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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. 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

  3. 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

  4. 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

  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. 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

  2. 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

  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. 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

  5. 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

  6. 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

  7. 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

  8. 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

  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. 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

  10. 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

  11. 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

  12. 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

  13. 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

  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. 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

  13. 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

  14. 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

  15. 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

  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. 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

  18. 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

  19. 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

  20. 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

  1. 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

  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. 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

  5. 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

  6. 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

  7. 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

  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. 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

  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. 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

  18. 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

  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. 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

  1. 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

  2. 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

  3. 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

  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. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  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. 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

  4. 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

  5. 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

  6. 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

  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. 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

  14. 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

  15. 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

  16. 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

  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. 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

  19. 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

  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. 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

  13. 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

  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. 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

  7. 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 ...

  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. 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

  17. 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

  18. 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

  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. 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

  2. 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

  3. 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

  4. 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.

  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. 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

  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. 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

  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 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

  15. 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

  16. 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

  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. 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

  7. 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

  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. 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

  10. 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