions of the reward pathway, the nucleus accumbens (NAc) and the ventral tegmental area (VTA) in rats during the early suckling (postnatal day (PND) 1 and 7) and late suckling/early post-weaning (PND 21 and 28) periods. Female rats were fed either a JF or a control diet for two weeks prior to mating and throughout pregnancy and lactation. MuR expression in the VTA was significantly reduced in female JF offspring on PND 21 and 28 (by 32% and 57% respectively, P<0.05), but not at earlier time points (PND 1 and 7). MuR ligand binding was also reduced (by 22%, P<0.05) in the VTA of female JF offspring on PND 28. No effects of perinatal junk food exposure on MuR mRNA expression or binding were detected at these time points in male offspring. These findings provide evidence that the opioid signalling system is a target of developmental programming by the end of the third postnatal week in females, but not in males. PMID:26718219

  15. Subchronic Polychlorinated Biphenyl (Aroclor 1254) Exposure Produces Oxidative Damage and Neuronal Death of Ventral Midbrain Dopaminergic Systems

    PubMed Central

    Lee, Donna W.; Notter, Sarah A.; Thiruchelvam, Mona; Dever, Daniel P.; Fitzpatrick, Richard; Kostyniak, Paul J.; Cory-Slechta, Deborah A.; Opanashuk, Lisa A.

    2012-01-01

    Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson’s disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult murine brain. We determined whether PCB exposure was associated with OS in dopaminergic neurons, a population of cells that selectively degenerate in PD. After 4 weeks of oral exposure to the PCB mixture Aroclor 1254, several congeners, mostly ortho substituted, accumulated throughout the brain. Significant increases in locomotor activity were observed within 2 weeks, which persisted after cessation of PCB exposure. Stereologic analyses revealed a significant loss of dopaminergic neurons within the substantia nigra and ventral tegmental area. However, striatal dopamine levels were elevated, suggesting that compensatory mechanisms exist to maintain dopamine homeostasis, which could contribute to the observed increases in locomotor activity following PCB exposure. Biochemical experiments revealed alterations in OS markers, including increases in SOD and HO-1 levels and the presence of oxidatively modified lipids and proteins. These findings were accompanied by elevated iron levels within the striatal and midbrain regions, perhaps due to the observed dysregulation of transferrin receptors and ferritin levels following PCB exposure. In this study, we suggest that both OS and the uncoupling of iron regulation contribute to dopamine neuron degeneration and hyperactivity following PCB exposure. PMID:22094459

  16. [Spontaneous tegmental-mesencephalic hematoma: neurobehavioral aspects of the rostral third of the human brainstem].

    PubMed

    De Oliveira-Souza, R; De Souza Bezerra, M L; De Figueiredo, W M; Andreiuolo, P A

    1995-12-01

    The tegmentum of the midbrain is a complex area traversed by a number of anatomical and functional systems, including local circuits, ascending activating systems and descending fibers from the cerebral hemispheres. In the present paper we report on the case of a 67-year-old man who suffered a spontaneous central tegmental hemorrhage and was initially supposed to be in coma due to bilateral ptosis and lack of speech and initiative. By the second hospital week, however, he was shown to be able to respond to verbal commands, sit, stand and walk. He died in sepsis one month later. This case shows that the clinical diagnosis of coma may be misleading in certain patients in whom wakefulness is preserved, though concealed from a casual bedside examination due to abulia and ophthalmoplegia. PMID:8729779

  17. 6-Hydroxydopamine-Induced Dopamine Reductions in the Nucleus Accumbens, but not the Medial Prefrontal Cortex, Impair Cincinnati Water Maze Egocentric and Morris Water Maze Allocentric Navigation in Male Sprague-Dawley Rats.

    PubMed

    Braun, Amanda A; Amos-Kroohs, Robyn M; Gutierrez, Arnold; Lundgren, Kerstin H; Seroogy, Kim B; Vorhees, Charles V; Williams, Michael T

    2016-08-01

    The nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) receive dopaminergic innervation from the ventral tegmental area and are involved in learning. Male rats with 6-hydroxydopamine (6-OHDA)-induced dopaminergic and noradrenergic reductions in the Nacc or mPFC were tested for allocentric and egocentric learning to determine their role in these forms of neuroplasticity. mPFC dopaminergic and noradrenergic reductions did not result in changes to either type of learning or memory. Nacc dopaminergic and noradrenergic reductions resulted in allocentric learning and memory deficits in the Morris water maze (MWM) on acquisition, reversal, and probe trials. MWM cued performance was also affected, but straight-channel swim times and swim speed during hidden platform trials in the MWM were not affected. Nacc dopaminergic and noradrenergic reductions also impaired egocentric learning in the Cincinnati water maze (CWM). Nacc-lesioned animals tested in the CWM in an alternate path through the maze were not significantly affected. 6-OHDA injections in the Nacc resulted in 63 % dopamine and 62 % norepinephrine reductions in the Nacc and 23 % reductions in adjacent dorsal striatum. 6-OHDA injections in the mPFC resulted in 88 % reductions in dopamine and 59 % reductions in norepinephrine. Hence, Nacc dopamine and/or norepinephrine play a role in egocentric and allocentric learning and memory, while mPFC dopamine and norepinephrine do not. PMID:27003940

  18. Ventral laparoscopic abomasopexy on adult cows

    PubMed Central

    Desrochers, André; Bouré, Ludovic; Hélie, Pierre

    2006-01-01

    Abstract Displacement of the abomasum is frequently diagnosed by veterinarians in bovine practice and numerous surgical techniques have been developed to treat and prevent this condition. Complications secondary to those techniques are related to their degree of invasiveness and the development of postoperative wound infections. The objectives of this study were to describe a safe and reliable abomasopexy technique by laparoscopy and to assess postoperative adhesion formation. A ventral laparoscopic abomasopexy was performed on 10 adult dry cows. The abomasum was fixed with 4 simple interrupted sutures using USP 2 polydioxanone suture material. No major complications were encountered during the surgery. Abomasal adhesions were visually evaluated by laparoscopy 3 mo postoperatively. This technique proved to be simple and safe, and it provided adequate abomasum fixation in healthy dry cows. It could be used to surgically correct left displaced abomasum. PMID:16642872

