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Sample records for accumbens da depletions

  1. Modifications in glutamatergic transmission after dopamine depletion of the nucleus accumbens. A combined in vivo/in vitro electrophysiological study in the rat.

    PubMed

    Mulder, A B; Manshanden, I; Vos, P E; Wolterink, G; van Ree, J M; Lopes da Silva, F H

    1996-06-01

    The interaction between the glutamatergic and dopaminergic input in the nucleus accumbens was examined by studying the effects of dopamine depletion of the nucleus accumbens on the local field potentials, and the L-glutamate elicited responses of the nucleus accumbens in anaesthetized rats in vivo. A characteristic field potential in the nucleus accumbens is evoked by electrical stimulation of the fornix/fimbria fibres, with a monosynaptic positive peak at 10 ms (P10). Rats were unilaterally injected with 6-hydroxydopamine in the nucleus accumbens. The contralateral accumbens was sham lesioned. The rats were divided into short-term and long-term survival groups of one to two weeks and 24 weeks, respectively. In the short-term group, a striking increase (up to three times) of the amplitude of the P10 components, at the site of the lesion, compared with the sham lesioned contralateral accumbens and untreated rats, was found. The long-term group could still display a slight increase although on average this was not significantly different from controls. In the short-term group, at the centre of the lesion, the paired-pulse facilitation ratio was significantly smaller than at the more ventral, less denervated, border of the accumbens. These differences were no longer visible in the long-term group. Single-unit activity of the accumbens, elicited by the iontophoretical application of L-glutamate showed, in controls, a maximal firing frequency ranging from 5 to 40 Hz (mean 25 Hz), whereas in the short-term group more than 50% of the accumbens neurons fired with higher frequencies, reaching up to 90 Hz (mean 55 Hz). In the long-term group the firing frequency varied from 5 to 60 Hz (mean 41 Hz). No changes in threshold ejection glutamate current were found for both lesioned groups. In control rats the L-glutamate elicited responses of six cells tested could be suppressed by dopamine whereas in lesioned rats three of the six cells tested were unresponsive to dopamine

  2. Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat.

    PubMed

    Millan, M J; Brocco, M; Gobert, A; Joly, F; Bervoets, K; Rivet, J; Newman-Tancredi, A; Audinot, V; Maurel, S

    1999-12-01

    In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

  3. Music and the nucleus accumbens.

    PubMed

    Mavridis, Ioannis N

    2015-03-01

    Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA.

  4. Stimulation-Evoked Dopamine Release in the Nucleus Accumbens Following Cocaine Administration in Rats Perinatally Exposed to Polychlorinated Biphenyls

    PubMed Central

    Sable, Helen J. K.

    2013-01-01

    Exposure to polychlorinated biphenyls (PCBs) alters brain dopamine (DA) concentrations and DA receptor/transporter function, suggesting the reinforcing properties of drugs of abuse acting on the DA system may be affected by PCB exposure. Female Long-Evans rats were orally exposed to 0, 3, or 6mg/kg/day PCBs from 4 weeks prior to breeding until litters were weaned on postnatal day 21. In vivo fixed potential amperometry (FPA) was used in adult anesthetized offspring to determine whether perinatal PCB exposure altered (1) presynaptic DA autoreceptor (DAR) sensitivity, (2) electrically evoked nucleus accumbens (NAc) DA efflux following administration of cocaine, and (3) the rate of depletion of presynaptic DA stores. One adult male and female littermate were tested using FPA following a single injection of cocaine (20mg/kg ip), whereas a second adult male and female littermate were tested following the last of seven daily cocaine injections of the same dose. The carbon fiber recording microelectrode was positioned in the NAc core, and DA oxidation currents (i.e., DA release) evoked by brief stimulation of the medial forebrain bundle (MFB) were quantified before and after administration of cocaine. PCB-exposed rats exhibited enhanced stimulation-evoked DA release (relative to baseline) following a single injection of cocaine. Although nonexposed controls exhibited typical DA sensitization following repeated cocaine administration, this effect was attenuated in PCB-exposed rats. In addition, DAR sensitivity was higher (males only), and the rate of depletion of presynaptic DA stores was greater in PCB-exposed animals relative to nonexposed controls. These results indicate that perinatal PCB exposure can modify DA synaptic transmission in the NAc in a manner previously shown to alter the reinforcing properties of cocaine. PMID:23912914

  5. Motivational states influence effort-based decision making in rats: the role of dopamine in the nucleus accumbens.

    PubMed

    Mai, Bettina; Sommer, Susanne; Hauber, Wolfgang

    2012-03-01

    Decision-making policies are subject to modulation by changing motivational states. However, so far, little is known about the neurochemical mechanisms that bridge motivational states with decision making. Here we examined whether dopamine (DA) in the nucleus accumbens core (AcbC) modulates the effects of motivational states on effort-based decision making. Using a cost-benefit T-maze task in rats, we examined the effects of AcbC DA depletions on effort-based decision making, in particular on the sensitivity of effort-based decision making to a shift from a hungry to a sated state. The results demonstrated that, relative to sham controls, rats with AcbC DA depletion in a hungry as well as in a sated state had a reduced preference for effortful but large-reward action. This finding provides further support for the notion that AcbC DA regulates how much effort to invest for rewards. Importantly, our results further revealed that effort-based decision making in lesioned rats, as in sham controls, was still sensitive to a shift from a hungry to a sated state; that is, their preferences for effortful large-reward actions became lower after a shift from a restricted to a free-feeding regimen. These finding indicate that AcbC DA is not necessarily involved in mediating the effects of a shift in motivational state on decision-making policies. PMID:22012275

  6. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

    Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

    2011-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

  7. Analysis of limb use by control rats and unilateral DA-depleted rats in the Montoya staircase test: movements, impairments and compensatory strategies.

    PubMed

    Whishaw, I Q; Woodward, N C; Miklyaeva, E; Pellis, S M

    1997-12-01

    The Montoya Staircase Test has been designed as a simple objective way of measuring changes in skilled movements following motor system damage. In the test, rats reach from a central platform for food pellets located on adjacent staircases and the measure of success is the number of food pellets obtained. As there has been no detailed behavioral analysis of how animals reach in this task, the present study evaluates reaching in the test by combining end point measures (success) with movement analysis based on video recordings. It is found that control rats locate food using olfaction and then reach using an identifiable sequence of movements, including (1) aiming the limb, (2) opening the digits in preparation for grasping, (3) grasping, and (4) supinating the paw, during limb withdrawal, to place food in the mouth. The nonreaching limbs adjust posture during the reaching sequence. Rats with unilateral DA-depletions show (1) severe impairments in success when using their contralateral-to-lesion limb (bad limb), (2) moderate impairments in using their ipsilateral-to-lesion limb (good limb), (3) abnormal reaching movements and posture, and (4) a variety of compensatory movements so as to enhance success. When success produced by compensatory adjustment is subtracted from total success, the DA-depleted rats show no recovery. The results confirm that the Staircase Test is a sensitive measure for motor system damage and demonstrate that when movement analysis is combined with end point measures, the test can dissociate impairment, recovery, and compensation.

  8. Nucleus accumbens stimulation in pathological obesity.

    PubMed

    Harat, Marek; Rudaś, Marcin; Zieliński, Piotr; Birska, Julita; Sokal, Paweł

    2016-01-01

    One of the potential treatment methods of obesity is deep brain stimulation (DBS) of nucleus accumbens. We describe the case of 19 years old woman with hypothalamic obesity. She weighted 151.4 kg before DBS and the non-surgical methods proved to be inefficient. She was treated with implantation of DBS electrode to nucleus accumbens bilaterally. Results were measured with body mass index and neuropsychological tests. Follow-up was 14 months. Fourteen months after surgery weight was 138 kg, BMI was 48.3. Neuropsychological test results were intact. The presented case supports the thesis of treatment of obesity with nucleus accumbens stimulation. PMID:27154450

  9. Characterization of the effects of serotonin on the release of (/sup 3/H)dopamine from rat nucleus accumbens and striatal slices

    SciTech Connect

    Nurse, B.; Russell, V.A.; Taljaard, J.J.

    1988-05-01

    The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of (/sup 3/H)dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal /sup 3/H overflow and reduced K+-induced release of (/sup 3/H)DA from nucleus accumbens slices. The effect of serotonin on basal /sup 3/H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of (/sup 3/H)DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of (/sup 3/H)DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.

  10. Dynamic risk control by human nucleus accumbens

    PubMed Central

    Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio

    2015-01-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID:26428667

  11. Dynamic risk control by human nucleus accumbens.

    PubMed

    Nachev, Parashkev; Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio; Strange, Bryan

    2015-12-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID:26428667

  12. Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors.

    PubMed

    Nunes, Eric J; Randall, Patrick A; Podurgiel, Samantha; Correa, Mercè; Salamone, John D

    2013-11-01

    Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Although nucleus accumbens (NAc) DA depletions or antagonism leave aspects of appetite and primary food motivation intact, rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and that stimulation of adenosine A2A receptors produces behavioral effects that are similar to those induced by DA antagonism. The present review summarizes the literature on the role of NAc DA and adenosine in effort-related processes, and also presents original data on the effects of local stimulation of muscarinic acetylcholine receptors in NAc core. Local injections of the muscarinic agonist pilocarpine directly into NAc core produces shifts in effort-related choice behavior similar to those induced by DA antagonism or A2A receptor stimulation, decreasing lever pressing but increasing chow intake in rats responding on a concurrent fixed ratio/chow feeding choice task. In contrast, injections into a neostriatal control site dorsal to the NAc were ineffective. The actions of pilocarpine on this task were attenuated by co-administration of the muscarinic antagonist scopolamine. Thus, drugs that act on DA, adenosine A2A, and muscarinic receptors regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.

  13. Polyamine depletion down-regulates expression of the Trichomonas vaginalis cytotoxic CP65, a 65-kDa cysteine proteinase involved in cellular damage.

    PubMed

    Alvarez-Sánchez, María Elizbeth; Carvajal-Gamez, Bertha Isabel; Solano-González, Eduardo; Martínez-Benitez, Máximo; Garcia, Ana F; Alderete, John F; Arroyo, Rossana

    2008-01-01

    Recently, we found that inhibition of putrescine synthesis by ornithine decarboxylase (ODC) significantly increased Trichomonas vaginalis adherence mediated by protein adhesins. Surprisingly and unexpectedly, trichomonal contact-dependent cytotoxicity was absent. Therefore, a role for polyamine depletion on regulation of T. vaginalis cytotoxicity mediated by the cysteine proteinase (CP) of 65-kDa, CP65, was investigated. We performed cytotoxicity and cell-binding assays followed by zymograms, as well as Western blot and indirect immunofluorescence assays using specific anti-CP65 antibodies to detect CP65. Trichomonads grown in the presence of the ODC inhibitor, 1-4-diamino-2-butanone (DAB) had lower levels of cytotoxicity that corresponded with diminished CP65 proteolytic activity when compared to untreated organisms handled identically. Likewise, semiquantitative and qRT-PCR as well as Western blot and immunofluorescence assays showed decreased amounts of tvcp65 mRNA and CP65 protein in DAB-treated parasites. These effects were reversed by addition of exogenous putrescine. These data show a direct link between polyamine metabolism and expression of the cytotoxic CP65 proteinase involved in trichomonal host cellular damage.

  14. Effects of alpha-methyl-p-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats.

    PubMed

    Watanabe, Shu; Fusa, Koichi; Takada, Koji; Aono, Yuri; Saigusa, Tadashi; Koshikawa, Noriaki; Cools, Alexander R

    2005-12-01

    Alpha-methyl-p-tyrosine (AMPT) is known to inhibit the formation of dopamine (DA) in the cytosol of dopaminergic neurons and is therefore used to study the role of the cytosolic DA pools. AMPT is usually administered systemically. In the present study, however, the effects of locally infused AMPT on the efflux of DA from the nucleus accumbens and dorsal striatum were analyzed, using in vivo brain microdialysis in unanesthetized rats. The administration of AMPT (100 microM, 4 h) into the nucleus accumbens reduced accumbal DA output to 30% of its baseline level. When it was infused into the dorsal striatum, however, it reduced striatal DA output to 60% of its baseline level. At first sight, these data suggest that the amount of DA available from the AMPT-sensitive pool is larger in the nucleus accumbens than in the striatum. However, this cannot be the case, as the decrease in accumbal and striatal DA efflux induced by systemic administration of AMPT (250 mg/kg given intra-peritoneally) was identical. These results show that local infusion of AMPT is a valuable tool for analyzing the role of AMPT-sensitive pools within a particular brain area, but it cannot be used to compare effects across different brain structures because a fixed dose of AMPT differentially affected the nucleus accumbens and the dorsal striatum.

  15. Functional and structural deficits at accumbens synapses in a mouse model of Fragile X

    PubMed Central

    Neuhofer, Daniela; Henstridge, Christopher M.; Dudok, Barna; Sepers, Marja; Lassalle, Olivier; Katona, István; Manzoni, Olivier J.

    2015-01-01

    Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings

  16. Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing.

    PubMed

    Bjork, James M; Grant, Steven J; Chen, Gang; Hommer, Daniel W

    2014-02-01

    Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

  17. Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing.

    PubMed

    Bjork, James M; Grant, Steven J; Chen, Gang; Hommer, Daniel W

    2014-02-01

    Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD. PMID:23995581

  18. Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

    PubMed

    Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

    2016-03-01

    Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not.

  19. Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

    PubMed

    Singer, Bryan F; Guptaroy, Bipasha; Austin, Curtis J; Wohl, Isabella; Lovic, Vedran; Seiler, Jillian L; Vaughan, Roxanne A; Gnegy, Margaret E; Robinson, Terry E; Aragona, Brandon J

    2016-03-01

    Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not. PMID:26613374

  20. Differential activation of accumbens shell and core dopamine by sucrose reinforcement with nose poking and with lever pressing.

    PubMed

    Bassareo, V; Cucca, F; Frau, R; Di Chiara, G

    2015-11-01

    In order to investigate the role of modus operandi in the changes of nucleus accumbens (NAc) dopamine (DA) transmission in sucrose reinforcement, extracellular DA was monitored by microdialysis in the NAc shell and core of rats trained on a fixed-ratio 1 schedule to respond for sucrose pellets by nose poking and lever pressing respectively. After training, rats were tested on three different sessions: sucrose reinforcement, extinction and passive sucrose presentation. In rats responding by nose poking dialysate DA increased in the shell but not in the core under reinforced as well as under extinction sessions. In contrast, in rats responding by lever pressing dialysate DA increased both in the accumbens shell and core under reinforced and extinction sessions. Response non-contingent sucrose presentation increased dialysate DA in the shell and core of rats trained to respond for sucrose by nose poking as well as in those trained by lever pressing. In rats trained to respond for sucrose by nose poking on a FR5 schedule dialysate DA also increased selectively in the NAc shell during reinforced responding and in both the shell and core under passive sucrose presentation. These findings, while provide an explanation for the discrepancies existing in the literature over the responsiveness of shell and core DA in rats responding for food, are consistent with the notion that NAc shell and core DA encode different aspects of reinforcement.