  19. Ventral laparoscopic abomasopexy on adult cows.

    PubMed

    Babkine, Marie; Desrochers, André; Bouré, Ludovic; Hélie, Pierre

    2006-04-01

    Displacement of the abomasum is frequently diagnosed by veterinarians in bovine practice and numerous surgical techniques have been developed to treat and prevent this condition. Complications secondary to those techniques are related to their degree of invasiveness and the development of postoperative wound infections. The objectives of this study were to describe a safe and reliable abomasopexy technique by laparoscopy and to assess postoperative adhesion formation. A ventral laparoscopic abomasopexy was performed on 10 adult dry cows. The abomasum was fixed with 4 simple interrupted sutures using USP 2 polydioxanone suture material. No major complications were encountered during the surgery. Abomasal adhesions were visually evaluated by laparoscopy 3 mo postoperatively. This technique proved to be simple and safe, and it provided adequate abomasum fixation in healthy dry cows. It could be used to surgically correct left displaced abomasum. PMID:16642872

  20. Lesions of the dorsal tegmental nuclei disrupt control of navigation by distal landmarks in cued, directional, and place variants of the Morris water task

    PubMed Central

    Clark, Benjamin; Rice, James P.; Akers, Katherine G.; Candelaria-Cook, Felicha T.; Taube, Jeffrey S.; Hamilton, Derek A.

    2014-01-01

    Navigation depends on a network of neural systems that accurately monitor an animal’s directional heading and location in an environment. Within this navigation system are head direction (HD) cells, which discharge as a function of an animal’s directional heading, providing an animal with a neural compass to guide ongoing spatial behavior. Experiments were designed to test this hypothesis by damaging the dorsal tegmental nucleus (DTN), a mid-brain structure that plays a critical role in the generation of the rodent HD cell signal, and evaluating landmark based navigation using variants of the Morris water task. In Experiments 1 and 2, shams and DTN lesioned rats were trained to navigate toward a cued platform in the presence of a constellation of distal landmarks located outside the pool. After reaching a training criteria, rats were tested in three probe trials in which 1) the cued platform was completely removed from the pool, 2) the pool was repositioned and the cued platform remained in the same absolute location with respect to distal landmarks, or 3) the pool was repositioned and the cued platform remained in the same relative location in the pool. In general, DTN-lesioned rats required more training trials to reach performance criterion, were less accurate to navigate to the platform position when it was removed, and navigated directly to the cued platform regardless of its position in the pool, indicating a general absence of control over navigation by distal landmarks. In Experiment 3, DTN and control rats were trained in directional and place navigation variants of the water task where the pool was repositioned for each training trial and a hidden platform was placed either in the same relative location (direction) in the pool or in the same absolute location (place) in the distal room reference frame. DTN-lesioned rats were initially impaired in the direction task, but ultimately performed as well as controls. In the place task, DTN-lesioned rats

  1. Separate Populations of Neurons in Ventral Striatum Encode Value and Motivation

    PubMed Central

    Gentry, Ronny N.; Goldstein, Brandon L.; Hearn, Taylor N.; Barnett, Brian R.; Kashtelyan, Vadim; Roesch, Matthew R.

    2013-01-01

    Neurons in the ventral striatum (VS) fire to cues that predict differently valued rewards. It is unclear whether this activity represents the value associated with the expected reward or the level of motivation induced by reward anticipation. To distinguish between the two, we trained rats on a task in which we varied value independently from motivation by manipulating the size of the reward expected on correct trials and the threat of punishment expected upon errors. We found that separate populations of neurons in VS encode expected value and motivation. PMID:23724077

  2. A functional difference in information processing between orbitofrontal cortex and ventral striatum during decision-making behaviour

    PubMed Central

    Stott, Jeffrey J.; Redish, A. David

    2014-01-01

    Both orbitofrontal cortex (OFC) and ventral striatum (vStr) have been identified as key structures that represent information about value in decision-making tasks. However, the dynamics of how this information is processed are not yet understood. We recorded ensembles of cells from OFC and vStr in rats engaged in the spatial adjusting delay-discounting task, a decision-making task that involves a trade-off between delay to and magnitude of reward. Ventral striatal neural activity signalled information about reward before the rat's decision, whereas such reward-related signals were absent in OFC until after the animal had committed to its decision. These data support models in which vStr is directly involved in action selection, but OFC processes decision-related information afterwards that can be used to compare the predicted and actual consequences of behaviour. PMID:25267815

  3. Retinotopic Organization of Human Ventral Visual Cortex

    PubMed Central

    Arcaro, Michael J.; McMains, Stephanie A.; Singer, Benjamin D.; Kastner, Sabine

    2009-01-01

    Functional magnetic resonance imaging (fMRI) studies have shown that human ventral visual cortex anterior to area hV4 contains two visual field maps, VO-1 and VO-2, that together form the VO-cluster (Brewer et al., 2005). This cluster is characterized by common functional response properties and responds preferentially to color and object stimuli. Here, we confirm the topographic and functional characteristics of the VO-cluster and describe two new visual field maps that are located anterior to VO-2 extending across the collateral sulcus into the posterior parahippocampal cortex (PHC). We refer to these visual field maps as parahippocampal areas PHC-1 and PHC-2. Each PHC map contains a topographic representation of contralateral visual space. The polar angle representation in PHC-1 extends from regions near the lower vertical meridian (that is the shared border with VO-2) to those close to the upper vertical meridian (that is the shared border with PHC-2). The polar angle representation in PHC-2 is a mirror-reversal of the PHC-1 representation. PHC-1 and PHC-2 share a foveal representation and show a strong bias towards representations of peripheral eccentricities. Both the foveal and peripheral representations of PHC-1 and PHC-2 respond more strongly to scenes than to objects or faces, with greater scene preference in PHC-2 than PHC-1. Importantly, both areas heavily overlap with the functionally defined parahippocampal place area (PPA). Our results suggest that ventral visual cortex can be subdivided on the basis of topographic criteria into a greater number of discrete maps than previously thought. PMID:19710316

  4. "Limulus" Psychophysics: Spectral Sensitivity of the Ventral Eye

    ERIC Educational Resources Information Center

    Wasserman, Gerald S.