  1. Modulation of Memory Consolidation by the Basolateral Amygdala or Nucleus Accumbens Shell Requires Concurrent Dopamine Receptor Activation in Both Brain Regions

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; Nawar, Erene M.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the…

  2. Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens.

    PubMed

    Tzeng, Wen-Yu; Cherng, Chian-Fang G; Wang, Shyi-Wu; Yu, Lung

    2016-06-01

    This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens. PMID:27001454

  3. Cocaine must enter the brain to evoke unconditioned dopamine release within the nucleus accumbens shell.

    PubMed

    Porter-Stransky, Kirsten A; Wescott, Seth A; Hershman, Molly; Badrinarayan, Aneesha; Vander Weele, Caitlin M; Lovic, Vedran; Aragona, Brandon J

    2011-10-17

    In addition to blocking dopamine (DA) uptake, cocaine also causes an unconditioned increase in DA release. In drug naive rats, this effect is most robust within the nucleus accumbens (NAc) shell. Recent studies have shown that, in rats trained to self-administer cocaine, cocaine may act in the periphery to enhance mesolimbic DA release. Further, these studies have suggested that peripheral cocaine action may also enhance unconditioned DA release. Here, we test if it is necessary for cocaine to enter the brain to evoke unconditioned increases in DA release within the NAc shell. Administration of a cocaine analogue that crosses the blood brain barrier (cocaine HCl) enhances electrically evoked DA release and the number of cocaine-evoked phasic DA release events (i.e., DA transients) within the NAc shell. However, administration of a cocaine analogue that does not cross the blood brain barrier (cocaine MI) does not alter either measure. We therefore conclude that cocaine must act within the central nervous system to evoke unconditioned DA release within the NAc shell. PMID:21888949

  4. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release.

    PubMed

    Melchior, James R; Ferris, Mark J; Stuber, Garret D; Riddle, David R; Jones, Sara R

    2015-09-01

    The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse microenvironments. Local electrical stimulation excites all of the neuronal processes in the stimulation field, potentially modulating the dopamine signal - measured using cyclic voltammetry. Optogenetically targeting light stimulation to dopamine

  5. CHRONIC INTERMITTENT ETHANOL EXPOSURE REDUCES PRESYNAPTIC DOPAMINE NEUROTRANSMISSION IN THE MOUSE NUCLEUS ACCUMBENS

    PubMed Central

    Karkhanis, Anushree N.; Rose, Jamie H.; Huggins, Kimberly N.; Konstantopoulos, Joanne K.; Jones, Sara R.

    2015-01-01

    BACKGROUND Increasing evidence suggests that chronic ethanol exposure decreases dopamine (DA) neurotransmission in the nucleus accumbens (NAc), contributing to a hypodopaminergic state during withdrawal. However, few studies have investigated adaptations in presynaptic DA terminals after chronic intermittent ethanol (CIE) exposure. In monkeys and rats, chronic ethanol exposure paradigms have been shown to increase DA uptake and D2 autoreceptor sensitivity. METHODS The current study examined the effects of ethanol on DA terminals in CIE exposed mice during two time-points after the cessation of CIE exposure. DA release and uptake were measured using fast scan cyclic voltammetry in NAc core slices from C57BL/6J mice, 0 and 72 hours following three weekly cycles (4 days of 16 hrs ethanol vapor/8 hrs room air/day + 3 days withdrawal) of CIE vapor exposure. RESULTS Current results showed that DA release was reduced, uptake rates were increased, and inhibitory D2-type autoreceptor activity was augmented following CIE exposure in mice. CONCLUSIONS Overall, these CIE-induced adaptations in the accumbal DA system reduce DA signaling and therefore reveal several potential mechanisms contributing to a functional hypodopaminergic state during alcohol withdrawal. PMID:25765483

  6. A thalamic input to the nucleus accumbens mediates opiate dependence.

    PubMed

    Zhu, Yingjie; Wienecke, Carl F R; Nachtrab, Gregory; Chen, Xiaoke

    2016-02-11

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.

  7. Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study.

    PubMed

    Rougé-Pont, F; Piazza, P V; Kharouby, M; Le Moal, M; Simon, H

    1993-01-29

    Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration. PMID:8448654

  8. Extinction and reinstatement of phasic dopamine signals in the nucleus accumbens core during Pavlovian conditioning.

    PubMed

    Sunsay, Ceyhun; Rebec, George V

    2014-10-01

    The prediction-error model of dopamine (DA) signaling has largely been confirmed with various appetitive Pavlovian conditioning procedures and has been supported in tests of Pavlovian extinction. Studies have repeatedly shown, however, that extinction does not erase the original memory of conditioning as the prediction-error model presumes, putting the model at odds with contemporary views that treat extinction as an episode of learning rather than unlearning of conditioning. Here, we combined fast-scan cyclic voltammetry (FSCV) with appetitive Pavlovian conditioning to assess DA release directly during extinction and reinstatement. DA was monitored in the nucleus accumbens core, which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, fast-scan cyclic voltammetry was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with noncontingent presentations of reward and then tested with cue presentation. Tone-food pairings produced transient (1- to 3-s) DA release in response to tone. During extinction, the amplitude of the DA response decreased significantly. Following presentation of 2 noncontingent food pellets, subsequent tone presentation reinstated the DA signal. Our results support the prediction-error model for appetitive Pavlovian extinction but not for reinstatement.

  9. Control of nucleus accumbens activity with neurofeedback.

    PubMed

    Greer, Stephanie M; Trujillo, Andrew J; Glover, Gary H; Knutson, Brian

    2014-08-01

    The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as "neurofeedback." In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive aroused affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function.

  10. Control of nucleus accumbens activity with neurofeedback

    PubMed Central

    Greer, Stephanie M.; Trujillo, Andrew J.; Glover, Gary H.; Knutson, Brian

    2014-01-01

    The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as “neurofeedback.” In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive arousal affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function. PMID:24705203

  11. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    PubMed

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.

  12. Roles of Nucleus Accumbens CREB and Dynorphin in Dysregulation of Motivation

    PubMed Central

    Muschamp, John W.; Carlezon, William A.

    2013-01-01

    Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the nucleus accumbens (NAc) (Volkow et al. 2009, Neuropharmacology 56: 3–8). These changes in forebrain DA transmission are similar to those evoked by natural reinforcers (Louilot et al. 1991, Brain Res 553: 313–317; Roitman et al. 2004, J Neurosci 24: 1265–1271), but are of greater magnitude and longer duration. Repeated drug exposure causes compensatory neuroadaptations in neurons of the NAc, some of which may modulate excess DA in a homeostatic fashion. One such adaptation is the activation of the transcription factor CREB (cAMP response element-binding protein) within neurons of the NAc. Although elevated levels of transcriptionally active CREB appear to attenuate DA transmission by increasing expression of the endogenous κ opioid receptor (KOR) ligand dynorphin, increased dynorphin transmission may ultimately have undesirable effects that contribute to drug withdrawal states as well as comorbid psychiatric illnesses such as depression. This state may prompt a return to drug use to mitigate the adverse effects of withdrawal. This article summarizes our current understanding of how CREB and dynorphin contribute to the dysregulation of motivation and describes novel therapeutic strategies that derive from preclinical research in this area. PMID:23293139

  13. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens.

    PubMed

    Danjo, Teruko; Yoshimi, Kenji; Funabiki, Kazuo; Yawata, Satoshi; Nakanishi, Shigetada

    2014-04-29

    Dopamine (DA) transmission from the ventral tegmental area (VTA) is critical for controlling both rewarding and aversive behaviors. The transient silencing of DA neurons is one of the responses to aversive stimuli, but its consequences and neural mechanisms regarding aversive responses and learning have largely remained elusive. Here, we report that optogenetic inactivation of VTA DA neurons promptly down-regulated DA levels and induced up-regulation of the neural activity in the nucleus accumbens (NAc) as evaluated by Fos expression. This optogenetic suppression of DA neuron firing immediately evoked aversive responses to the previously preferred dark room and led to aversive learning toward the optogenetically conditioned place. Importantly, this place aversion was abolished by knockdown of dopamine D2 receptors but not by that of D1 receptors in the NAc. Silencing of DA neurons in the VTA was thus indispensable for inducing aversive responses and learning through dopamine D2 receptors in the NAc.

  14. Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice.

    PubMed

    Ito, Mina; Nagai, Taku; Kamei, Hiroyuki; Nakamichi, Noritaka; Nabeshima, Toshitaka; Takuma, Kazuhiro; Yamada, Kiyofumi

    2006-11-01

    Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mice, by using in vivo microdialysis. Microinjection of either tPA or plasmin significantly potentiated 40 mM KCl-induced DA release without affecting basal DA levels. In contrast, plasminogen activator inhibitor-1 dose-dependently reduced 60 mM KCl-induced DA release. The 60 mM KCl-evoked DA release in the NAc was markedly diminished in tPA-deficient (tPA-/-) mice compared with wild-type mice, although basal DA levels did not differ between the two groups. Microinjections of either exogenous tPA (100 ng) or plasmin (100 ng) into the NAc of tPA-/-mice restored 60 mM KCl-induced DA release, as observed in wild-type mice. In contrast, there was no difference in either basal or 60 mM KCl-induced ACh release in the hippocampus between wild-type and tPA-/-mice. Our findings suggest that the tPA-plasmin system is involved in the regulation of depolarization-evoked DA release in the NAc.

  15. Nucleus accumbens shell, but not core, tracks motivational value of salt.

    PubMed

    Loriaux, Amy L; Roitman, Jamie D; Roitman, Mitchell F

    2011-09-01

    To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state. PMID:21697439

  16. Altered levels of synapsin I, dopamine transporter, dynorphin A, and neuropeptide Y in the nucleus accumbens and striatum at post-puberty in rats treated neonatally with pregnenolone or DHEA.

    PubMed

    Muneoka, Katsumasa; Iwata, Masaaki; Shirayama, Yukihiko

    2009-10-01

    It is well documented that neonatal neurosteroid administration influences brain development. In our previous studies, administration of pregnenolone, the precursor of neurosteroids, during the neonatal period altered the activity of dopamine (DA) in the striatum. Furthermore, neonatal treatment with pregnenolone or dehydroepiandrosterone (DHEA) increased synapse-related protein synapsin I as well as neuropeptide Y (NPY) in the hippocampus. The present study examined the effects of neonatal treatment with pregnenolone or DHEA on synapsin I, DA transporter (DAT), dynorphin A, and NPY in the striatum and the core and shell of the nucleus accumbens at post-puberty. Administration of pregnenolone or DHEA during the neonatal period increased immunodensity of synapsin I in the dorsomedial or ventrolateral striatum. DAT immunodensity in the striatum and the nucleus accumbens core as well as dynorphin A immunodensity in the nucleus accumbens core were increased in DHEA-treated but not in pregnenolone-treated rats. In addition, the size, but not numbers, of NPY-positive cells in the nucleus accumbens core was increased in pregnenolone- and DHEA-treated rats. The results suggest that neurosteroid levels during the neonatal period have larger impact on synaptic formation, development of DA and NPY systems in the nigrostriatal rather than the mesolimbic pathway.

  17. Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

    PubMed

    St Onge, Jennifer R; Ahn, Soyon; Phillips, Anthony G; Floresco, Stan B

    2012-11-21

    Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

  18. The topographic order of inputs to nucleus accumbens in the rat.

    PubMed

    Phillipson, O T; Griffiths, A C

    1985-10-01

    Afferents to the nucleus accumbens have been studied with the retrograde transport of unconjugated wheatgerm agglutinin as detected by immunohistochemistry using the peroxidase-antiperoxidase method, in order to define precisely afferent topography from the cortex, thalamus, midbrain and amygdala. Cortical afferent topography was extremely precise. The largest number of cells was found following injections to the anterior accumbens. Anteromedial injections labelled a very large extent of the subiculum and part of the entorhinal cortex. Anterolateral injections produced less subicular and entorhinal label but also labelled the posterior perirhinal cortex. Posteromedial injections labelled only the ventral subiculum and a few cells in the adjacent medial entorhinal cortex. Posterolateral injections labelled few lateral entorhinal neurones but did label a long anteroposterior strip of perirhinal cortex. Prefrontal cortex label was found only after anterior accumbens injections. In the amygdala labelled neurones were found in cortical, central, lateral posterior, anteromedial and basolateral nuclei. Basolateral amygdala projected chiefly to the anteromedial accumbens and central nucleus to anterolateral accumbens. Only a weak amygdala label was found after posterior accumbens injections. In the ventral tegmental area, the midline interfascicular nucleus projected only to medial accumbens. The paranigral ventral tegmentum projected chiefly to the medial accumbens and the parabrachial area chiefly to the lateral accumbens. In the thalamus, heaviest label was found after anterior accumbens injections. Most cells were found in the paraventricular, reuniens and rhomboid nuclei and at posterior thalamic levels lying medial to the fasciculus retroflexus. There was only restricted topography found from thalamic sites. Retrograde label was also found in the ventral pallidum and lateral hypothalamus. Single small injection sites within accumbens received input from the whole

  19. Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

    PubMed Central

    Cacciapaglia, Fabio; Wightman, R. Mark; Carelli, Regina M.

    2015-01-01

    Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. SIGNIFICANCE STATEMENT Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have

  20. Intranasal dopamine application increases dopaminergic activity in the neostriatum and nucleus accumbens and enhances motor activity in the open field.

    PubMed

    de Souza Silva, M A; Topic, B; Huston, J P; Mattern, C

    2008-03-01

    Dopamine (DA) plays an important role in a number of behavioral processes and neurological disorders. The intranasal administration of DA provides improved brain penetrability in comparison to systemic administration. We investigated the effects of intranasal administration of DA on the activity of dopaminergic neurons of the mesostriatal and mesolimbic systems and on motor activity. Rats previously implanted with guide-cannulae in the neostriatum (NS) and nucleus accumbens (NAc) were submitted to microdialysis procedure under urethane anesthesia. Vehicle or DA (0.03, 0.3, or 3.0 mg/kg) was administered bilaterally into the nostrils. In a separate study, animals received an intraperitoneal (i.p.) injection of vehicle or DA (0.03, 0.3, 3.0, or 30.0 mg/kg). Samples were collected every 10 min and analyzed for the content of DA and metabolites using high-performance liquid chromatography. For the open field study, rats were given intranasal vehicle or DA (0.03, 0.3, or 3.0 mg/kg) and placed into the field for 30 min. Motor activity (locomotion and rearing) and grooming were analyzed in blocks of 10 min using Ethovision. Intranasal DA (3.0 mg/kg) significantly increased DA levels in the NS and NAc immediately after administration. A comparable effect was obtained only after i.p. administration of 30 mg/kg DA. In the open field, the 3.0 mg/kg dose significantly decreased grooming behavior in the second 10 min interval and significantly increased locomotor activity in the third 10 min interval. The data indicate that intranasal administration of DA can influence dopaminergic functions and motor activity, and has a potential application in the therapy of diseases affecting the dopaminergic system.