    1976-01-01

    The ventral eye of "Limulus" (horseshoe crab) contains only one type of photoreceptor. Behaviors mediated by the ventral eye provide an unambiguous representation of the function of that single-receptor type. Compares such behaviors with results of acute, single-cell investigations to assay for the contributions of candidate neural codes in the…

  5. Ventral Decompression in Chiari Malformation, Basilar Invagination, and Related Disorders.

    PubMed

    Ridder, Thomas; Anderson, Richard C E; Hankinson, Todd C

    2015-10-01

    Ventral brainstem compression is an uncommon clinical diagnosis seen by pediatric neurosurgeons and associated with Chiari malformation, type I. Presenting clinical symptoms often include headaches, lower cranial neuropathies, myelopathy, central sleep apnea, ataxia, and nystagmus. When ventral decompression is required, both open and endoscopic transoral/transnasal approaches are highly effective. PMID:26408067

  6. Pain relief induces dopamine release in the rat nucleus accumbens during the early but not late phase of neuropathic pain.

    PubMed

    Kato, Takahiro; Ide, Soichiro; Minami, Masabumi

    2016-08-26

    Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications. PMID:27369326

  7. Immediate early gene expression reveals interactions between social and nicotine rewards on brain activity in adolescent male rats.

    PubMed

    Bastle, Ryan M; Peartree, Natalie A; Goenaga, Julianna; Hatch, Kayla N; Henricks, Angela; Scott, Samantha; Hood, Lauren E; Neisewander, Janet L

    2016-10-15

    Smoking initiation predominantly occurs during adolescence, often in the presence of peers. Therefore, understanding the neural mechanisms underlying the rewarding effects of nicotine and social stimuli is vital. Using the conditioned place preference (CPP) procedure, we measured immediate early gene (IEG) expression in animals following exposure either to a reward-conditioned environment or to the unconditioned stimuli (US). Adolescent, male rats were assigned to the following CPP US conditions: (1) Saline+Isolated, (2) Nicotine+Isolated, (3) Saline+Social, or (4) Nicotine+Social. For Experiment 1, brain tissue was collected 90min following the CPP expression test and processed for Fos immunohistochemistry. We found that rats conditioned with nicotine with or without a social partner exhibited CPP; however, we found no group differences in Fos expression in any brain region analyzed, with the exception of the nucleus accumbens core that exhibited a social-induced attenuation in Fos expression. For Experiment 2, brain tissue was collected 90min following US exposure during the last conditioning session. We found social reward-induced increases in IEG expression in striatal and amydalar subregions. In contrast, nicotine reduced IEG expression in prefrontal and striatal subregions. Reward interactions were also found in the dorsolateral striatum, basolateral amygdala, and ventral tegmental area where nicotine alone attenuated IEG expression and social reward reversed this effect. These results suggest that in general social rewards enhance, whereas nicotine attenuates, activation of mesocorticolimbic regions; however, the rewards given together interact to enhance activation in some regions. The findings contribute to knowledge of how a social environment influences nicotine effects. PMID:27435419

  8. Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal

    PubMed Central

    Li, Hao; Scholl, Jamie L.; Tu, Wenyu; Hassell, James; Watt, Michael J.; Forster, Gina L.; Renner, Kenneth J.

    2014-01-01

    Withdrawal from amphetamine increases anxiety and reduces the ability to cope with stress, factors that are believed to contribute to drug relapse. Stress-induced serotonergic transmission in the central nucleus of the amygdala is associated with anxiety states and fear. Conversely, increases in stress-induced ventral hippocampal serotonin have been linked to coping mechanisms. The goal of this study is to understand neurobiological changes induced by amphetamine that contribute to stress-sensitivity during withdrawal. We tested the hypothesis that limbic serotonergic responses to restraint stress would be altered in male Sprague-Dawley rats chronically pre-treated with amphetamine (2.5 mg/kg, ip.) followed by two weeks withdrawal. Amphetamine withdrawal resulted in increased stress-induced behavioral arousal relative to control treatment, suggesting that drug withdrawal induced a greater sensitivity to the stressor. When microdialysis was used to determine the effects of restraint on extracellular serotonin, stress-induced increases in serotonin were abolished in the ventral hippocampus and augmented in the central amygdala during amphetamine withdrawal. Reverse dialysis of the glucocorticoid receptor antagonist mifepristone into the ventral hippocampus blocked the stress-induced serotonin increase in saline pre-treated rats, suggesting that glucocorticoid receptors mediate stress-induced serotonin increases in the ventral hippocampus. However, mifepristone had no effect on stress-induced serotonin increases in the central amygdala, indicating that stress increases serotonin in this region independent of glucocorticoid receptors. During amphetamine withdrawal, the absence of stress-induced increases in ventral hippocampus serotonin combined with enhanced stress-induced serotonergic responses in the central amygdala may contribute to drug relapse by decreasing stress-coping ability and heightening stress responsiveness. PMID:25234335

  9. Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal.