  1. Effects of cytotoxic nucleus accumbens lesions on instrumental conditioning in rats.

    PubMed

    de Borchgrave, R; Rawlins, J N P; Dickinson, A; Balleine, B W

    2002-05-01

    In two experiments the involvement of the nucleus accumbens in instrumental conditioning was investigated using rats as subjects. In experiment 1, extensive bilateral cytotoxic lesions of the nucleus accumbens mildly suppressed instrumental responding reinforced with food, but had no detectable effect on the sensitivity of the rats' performance either to outcome devaluation or to degradation of the instrumental contingency. In experiment 2, restricted accumbens lesions reliably attenuated the excitatory effect of systemically administered d-amphetamine on lever pressing for a conditioned reinforcer, and completely abolished Pavlovian-instrumental transfer. Taken together these results give a picture of the involvement of the rat nucleus accumbens in instrumental conditioning. They support the widely held theory that the nucleus accumbens mediates the excitatory effects of appetitively conditioned Pavlovian signals on instrumental performance and refute the hypothesis that the nucleus accumbens is part of the neural circuitry by which incentive value is attached to the representations of instrumental outcomes.

  2. Relief memory consolidation requires protein synthesis within the nucleus accumbens.

    PubMed

    Bruning, Johann E A; Breitfeld, Tino; Kahl, Evelyn; Bergado-Acosta, Jorge R; Fendt, Markus

    2016-06-01

    Relief learning refers to the association of a stimulus with the relief from an aversive event. The thus-learned relief stimulus then can induce, e.g., an attenuation of the startle response or approach behavior, indicating positive valence. Previous studies revealed that the nucleus accumbens is essential for the acquisition and retrieval of relief memory. Here, we ask whether the nucleus accumbens is also the brain site for consolidation of relief memory into a long-term form. In rats, we blocked local protein synthesis within the nucleus accumbens by local infusions of anisomycin at different time points during a relief conditioning experiment. Accumbal anisomycin injections immediately after the relief conditioning session, but not 4 h later, prevented the consolidation into long-term relief memory. The retention of already consolidated relief memory was not affected by anisomycin injections. This identifies a time window and site for relief memory consolidation. These findings should complement our understanding of the full range of effects of adverse experiences, including cases of their distortion in humans such as post-traumatic stress disorder and/or phobias. PMID:26792192

  3. Left nucleus accumbens atrophy in deficit schizophrenia: A preliminary study.

    PubMed

    De Rossi, Pietro; Dacquino, Claudia; Piras, Fabrizio; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-08-30

    A question that remains to be answered is whether schizophrenia can be characterized by a single etiopathophysiology or whether separate sub-syndromes should be differentiated to define specific mechanisms for each sub-type. Individuals affected by the deficit subtype of schizophrenia (DSZ) display avolitional/amotivational features that respond poorly to conventional treatments. Characterizing DSZ from a neuroanatomical point of view may help clarify this issue and develop new treatment strategies. To determine if DSZ is associated with structural alterations in specific deep grey matter structures linked to its key clinical features, 22 DSZ patients, 22 non-deficit schizophrenia (NDSZ) patients and 22 healthy controls (HC) were recruited for a case-control cross-sectional study. High-resolution magnetic resonance imaging was performed in all subjects and volumes of deep grey matter structures were measured using FreeSurfer. DSZ patients displayed smaller left accumbens volumes compared to both NDSZ patients and HC. Moreover, age and duration of illness were significantly associated with lower volume of the left accumbens in DSZ but not in NDSZ. Findings indicate that DSZ is associated with lower volume of the nucleus accumbens in the dominant hemisphere. This is consistent with the psychopathological features and functional impairments present in DSZ and thus indicates a potential mechanism. PMID:27322868

  4. Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens

    NASA Technical Reports Server (NTRS)

    During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

    1988-01-01

    Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

  5. Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats.

    PubMed

    Wallin-Miller, Kathryn; Li, Grace; Kelishani, Diana; Wood, Ruth I

    2016-08-25

    Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle-treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior.

  6. Dopamine and opioid systems interact within the nucleus accumbens to maintain monogamous pair bonds.

    PubMed

    Resendez, Shanna L; Keyes, Piper C; Day, Jeremy J; Hambro, Caely; Austin, Curtis J; Maina, Francis K; Eidson, Lori; Porter-Stransky, Kirsten A; Nevárez, Natalie; McLean, J William; Kuhnmuench, Morgan A; Murphy, Anne Z; Mathews, Tiffany A; Aragona, Brandon J

    2016-01-01

    Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds. PMID:27371827

  7. Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats.

    PubMed

    Wallin-Miller, Kathryn; Li, Grace; Kelishani, Diana; Wood, Ruth I

    2016-08-25

    Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle-treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior. PMID:27238893

  8. Dopamine and opioid systems interact within the nucleus accumbens to maintain monogamous pair bonds

    PubMed Central

    Resendez, Shanna L; Keyes, Piper C; Day, Jeremy J; Hambro, Caely; Austin, Curtis J; Maina, Francis K; Eidson, Lori N; Porter-Stransky, Kirsten A; Nevárez, Natalie; McLean, J William; Kuhnmuench, Morgan A; Murphy, Anne Z; Mathews, Tiffany A; Aragona, Brandon J

    2016-01-01

    Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds. DOI: http://dx.doi.org/10.7554/eLife.15325.001 PMID:27371827

  9. Simplified dietary acute tryptophan depletion: effects of a novel amino acid mixture on the neurochemistry of C57BL/6J mice

    PubMed Central

    Sánchez, Cristina L.; Van Swearingen, Amanda E. D.; Arrant, Andrew E.; Biskup, Caroline S.; Kuhn, Cynthia M.; Zepf, Florian D.

    2015-01-01

    Background Diet and nutrition can impact on the biological processes underpinning neuropsychiatric disorders. Amino acid (AA) mixtures lacking a specific neurotransmitter precursor can change the levels of brain serotonin (5-HT) or dopamine (DA) in the central nervous system. The availability of these substances within the brain is determined by the blood–brain barrier (BBB) that restricts the access of peripheral AA into the brain. AA mixtures lacking tryptophan (TRP) compete with endogenous TRP for uptake into the brain across the BBB, which in turn leads to a decrease in central nervous 5-HT synthesis. Objective The present study compared the effects of a simplified acute tryptophan depletion (SATD) mixture in mice on blood and brain serotonergic and dopaminergic metabolites to those of a commonly used acute tryptophan depletion mixture (ATD Moja-De) and its TRP-balanced control (BAL). Design The SATD formula is composed of only three large neutral AAs: phenylalanine (PHE), leucine (LEU), and isoleucine (ILE). BAL, ATD Moja-De, or SATD formulas were delivered to adult male C57BL/6J mice by gavage. TRP, monoamines, and their metabolites were quantified in blood and brain regions (hippocampus, frontal cortex, amygdala, caudate putamen, and nucleus accumbens). Results Both ATD Moja-De and SATD significantly decreased levels of serum and brain TRP, as well as brain 5-HIAA and 5-HT compared with BAL. SATD reduced HVA levels in caudate but did not alter total DA levels or DOPAC. SATD decreased TRP and serotonergic metabolites comparably to ATD Moja-De administration. Conclusion A simplified and more palatable combination of AAs can manipulate serotonergic function and might be useful to reveal underlying monoamine-related mechanisms contributing to different neuropsychiatric disorders. PMID:26278978

  10. Water Depletion Threatens Agriculture

    NASA Astrophysics Data System (ADS)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  11. CCK-8 injected into the nucleus accumbens attenuates the supersensitive locomotor response to apomorphine in 6-OHDA and chronic-neuroleptic treated rats.

    PubMed

    Weiss, F; Ettenberg, A; Koob, G F

    1989-01-01

    Postsynaptic dopamine-cholecystokinin (CCK) interactions in the nucleus accumbens were studied in two behavioral preparations of DA receptor supersensitivity: chronic-neuroleptic treated and 6-hydroxydopamine (6-OHDA) denervated rats. Subcutaneous (SC) injections of apomorphine (APO; 0.15 mg/kg) in experiment 1 produced marked hyperlocomotion in rats following 12 days of pretreatment with cis-[Z]-flupenthixol (2 mg/kg; twice per day). Bilateral intra-accumbens (N.Acc.) microinjections of CCK-8 (2 ng and 2 micrograms) reliably reduced APO-stimulated hyperlocomotion. An intermediate CCK dose (20 ng) was without effect. No change in APO responsivity following chronic vehicle treatment was observed and the baseline APO response was not altered by CCK at any dose. Denervation of mesolimbic dopamine (DA) terminals by intra-N.Acc. injections of 6-hydroxydopamine (6-OHDA; 8 micrograms/side) in experiment 2 similarly resulted in intense locomotor hyperactivity after APO stimulation (0.1 mg/kg; SC). Bilateral intra-N.Acc. injections of CCK-8 (1, 10, 100 ng, and 1 micrograms) significantly attenuated the supersensitive locomotor response to APO. As in experiment 1, CCK produced "biphasic" dose-response effects with strong attenuation that persisted throughout the entire 60-min test at both high (1 microgram) and low (1 ng) doses. Intermediate CCK doses (10 and 100 ng) produced only short-term reductions in activity. Hypomotility induced by APO in SHAM-lesioned rats was not effectively reversed by CCK treatments. CCK had no effect on unstimulated baseline locomotor activity in either 6-OHDA or SHAM-lesioned rats. These results provide further evidence that CCK-8 modulates mesolimbic DA activity by functionally opposing the postsynaptic effects of DA in the region of the nucleus accumbens. PMID:2574480

  12. Extracellular dopamine and its metabolites in the nucleus accumbens of Fisher and Lewis rats: Basal levels and cocaine-induced changes

    SciTech Connect

    Strecker, R.E.; Eberle, W.F.; Ashby, C.R. Jr.

    1995-11-01

    Rats of the Lewis (LEW) strain show a greater preference for drugs of abuse than do Fisher 344 (F344) rats. The in vivo microdialysis procedure was used to examine basal and cocaine-evoked extracellular (EC) levels of dopamine (DA), DOPAC, and HVA in the nucleus accumbens (NAc) of F344 and LEW rats. The basal EC levels of the DA metabolites DOPAC and HVA in the NAc were markedly lower in LEW than in F344 rats. Although the increase in ECDA after 3, 10 or 30 mg/kg, i/p. of cocaine was similar in both strains, LEW rats had a smaller peak DA elevation followed by a slower return to basal DA levels at the 30 mg/kg dose. The neurochemical differences observed may contribute to the strain differences in the behavioral response to cocaine. 20 refs., 3 figs.

  13. Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration.

    PubMed

    Wise, R A; Leone, P; Rivest, R; Leeb, K

    1995-10-01

    Extracellular dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) levels in nucleus accumbens were sampled by microdialysis and quantified with high-performance liquid chromatography during intravenous heroin self-administration sessions in rats. Dopamine levels in 10 and 20 min samples were elevated following the first injection of each session, reaching a plateau of elevation within the first two or three injections and falling back toward baseline only when drug access was terminated. Elevations were in the range of 150-300% when unit dosages of 0.05-0.2 mg/kg were given. Increasing the work requirement from FR-1 to FR-10 did not appear to alter the degree of elevation of dopamine levels, and dopamine levels fell during extinction while lever-pressing rates increased 20-fold. While animals compensated for unit dose changes between 0.05 and 0.2 mg/kg/injection, adjusting their response rate such that the same hourly drug intake and the same asymptotic dopamine levels were maintained across these conditions, at 0.4 mg/kg/injection hourly drug intake and asymptotic dopamine levels were elevated beyond the levels sustained by the lower doses. These findings confirm that self-administered doses of intravenous heroin are sufficient to activate the mesolimbic dopamine system and suggest that significant heroin "craving" can emerge when dopamine levels are still moderately elevated, long before the development of dopamine depletion associated with opiate withdrawal.

  14. Aversive stimuli differentially modulate real-time dopamine transmission dynamics within the nucleus accumbens core and shell.

    PubMed

    Badrinarayan, Aneesha; Wescott, Seth A; Vander Weele, Caitlin M; Saunders, Benjamin T; Couturier, Brenann E; Maren, Stephen; Aragona, Brandon J

    2012-11-01

    Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems. PMID:23136417

  15. Aversive Stimuli Differentially Modulate Real-Time Dopamine Transmission Dynamics within the Nucleus Accumbens Core and Shell

    PubMed Central

    Badrinarayan, Aneesha; Wescott, Seth A.; Vander Weele, Caitlin M.; Saunders, Benjamin T.; Couturier, Brenann E.; Maren, Stephen

    2012-01-01

    Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems. PMID:23136417

  16. Certain or uncertain cocaine expectations influence accumbens dopamine responses to self-administered cocaine and non-rewarded operant behavior.

    PubMed

    D'Souza, Manoranjan S; Duvauchelle, Christine L

    2008-09-01

    Uncertainty and errors in predicting natural rewards influence associative learning and dopamine activity. The present study was conducted to determine the influence of cue-induced cocaine uncertainty, certainty and prediction error on nucleus accumbens dopamine (NAcc DA) in rats. For Certainty training, distinctive sensory cues were present during cocaine availability and alternate cues were paired with non-reinforced (saline) operant sessions. For Uncertainty training, all cues were equally associated with both cocaine and non-reinforcement. After training, animals self-administered cocaine or saline in the presence of conditioned cues while NAcc DA responses were assessed using in vivo microdialysis. Findings revealed cocaine-stimulated NAcc DA increased significantly less in Certainty--compared to Uncertainty-trained animals, and cocaine-paired cues in the absence of cocaine (Negative Prediction Error) resulted in a significant depression of baseline NAcc DA. These findings provide support for enhanced DA activity during cocaine uncertainty or the development of conditioned cocaine tolerance in subjects certain of a cocaine outcome.

  17. Halo Star Lithium Depletion

    SciTech Connect

    Pinsonneault, M. H.; Walker, T. P.; Steigman, G.; Narayanan, Vijay K.