    PubMed

    Li, Hao; Scholl, Jamie L; Tu, Wenyu; Hassell, James E; Watt, Michael J; Forster, Gina L; Renner, Kenneth J

    2014-12-01

    Withdrawal from amphetamine increases anxiety and reduces the ability to cope with stress, which are factors that are believed to contribute to drug relapse. Stress-induced serotonergic transmission in the central nucleus of the amygdala is associated with anxiety states and fear. Conversely, stress-induced increases in ventral hippocampal serotonin (5-HT) levels have been linked to coping mechanisms. The goal of this study was to investigate the neurobiological changes induced by amphetamine that contribute to stress sensitivity during withdrawal. We tested the hypothesis that limbic serotonergic responses to restraint stress would be altered in male Sprague-Dawley rats chronically pretreated with amphetamine (2.5 mg/kg, intraperitoneal) and then subjected to 2 weeks of withdrawal. Amphetamine withdrawal resulted in increased stress-induced behavioral arousal relative to control treatment, suggesting that drug withdrawal induced greater sensitivity to the stressor. When microdialysis was used to determine the effects of restraint on extracellular 5-HT, stress-induced increases in 5-HT levels were abolished in the ventral hippocampus and augmented in the central amygdala during amphetamine withdrawal. Reverse dialysis of the glucocorticoid receptor antagonist mifepristone into the ventral hippocampus blocked the stress-induced increase in 5-HT levels in saline-pretreated rats, suggesting that glucocorticoid receptors mediate stress-induced increases in 5-HT levels in the ventral hippocampus. However, mifepristone had no effect on stress-induced increases in 5-HT levels in the central amygdala, indicating that stress increases 5-HT levels in this region independently of glucocorticoid receptors. During amphetamine withdrawal, the absence of stress-induced increases in ventral hippocampal 5-HT levels combined with enhanced stress-induced serotonergic responses in the central amygdala may contribute to drug relapse by decreasing stress-coping ability and heightening

  10. Activation of the trigeminal medullary dorsal horn during voluntary diving in rats.

    PubMed

    McCulloch, Paul F

    2005-07-27

    Fos immunohistochemistry was used to indicate whether activation of trigeminal neurons occurs in voluntarily diving rats. In rats trained to dive underwater, significant increases in Fos labeling were found within the ventral superficial MDH and paratrigeminal nucleus, 100-150 microm caudal to the obex compared to control rats. The conclusion is that the ventral superficial MDH is the initial brainstem afferent relay of diving response in voluntarily diving rats. PMID:15978555

  11. Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury

    PubMed Central

    2013-01-01

    Background Peripheral nerve (PN) transplantation and ventral root implantation are the two common types of recovery operations to restore the connection between motoneurons and their target muscles after brachial plexus injury. Despite experience accumulated over the past decade, fundamental knowledge is still lacking concerning the efficacy of the two microsurgical interventions. Methods Thirty-eight adult female Sprague–Dawley rats were divided into 5 groups. Immediately following root avulsion, animals in the first group (n = 8) and the second group (n = 8) received PN graft and ventral root implantation respectively. The third group (n = 8) and the fourth group (n = 8) received PN graft and ventral root implantation respectively at one week after root avulsion. The fifth group received root avulsion only as control (n = 6). The survival and axonal regeneration of severed motoneurons were investigated at 6 weeks post-implantation. Results Re-implantation of ventral roots, both immediately after root avulsion and in delay, significantly increased the survival and regeneration of motoneurons in the avulsed segment of the spinal cord as compared with PN graft transplantation. Conclusions The ventral root re-implantation is a better surgical repairing procedure than PN graft transplantation for brachial plexus injury because of its easier manipulation for re-implanting avulsed ventral roots to the preferred site, less possibility of causing additional damage and better effects on motoneuron survival and axonal regeneration. PMID:23799915

  12. Afferent projections to the mammillary complex of the rat, with special reference to those from surrounding hypothalamic regions

    NASA Technical Reports Server (NTRS)

    Gonzalo-Ruiz, A.; Alonso, A.; Sanz, J. M.; Llinas, R. R.

    1992-01-01

    To better understand the functional organization of the mammillary nuclei, we investigated the afferents to this nuclear complex in the rat with iontophoretically injected wheat germ agglutinin conjugated to horseradish peroxidase. Particular attention was paid to tracing local hypothalamic afferents to these nuclei. Injections into the medial mammillary nucleus (MMN) revealed strong projections from the subicular region, and weaker projections from the prefrontal cortex, medial septum, and the nucleus of the diagonal band of Broca. Other descending subcortical projections to the MMN arise from the anterior and the lateral hypothalamic area, the medial preoptic area, and the bed nucleus of the stria terminalis. Ascending afferents to the MMN were found to originate in the raphe and various tegmental nuclei. Following all injections into the MMN, labelled neurons were found in nuclei surrounding the mammillary body. The lateral and posterior subdivisions of the tuberomammillary nucleus projected mainly to the pars medianus and pars medialis of the MMN. The dorsal and ventral premammillary nuclei projected to the pars lateralis of the MMN. The supramammillary nucleus at rostral level had a small projection to the pars medialis and lateralis of the MMN. However, the most obvious projection from this nucleus was to the pars posterior of the MMN, chiefly from the lateral part of the caudal supramammillary nucleus. Injections into the lateral mammillary nucleus revealed inputs from the presubiculum, parasubiculum, septal region, dorsal tegmental nucleus, dorsal raphe nucleus, and periaqueductal gray. In addition, the lateral mammillary nucleus was found to receive a moderate projection from the medial part of the supramammillary nucleus and stronger projections from the lateral part of the caudal supramammillary nucleus. A very light projection was also seen from the lateral and posterior subdivisions of the tuberomammillary nucleus. These findings add to our knowledge

  13. Are The Dorsal and Ventral Hippocampus functionally distinct structures?

    PubMed Central

    Fanselow, Michael S.; Dong, Hong-Wei

    2009-01-01

    One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into 3 hippocampal compartments dorsal, intermediate and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus). PMID:20152109

  14. Developmental neuroimaging of the human ventral visual cortex

    PubMed Central

    Grill-Spector, Kalanit; Golarai, Golijeh; Gabrieli, John

    2013-01-01

    Here, we review recent results that investigate the development of the human ventral stream from childhood, through adolescence and into adulthood. Converging evidence suggests a differential developmental trajectory across ventral stream regions, in which face-selective regions show a particularly long developmental time course, taking more than a decade to become adult-like. We discuss the implications of these recent findings, how they relate to age-dependent improvements in recognition memory performance and propose possible neural mechanisms that might underlie this development. These results have important implications regarding the role of experience in shaping the ventral stream and the nature of the underlying representations. PMID:18359267

  15. Internal dialysis of Limulus ventral photoreceptors.

    PubMed Central

    Stern, J H; Lisman, J E

    1982-01-01

    The internal dialysis technique has been applied to Limulus ventral photoreceptors. This method potentially allows quantitative control of the concentration of diffusible molecules within living cells. During dialysis, Limulus photoreceptors retained their ability to respond to light. Under conditions of dim illumination, responses were normal for close to an hour. In bright light, abnormalities developed more rapidly. The reversible effects of raising the dialysate Mg2+ concentration and the entrance of rhodamine-labeled albumin into cells shows that the dialysis method is useful for assaying the effects of small or large molecules on visual transduction. This method has been used to examine the effects of nucleotide triphosphates and cyclic nucleotides. The results show that nucleotide triphosphates (5-10 mM) are required to maintain a low rate of spontaneous quantum bumps. The importance of cyclic nucleotides in transduction is less clear; the light response was reduced by either cGMP or cAMP but only at very high concentrations (10 mM). Images PMID:6961434

  16. Functional consequences of ethidium bromide demyelination of the mouse ventral spinal cord

    PubMed Central

    Kuypers, Nicholas J.; James, Kurtis T.; Enzmann, Gaby U.; Magnuson, David S.K.; Whittemore, Scott R.

    2013-01-01

    Ethidium bromide (EB) has been extensively used in the rat as a model of spinal cord demyelination. However, this lesion has not been addressed in the adult mouse, a model with unlimited genetic potential. Here we characterize behavioral function, inflammation, myelin status and axonal viability following bilateral injection of 0.20 mg/mL ethidium bromide or saline into the ventral white matter (VWM) of female C57Bl/6 mice. EB-induced VWM demyelination significantly reduced spared VWM and Basso Mouse Scale (BMS) scores persisting out to 2 months. Chronic hindlimb dysfunction was accompanied by a persistent inflammatory response (demonstrated by CD45+ immunofluorescence) and axonal loss (demonstrated by NF-M immunofluorescence and electron microscopy; EM). These cellular responses differ from the rat where inflammation resolves by 3–4 weeks and axon loss is minimal following EB demyelination. As these data suggest that EB-injection in the mouse spinal cord is a non-remyelinating lesion, we sought to ask whether wheel running could promote recovery by enhancing plasticity of local lumbar circuitry independent of remyelination. This did not occur as BMS and Treadscan® assessment revealed no significant effect of wheel running on recovery. However, this study defines the importance of descending ventral motor pathways to locomotor function in the mouse as VWM loss results in a chronic hindlimb deficit. PMID:23466931

  17. Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear.

    PubMed

    Rodriguez-Romaguera, Jose; Do Monte, Fabricio H M; Quirk, Gregory J

    2012-05-29

    Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD. PMID:22586125

  18. Neuroprotection and immunomodulation by xenografted human mesenchymal stem cells following spinal cord ventral root avulsion

    PubMed Central

    Ribeiro, Thiago B.; Duarte, Adriana S. S.; Longhini, Ana Leda F.; Pradella, Fernando; Farias, Alessandro S.; Luzo, Angela C. M.; Oliveira, Alexandre L. R.; Olalla Saad, Sara Teresinha

    2015-01-01

    The present study investigates the effects of xenotransplantation of Adipose Tissue Mesenchymal Stem Cells (AT-MSCs) in animals after ventral root avulsion. AT-MSC has similar characteristics to bone marrow mesenchymal stem cells (BM-MSCs), such as immunomodulatory properties and expression of neurotrophic factors. In this study, Lewis rats were submitted to surgery for unilateral avulsion of the lumbar ventral roots and received 5 × 105 AT-MSCs via the lateral funiculus. Two weeks after cell administration, the animals were sacrificed and the moto neurons, T lymphocytes and cell defense nervous system were analyzed. An increased neuronal survival and partial preservation of synaptophysin-positive nerve terminals, related to GDNF and BDNF expression of AT-MSCs, and reduction of pro-inflammatory reaction were observed. In conclusion, AT-MSCs prevent second phase neuronal injury, since they suppressed lymphocyte, astroglia and microglia effects, which finally contributed to rat motor-neuron survival and synaptic stability of the lesioned motor-neuron. Moreover, the survival of the injected AT- MSCs lasted for at least 14 days. These results indicate that neuronal survival after lesion, followed by mesenchymal stem cell (MSC) administration, might occur through cytokine release and immunomodulation, thus suggesting that AT-MSCs are promising cells for the therapy of neuronal lesions. PMID:26548646

  19. Neuroprotection and immunomodulation by xenografted human mesenchymal stem cells following spinal cord ventral root avulsion.

    PubMed

    Ribeiro, Thiago B; Duarte, Adriana S S; Longhini, Ana Leda F; Pradella, Fernando; Farias, Alessandro S; Luzo, Angela C M; Oliveira, Alexandre L R; Olalla Saad, Sara Teresinha

    2015-01-01

    The present study investigates the effects of xenotransplantation of Adipose Tissue Mesenchymal Stem Cells (AT-MSCs) in animals after ventral root avulsion. AT-MSC has similar characteristics to bone marrow mesenchymal stem cells (BM-MSCs), such as immunomodulatory properties and expression of neurotrophic factors. In this study, Lewis rats were submitted to surgery for unilateral avulsion of the lumbar ventral roots and received 5 × 10(5) AT-MSCs via the lateral funiculus. Two weeks after cell administration, the animals were sacrificed and the moto neurons, T lymphocytes and cell defense nervous system were analyzed. An increased neuronal survival and partial preservation of synaptophysin-positive nerve terminals, related to GDNF and BDNF expression of AT-MSCs, and reduction of pro-inflammatory reaction were observed. In conclusion, AT-MSCs prevent second phase neuronal injury, since they suppressed lymphocyte, astroglia and microglia effects, which finally contributed to rat motor-neuron survival and synaptic stability of the lesioned motor-neuron. Moreover, the survival of the injected AT- MSCs lasted for at least 14 days. These results indicate that neuronal survival after lesion, followed by mesenchymal stem cell (MSC) administration, might occur through cytokine release and immunomodulation, thus suggesting that AT-MSCs are promising cells for the therapy of neuronal lesions. PMID:26548646

  20. The medial preoptic area modulates cocaine-induced activity in female rats

    PubMed Central

    Tobiansky, Daniel J.; Roma, Peter G.; Hattori, Tomoko; Will, Ryan G.; Nutsch, Victoria L.; Dominguez, Juan M.