    1999-12-10

    The depletion of lithium during the pre-main-sequence and main-sequence phases of stellar evolution plays a crucial role in the comparison of the predictions of big bang nucleosynthesis with the abundances observed in halo stars. Previous work has indicated a wide range of possible depletion factors, ranging from minimal in standard (nonrotating) stellar models to as much as an order of magnitude in models that include rotational mixing. Recent progress in the study of the angular momentum evolution of low-mass stars permits the construction of theoretical models capable of reproducing the angular momentum evolution of low-mass open cluster stars. The distribution of initial angular momenta can be inferred from stellar rotation data in young open clusters. In this paper we report on the application of these models to the study of lithium depletion in main-sequence halo stars. A range of initial angular momenta produces a range of lithium depletion factors on the main sequence. Using the distribution of initial conditions inferred from young open clusters leads to a well-defined halo lithium plateau with modest scatter and a small population of outliers. The mass-dependent angular momentum loss law inferred from open cluster studies produces a nearly flat plateau, unlike previous models that exhibited a downward curvature for hotter temperatures in the 7Li-Teff plane. The overall depletion factor for the plateau stars is sensitive primarily to the solar initial angular momentum used in the calibration for the mixing diffusion coefficients. Uncertainties remain in the treatment of the internal angular momentum transport in the models, and the potential impact of these uncertainties on our results is discussed. The 6Li/7Li depletion ratio is also examined. We find that the dispersion in the plateau and the 6Li/7Li depletion ratio scale with the absolute 7Li depletion in the plateau, and we use observational data to set bounds on the 7Li depletion in main-sequence halo

  18. Battery depletion monitor

    SciTech Connect

    Lee, Y.S.

    1982-01-26

    A cmos inverter is used to compare pacemaker battery voltage to a referenced voltage. When the reference voltage exceeds the measured battery voltage, the inverter changes state to indicate battery depletion.

  19. Characterization of a folate-induced hypermotility response after bilateral injection into the rat nucleus accumbens

    SciTech Connect

    Stephens, R.L. Jr.

    1986-01-01

    The objective of these studies was to pharmacologically characterize the mechanism responsible for a folate-induced stimulation of locomotor activity in rats after bilateral injection into the nucleus accumbens region of the brain. Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) produced this hypermotility response after intra-accumbens injection, while other reduced folic acid derivatives dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Studies were designed to determine the role of catecholamines in the nucleus accumbens in the folate-induced hypermotility response. The findings suggest that the folate-induced response is dependent on intact neuronal dopamine stores, and is mediated by stimulation of dopamine receptors of the nucleus accumbens. However the folates do not appear to enhance dopaminergic neutransmission. Thus, FA and FTHF were inefficient at 1 mM concentrations in stimulating /sup 3/H-dopamine release from /sup 3/H-dopamine preloaded nucleus accumbens slices or dopamine from endogenous stores. Pteroic acid, the chemical precursor of folic acid which lacks the glutamate moiety, was ineffective in producing a stimulation of locomotor activity after intra-accumbens injection. Since glutamate is an excitatory amino acid (EAA), compounds characterized as EAA receptor antagonists were utilized to determine if the folate-induced hypermotility response is mediated by activation of EAA receptors in the nucleus accumbens. These results suggest that activation of quisqualate receptors of the nucleus accumbens may mediate the folate-induced hypermotility response.

  20. Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens

    PubMed Central

    Sun, Ninglei; Laviolette, Steven R

    2014-01-01

    The mesolimbic pathway comprising the ventral tegmental area (VTA) and projection terminals in the nucleus accumbens (NAc) has been identified as a critical neural system involved in processing both the rewarding and aversive behavioral effects of nicotine. Transmission through dopamine (DA) receptors functionally modulates these effects directly within the NAc. Nevertheless, the neuronal mechanisms within the NAc responsible for these bivalent behavioral effects are presently not known. Using an unbiased conditioned place preference procedure combined with in vivo neuronal recordings, we examined the effects of nicotine reward and aversion conditioning on intra-NAc neuronal sub-population activity patterns. We report that intra-VTA doses of nicotine that differentially produce rewarding or aversive behavioral effects produce opposite effects on sub-populations of fast-spiking interneurons (FSIs) or medium spiny neurons (MSNs) within the shell region of the NAc (NAshell). Thus, while the rewarding effects of intra-VTA nicotine were associated with inhibition of FSI and activation of MSNs, the aversive effects of nicotine produced the opposite pattern of NAshell neuronal population activity. Blockade of DA transmission with a broad-spectrum DA receptor antagonist, α-flupenthixol, strongly inhibited the spontaneous activity of NAshell FSIs, and reversed the conditioning properties of intra-VTA nicotine, switching nicotine-conditioned responses from aversive to rewarding. Remarkably, DA receptor blockade switched intra-NAshell neuronal population activity from an aversion to a reward pattern, concomitant with the observed switch in behavioral conditioning effects. PMID:24896614

  1. Cocaine exposure alters dopaminergic modulation of prefronto-accumbens transmission.

    PubMed

    Wang, Xiusong; Liu, Lei; Adams, Wendy; Li, Shouxin; Zhang, Qian; Li, Bingjin; Wang, Min; Cui, Ranji

    2015-06-01

    In the nucleus accumbens (NAc), dopamine transmission modulates glutamatergic input from the prefrontal cortex (PFC). This neuromodulatory action of dopamine can be disrupted by repeated exposure to psychostimulants such as cocaine. However, it is unclear whether this modulation depends on the precise timing of transmission at the same medium spiny neurons (MSNs) and if so, then whether this timing related modulation is also influenced by cocaine experience. Here, combining cocaine self-administration and in vivo extracellular recordings in anesthetized rats, we show that dopamine efflux in the NAc evoked by electrically stimulating the ventral tegmental area (VTA) exerted timing-dependent regulation of the excitatory accumbens response to stimulation of the medial prefrontal cortex (mPFC), and also that this modulation was blunted following prolonged abstinence from cocaine self-administration. These data indicate that dopaminergic timing-dependent dysregulation of mPFC-NAc glutamatergic transmission is implicated in cocaine addiction and might contribute to vulnerability to drug relapse after prolonged abstinence.

  2. Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration.

    PubMed

    Piazza, P V; Rougé-Pont, F; Deminière, J M; Kharoubi, M; Le Moal, M; Simon, H

    1991-12-13

    Individual vulnerability to the reinforcing effects of drugs appear to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1726140

  3. Pain relief induces dopamine release in the rat nucleus accumbens during the early but not late phase of neuropathic pain.

    PubMed

    Kato, Takahiro; Ide, Soichiro; Minami, Masabumi

    2016-08-26

    Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications. PMID:27369326

  4. The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.

    PubMed

    Scofield, M D; Heinsbroek, J A; Gipson, C D; Kupchik, Y M; Spencer, S; Smith, A C W; Roberts-Wolfe, D; Kalivas, P W

    2016-07-01

    The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances. PMID:27363441

  5. Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation.

    PubMed

    Cohen, Michael X; Bour, Lo; Mantione, Mariska; Figee, Martijn; Vink, Matthijs; Tijssen, Marina A J; van Rootselaar, Anne-Fleur; van den Munckhof, Pepijn; Schuurman, P Richard; Denys, Damiaan

    2012-01-01

    The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex → nucleus accumbens)- from "bottom-up" (nucleus accumbens → cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions. PMID:21547982

  6. Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection

    PubMed Central

    Litvak, Vladimir; Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

    2015-01-01

    The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection. PMID:25878159

  7. Cholesterol depletion induces autophagy

    SciTech Connect

    Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi . E-mail: tfujimot@med.nagoya-u.ac.jp

    2006-12-08

    Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

  8. Charge depletion meter

    NASA Astrophysics Data System (ADS)

    Schneider, J. F.

    1984-11-01

    This invention relates to a charge depletion meter apparatus having a current to frequency converter to sense and convert the current drain of a battery source to a digital signal which is divided and then accumulated in a counter. An LCD display unit displays the accumulated charge which is received from the counter.