    2014-01-01

    Drugs of abuse exert their effects by exploiting natural neurobiological reward mechanisms, especially the mesolimbic dopamine (DA) system. However, the mesolimbic system does not operate in isolation, and input from other reward-relevant structures may play a role in cocaine’s rewarding effects. The medial preoptic area (mPOA) of the hypothalamus is involved in the regulation of two essential and naturally rewarding behaviors, sexual and maternal behaviors. It also makes strong neuroanatomical connections with areas of the mesolimbic system, particularly the ventral tegmental area (VTA). As such, the mPOA is a logical candidate for a neuroanatomical locus modulating activity in the mesolimbic system and emergent behavioral expressions of drug reward, yet the role of this structure is largely unexplored. Here, using a female rat model, we show that the mPOA innervates the VTA in a region-specific manner, lesions of the mPOA augment cocaine-induced Fos expression in the nucleus accumbens and cocaine-induced conditioned place preference. We also show that approximately 68% of mPOA-VTA efferents release γ-aminobutyric acid (GABA), over 75% are sensitive to DA as evidenced by co-localization with DA receptors, and nearly 60% of these contain both DA receptors and GABA, which suggests a novel key role for the mPOA in the inhibition of the mesolimbic DA circuit. Combined, these results reveal the mPOA as a critical modulating structure in cocaine-induced mesolimbic activity and behavioral manifestation of reward, at least in part via GABAergic output that is sensitive to DA input. PMID:23565937

  1. Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain.

    PubMed

    Sagheddu, Claudia; Aroni, Sonia; De Felice, Marta; Lecca, Salvatore; Luchicchi, Antonio; Melis, Miriam; Muntoni, Anna Lisa; Romano, Rosaria; Palazzo, Enza; Guida, Francesca; Maione, Sabatino; Pistis, Marco

    2015-10-01

    In humans, affective consequences of neuropathic pain, ranging from depression to anxiety and anhedonia, severely impair quality of life and are a major disease burden, often requiring specific medications. Depressive- and anxiety-like behaviors have also been observed in animal models of peripheral nerve injury. Dysfunctions in central nervous system monoamine transmission have been hypothesized to underlie depressive and anxiety disorders in neuropathic pain. To assess whether these neurons display early changes in their activity that in the long-term might lead to chronicization, maladaptive plasticity and affective consequences, we carried out in vivo extracellular single unit recordings from serotonin neurons in the dorsal raphe nucleus (DRN) and from dopamine neurons in ventral tegmental area (VTA) in the spared nerve injury (SNI) model of neuropathic pain in rats. Extracellular dopamine levels and the expression of dopamine D1, D2 receptors and tyrosine hydroxylase (TH) were measured in the nucleus accumbens. We report that, two weeks following peripheral nerve injury, discharge rate of serotonin DRN neurons and burst firing of VTA dopamine cells are enhanced, when compared with sham-operated animals. We also observed higher extracellular dopamine levels and reduced expression of D2, but not D1, receptors and TH in the nucleus accumbens. Our study confirms that peripheral neuropathy induces changes in the serotonin and dopamine systems that might be the early result of chronic maladaptation to persistent pain. The allostatic activation of these neural systems, which mirrors that already described as a consequence of stress, might lead to depression and anxiety previously observed in neuropathic animals but also an attempt to cope positively with the negative experience. PMID:26113399

  2. Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training

    PubMed Central

    Snyder, Jason S.; Radik, Ruvim; Wojtowicz, J. Martin; Cameron, Heather A.

    2009-01-01

    Hippocampal function varies in a subregion-specific fashion: spatial processing is thought to rely on the dorsal hippocampus, while anxiety-related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion-specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in dentate gyrus subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c-fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral dentate gyrus. In contrast, c-fos expression in adult-born granule cells, identified by PSA-NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral dentate gyrus. Interestingly, c-fos expression in the entire granule cell population was equivalent in water maze-trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally-relevant experience activates young and mature neurons in different dentate gyrus subregions and with different experiential specificity, and suggest that adult-born neurons may play a specific role in anxiety-related behavior or other non-spatial aspects of hippocampal function. PMID:19004012

  3. Localization of the mRNA for the dopamine D sub 2 receptor in the rat brain by in situ hybridization histochemistry

    SciTech Connect

    Mengod, G.; Martinez-Mir, M.I.; Vilaro, M.T.; Palacios, J.M. )

    1989-11-01

    {sup 32}P-labeled oligonucleotides derived from the coding region of rat dopamine D{sub 2} receptor cDNA were used as probes to localize cells in the rat brain that contain the mRNA coding for this receptor by using in situ hybridization histochemistry. The highest level of hybridization was found in the intermediate lobe of the pituitary gland. High mRNA content was observed in the anterior lobe of the pituitary gland, the nuclei caudate-putamen and accumbens, and the olfactory tubercle. Lower levels were seen in the substantia nigra pars compacta and the ventral tegmental area, as well as in the lateral mammillary body. In these areas the distribution was comparable to that of the dopamine D{sub 2} receptor binding sites as visualized by autoradiography using ({sup 3}H)SDZ 205-502 as a ligand. However, in some areas such as the olfactory bulb, neocortex, hippocampus, superior colliculus, and cerebellum, D{sub 2} receptors have been visualized but no significant hybridization signal could be detected. The mRNA coding for these receptors in these areas could be contained in cells outside those brain regions, be different from the one recognized by our probes, or be present at levels below the detection limits of our procedure. The possibility of visualizing and quantifying the mRNA coding for dopamine D{sub 2} receptor at the microscopic level will yield more information about the in vivo regulation of the synthesis of these receptor and their alteration following selective lesions or drug treatments.

  4. Interleukin-1β-induced brain injury in the neonatal rat can be ameliorated by α-phenyl-n-tert-butyl-nitrone

    PubMed Central

    Fan, Lir-Wan; Mitchell, Helen J.; Tien, Lu-Tai; Rhodes, Philip G.; Cai, Zhengwei

    2009-01-01

    To examine the possible role of inflammatory cytokines in mediating perinatal brain injury, we investigated effects of intracerebral injection of interleukin-1beta (IL-1β) on brain injury in the neonatal rat and the mechanisms involved. Intracerebral administration of IL-1β (1 μg/kg) resulted in acute brain injury, as indicated by enlargement of ventricles bilaterally, apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. IL-1β also induced axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of β-amyloid precursor protein, short beaded axons and dendrites, and loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas. Administration of α-phenyl-n-tert-butyl-nitrone (PBN, 100 mg/kg i.p.) immediately after the IL-1β injection protected the brain from IL-1β-induced injury. Protection of PBN was linked with the attenuated oxidative stress induced by IL-1β, as indicated by decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde or nitrotyrosine positive cells following IL-1β exposure. PBN also attenuated IL-1β-stimulated inflammatory responses as indicated by the reduced activation of microglia. The finding that IL-1β induced perinatal brain injury was very similar to that induced by lipopolysaccharide (LPS), as we previously reported and that PBN was capable to attenuate the injury induced by either LPS or IL-1β suggests that IL-1β may play a critical role in mediating brain injury associated with perinatal infection/inflammation. PMID:19682987

  5. Scale model test results of several STOVL ventral nozzle concepts

    NASA Technical Reports Server (NTRS)

    Meyer, B. E.; Re, R. J.; Yetter, J. A.

    1991-01-01

    Short take-off and vertical landing (STOVL) ventral nozzle concepts are investigated by means of a static cold flow scale model at a NASA facility. The internal aerodynamic performance characteristics of the cruise, transition, and vertical lift modes are considered for four ventral nozzle types. The nozzle configurations examined include those with: butterfly-type inner doors and vectoring exit vanes; circumferential inner doors and thrust vectoring vanes; a three-port segmented version with circumferential inner doors; and a two-port segmented version with cylindrical nozzle exit shells. During the testing, internal and external pressure is measured, and the thrust and flow coefficients and resultant vector angles are obtained. The inner door used for ventral nozzle flow control is found to affect performance negatively during the initial phase of transition. The best thrust performance is demonstrated by the two-port segmented ventral nozzle due to the elimination of the inner door.

  6. Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems.

    PubMed

    Everitt, B J; Parkinson, J A; Olmstead, M C; Arroyo, M; Robledo, P; Robbins, T W

    1999-06-29

    Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic-cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal-directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli control goal-directed action), and also more general response-invigorating processes (often called "activation," "stress," or "drive") may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second-order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug-seeking response can be seen to operate both serially and concurrently. The power of

  7. Reduced structural connectivity in ventral visual cortex in congenital prosopagnosia.

    PubMed

    Thomas, Cibu; Avidan, Galia; Humphreys, Kate; Jung, Kwan-jin; Gao, Fuqiang; Behrmann, Marlene

    2009-01-01

    Using diffusion tensor imaging and tractography, we found that a disruption in structural connectivity in ventral occipito-temporal cortex may be the neurobiological basis for the lifelong impairment in face recognition that is experienced by individuals who suffer from congenital prosopagnosia. Our findings suggest that white-matter fibers in ventral occipito-temporal cortex support the integrated function of a distributed cortical network that subserves normal face processing. PMID:19029889

  8. Deep cytoplasmic rearrangements in ventralized Xenopus embryos

    NASA Technical Reports Server (NTRS)

    Brown, E. E.; Denegre, J. M.; Danilchik, M. V.

    1993-01-01

    Following fertilization in Xenopus, dramatic rearrangements of the egg cytoplasm relocalize maternally synthesized egg components. During the first cell cycle the vegetal yolk mass rotates relative to the egg surface, toward the sperm entry point (SEP) (J. P. Vincent, G. F. Oster, and J. C. Gerhart, 1986, Dev. Biol. 113, 484-500), while concomitant deep cytoplasmic rearrangements occur in the animal hemisphere (M. V. Danilchik and J. M. Denegre, 1991, Development 111, 845-856). In this paper we examine the role of vegetal yolk mass rotation in producing the animal cytoplasmic rearrangements. We inhibited rotation by uv-irradiating embryos during the first cell cycle, a treatment that yields an extremely ventralized phenotype. Both uv-irradiated embryos and unirradiated control embryos show cytoplasmic rearrangements in the animal hemisphere during the first cell cycle. Cytoplasmic rearrangements on the SEP side of the embryo associated with the path of the sperm pronucleus, plus a swirl on the anti-SEP (dorsal) side, are seen, whether or not yolk mass rotation has occurred. This result suggests a role for the expanding sperm aster in directing animal hemisphere cytoplasmic movements. In unirradiated control embryos the anti-SEP (dorsal) swirl is larger than that in uv-irradiated embryos and often extends into the vegetal hemisphere, consistent with the animal cytoplasm having been pulled dorsally and vegetally by the sliding vegetal yolk mass. Thus the yolk mass rotation may normally enhance the dorsalward cytoplasmic movement, begun by the sperm aster, enough to induce normal axis formation. We extended our observations of unirradiated control and uv-irradiated embryos through early cleavages. The vegetal extent of the anti-SEP (dorsal) swirl pattern seen in control embryos persists through the early cleavage period, such that labeled animal cytoplasm extends deep into dorsal third-tier blastomeres at the 32-cell stage. Significantly, in uv-irradiated embryos

  9. [THE ORGANIZATION OF PROJECTIONS OF MIDBRAIN LATERAL TEGMENTAL NUCLEI THE TO BRAIN BASAL GANGLIA IN DOGS].

    PubMed

    Gorbachevskaya, A I

    2015-01-01

    The organization of the projections of midbrain lateral tegmental nuclei (peripeduncular nucleus, paralemniscal nucleus, nucleus of the brachium of inferior colliculus) to functionally diverse nuclei of the basal ganglia system was studied in dogs (n = 34) by the method of retrograde axonal transport of horse-radish peroxidase. It was found that the midbrain nuclei studied were involved in functionally different circuits, containing the basal ganglia as their components. These nuclei innervate the regions of the putamen, globus pallidus, cuneate nucleus, subcuneate nucleus, which are the motor or the limbic structures on the basis of their predominant connections with the motor or the limbic brain nuclei, and also regions of the caudate nucleus, nucleus accumbens, entopeduncular nucleus, compact part of the pedunculopontine nucleus, which receive the projections from the functionally various structures. The analysis of Nissl-stained frontal sections allowed to refine the anatomical topography of the individual nuclei of the midbrain lateral tegmentum. The cholinergic nature of their neurons was demonstrated based on of the positive histochemical reaction to NADPH diaphorase. PMID:27141581

  10. GABAergic mechanisms in the pedunculopontine tegmental nucleus of the cat promote active (REM) sleep.

    PubMed

    Torterolo, Pablo; Morales, Francisco R; Chase, Michael H

    2002-07-19

    The pedunculopontine tegmental nucleus (PPT) has been implicated in the generation and/or maintenance of both active sleep (AS) and wakefulness (W). GABAergic neurons are present within this nucleus and recent studies have shown that these neurons are active during AS. In order to examine the role of mesopontine GABAergic processes in the generation of AS, the GABA(A) agonist muscimol and the GABA(A) antagonist bicuculline were microinjected into the PPT of chronic cats that were prepared for recording the states of sleep and wakefulness. Muscimol increased the time spent in AS by increasing the frequency and duration of AS episodes; this increase in AS was at the expense of the time spent in wakefulness. A decrease in PGO density during AS was also observed following the microinjection of muscimol. On the other hand, bicuculline decreased both AS and quiet sleep and increased the time spent in wakefulness. These data suggest that GABA acts on GABA(A) receptors within the PPT to facilitate the generation of AS by suppressing the activity of waking-related processes within this nucleus. PMID:12106660

  11. Interactions between dorsal and ventral streams for controlling skilled grasp.

    PubMed

    van Polanen, Vonne; Davare, Marco

    2015-12-01

    The two visual systems hypothesis suggests processing of visual information into two distinct routes in the brain: a dorsal stream for the control of actions and a ventral stream for the identification of objects. Recently, increasing evidence has shown that the dorsal and ventral streams are not strictly independent, but do interact with each other. In this paper, we argue that the interactions between dorsal and ventral streams are important for controlling complex object-oriented hand movements, especially skilled grasp. Anatomical studies have reported the existence of direct connections between dorsal and ventral stream areas. These physiological interconnections appear to be gradually more active as the precision demands of the grasp become higher. It is hypothesised that the dorsal stream needs to retrieve detailed information about object identity, stored in ventral stream areas, when the object properties require complex fine-tuning of the grasp. In turn, the ventral stream might receive up to date grasp-related information from dorsal stream areas to refine the object internal representation. Future research will provide direct evidence for which specific areas of the two streams interact, the timing of their interactions and in which behavioural context they occur. PMID:26169317

  12. Interactions between dorsal and ventral streams for controlling skilled grasp

    PubMed Central

    van Polanen, Vonne; Davare, Marco

    2015-01-01

    The two visual systems hypothesis suggests processing of visual information into two distinct routes in the brain: a dorsal stream for the control of actions and a ventral stream for the identification of objects. Recently, increasing evidence has shown that the dorsal and ventral streams are not strictly independent, but do interact with each other. In this paper, we argue that the interactions between dorsal and ventral streams are important for controlling complex object-oriented hand movements, especially skilled grasp. Anatomical studies have reported the existence of direct connections between dorsal and ventral stream areas. These physiological interconnections appear to be gradually more active as the precision demands of the grasp become higher. It is hypothesised that the dorsal stream needs to retrieve detailed information about object identity, stored in ventral stream areas, when the object properties require complex fine-tuning of the grasp. In turn, the ventral stream might receive up to date grasp-related information from dorsal stream areas to refine the object internal representation. Future research will provide direct evidence for which specific areas of the two streams interact, the timing of their interactions and in which behavioural context they occur. PMID:26169317

  13. Involvement of the Cannabinoid CB1 Receptor in Modulation of Dopamine Output in the Prefrontal Cortex Associated with Food Restriction in Rats

    PubMed Central

    Biggio, Francesca; Utzeri, Cinzia; Lallai, Valeria; Licheri, Valentina; Lutzu, Stefano; Mostallino, Maria Cristina; Secci, Pietro Paolo; Biggio, Giovanni; Sanna, Enrico

    2014-01-01

    Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this

  14. Involvement of the cannabinoid CB1 receptor in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats.

    PubMed

    Dazzi, Laura; Talani, Giuseppe; Biggio, Francesca; Utzeri, Cinzia; Lallai, Valeria; Licheri, Valentina; Lutzu, Stefano; Mostallino, Maria Cristina; Secci, Pietro Paolo; Biggio, Giovanni; Sanna, Enrico

    2014-01-01

    Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this

  15. Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

    PubMed Central

    Yin, Hong Z.; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J.; Weiss, John H.

    2014-01-01

    The neurotoxin beta-N-methylamino-L-alanine (BMAA) was first identified as a “toxin of interest” in regard to the amyotrophic lateral sclerosis–Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30 day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2 days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resembles those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease. PMID:24918341

  16. Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord.

    PubMed

    Yin, Hong Z; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J; Weiss, John H

    2014-1