  9. Terminal Dopamine Release Kinetics in the Accumbens Core and Shell Are Distinctly Altered after Withdrawal from Cocaine Self-Administration

    PubMed Central

    2016-01-01

    Abstract Repeated self-administration of cocaine is associated with impairments in motivated behaviors as well as alterations in both dopamine (DA) release and neural signaling within the nucleus accumbens (NAc). These impairments are present even after several weeks of abstinence from drug taking, suggesting that the self-administration experience induces long-lasting neuroplastic alterations in the mesolimbic DA circuit. To understand these changes at the terminal level, rats were allowed to self-administer either cocaine intravenously (∼1 mg/kg per infusion) or water to a receptacle (control) in 2-h sessions over 14 days, followed by 30 days of enforced abstinence. Fast-scan cyclic voltammetry was used to record real-time DA release in either NAc core or shell after electrical stimulations of the ventral tegmental area (VTA) in freely-moving animals. In controls, the kinetics of DA release in the core and shell strikingly differed, with shell displaying slower release and reuptake rates than core. However, cocaine experience differentially altered these signaling patterns by NAc subregion. In the shell, cocaine rats showed less sensitivity to the dynamic range of applied stimulations than controls. In the core, by contrast, cocaine rats displayed robustly reduced peak DA release given the same stimulation, while also showing slower release and reuptake kinetics. The differential effects of cocaine self-administration on terminal function between core and shell is consistent with a region-specific functional reorganization of the mesolimbic DA system after repeated exposure and may provide an anatomical substrate for altered cognitive function after chronic drug-taking and addiction. PMID:27752541

  10. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    PubMed Central

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  11. Taste pathways that mediate accumbens dopamine release by sapid sucrose.

    PubMed

    Hajnal, Andras; Norgren, Ralph

    2005-03-16

    Although it has been associated with the release of dopamine in the forebrain, reward remains a conundrum in neuroscience. Sucrose is inherently rewarding and its sensory message reaches the brain via the gustatory system. In rodents, the central gustatory system bifurcates in the pontine parabrachial nuclei, one arm forming a standard thalamocortical axis, the other distributing widely in the limbic forebrain. We report here that lesions of the gustatory thalamus fail to affect dopamine overflow during sucrose licking (149+/-5% vs. 149+/-4% for controls). Similar damage to the parabrachial nuclei, which severs the limbic taste projection, substantially reduces dopamine release from the nucleus accumbens (121+/-4% vs. 168+/-9% for sham operated controls; p<0.02). This represents the first demonstration that the affective character of a sensory stimulus might separate from the thalamocortical system as early as the second central synapse. PMID:15763573

  12. Nucleus accumbens core lesions enhance two-way active avoidance

    PubMed Central

    Lichtenberg, Nina T.; Kashtelyan, Vadim; Burton, Amanda C.; Bissonette, Gregory B.; Roesch, Matthew R.

    2014-01-01

    The majority of work examining nucleus accumbens core (NAc) has focused on functions pertaining to behaviors guided by appetitive outcomes. These studies have pointed to NAc as being critical for motivating behavior toward desirable outcomes. For example, we have recently shown that lesions of NAc impaired performance on a reward-guided decision-making task that required rats to choose between differently valued rewards. Unfortunately, much less is known about the role that NAc plays in motivating behavior when aversive outcomes are predicted. To address this issue we asked if NAc lesions impact performance on a two-way active avoidance task in which rats must learn to shuttle back and forth in a behavioral training box in order to avoid a footshock predicted by an auditory tone. Although bilateral NAc lesions initially impaired reward-guided decision-making, we found that the same lesions improved acquisition and retention of two-way active avoidance. PMID:24275320

  13. SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens.

    PubMed

    Ferguson, Deveroux; Shao, Ningyi; Heller, Elizabeth; Feng, Jian; Neve, Rachael; Kim, Hee-Dae; Call, Tanessa; Magazu, Samantha; Shen, Li; Nestler, Eric J

    2015-02-18

    Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action. PMID:25698746

  14. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

    PubMed

    Sakae, D Y; Marti, F; Lecca, S; Vorspan, F; Martín-García, E; Morel, L J; Henrion, A; Gutiérrez-Cuesta, J; Besnard, A; Heck, N; Herzog, E; Bolte, S; Prado, V F; Prado, M A M; Bellivier, F; Eap, C B; Crettol, S; Vanhoutte, P; Caboche, J; Gratton, A; Moquin, L; Giros, B; Maldonado, R; Daumas, S; Mameli, M; Jamain, S; El Mestikawy, S

    2015-11-01

    Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse. PMID:26239290

  15. α-1 Adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission.

    PubMed

    Mitrano, Darlene A; Schroeder, Jason P; Smith, Yoland; Cortright, James J; Bubula, Nancy; Vezina, Paul; Weinshenker, David

    2012-08-01

    Brainstem noradrenergic neurons innervate the mesocorticolimbic reward pathway both directly and indirectly, with norepinephrine facilitating dopamine (DA) neurotransmission via α1-adrenergic receptors (α1ARs). Although α1AR signaling in the prefrontal cortex (PFC) promotes mesolimbic transmission and drug-induced behaviors, the potential contribution of α1ARs in other parts of the pathway, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc), has not been investigated before. We found that local blockade of α1ARs in the medial NAc shell, but not the VTA, attenuates cocaine- and morphine-induced locomotion. To determine the neuronal substrates that could mediate these effects, we analyzed the cellular, subcellular, and subsynaptic localization of α1ARs and characterized the chemical phenotypes of α1AR-containing elements within the mesocorticolimbic system using single and double immunocytochemical methods at the electron microscopic (EM) level. We found that α1ARs are found mainly extra-synaptically in axons and axon terminals in the NAc and are enriched in glutamatergic and dopaminergic elements. α1ARs are also abundant in glutamatergic terminals in the PFC, and in GABA-positive terminals in the VTA. In line with these observations, microdialysis experiments revealed that local blockade of α1ARs attenuated the increase in extracellular DA in the medial NAc shell following administration of cocaine. These data indicate that local α1ARs control DA transmission in the medial NAc shell and behavioral responses to drugs of abuse.

  16. Social Stress and Escalated Drug Self-administration in Mice II. Cocaine and Dopamine in Nucleus Accumbens

    PubMed Central

    Han, Xiao; Albrechet-Souza, Lucas; Doyle, Michelle R.; Shimamoto, Akiko; DeBold, Joseph F.; Miczek, Klaus A.

    2014-01-01

    Rationale Social defeat stress results in escalation of cocaine taking and long-term neural adaptations in rats. How the intensity and timing of social defeat stress determine these effects, particularly in mice, have not been well characterized. Objective This study investigated the effects of mild vs. moderate intensities and durations of social stress on intravenous cocaine self-administration as well as on dopamine (DA) release in nucleus accumbens shell (NAcSh) by using in vivo microdialysis. Methods Adult male CFW mice experienced 10 days of social defeat stress, either mild (15 attack bites in ca. 1.8 min) or moderate (30 attack bites in ca. 3.6 min), and compared to controls that were handled daily. Subsequently, the socially stressed mice were assessed for either (1) intravenous cocaine self-administration, using several unit doses (0, 0.3, 0.6, 1.0 mg/kg/infusion) under limited access conditions, or (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAcSh in response to acute d-amphetamine challenge. Results Social defeat stress resulted in escalated cocaine self-administration in both mild and moderate socially stressed groups. In addition, social defeat stress led to increased DA release after d-amphetamine challenge. Conclusions These data suggest that both mild and moderate socially stressed mice exhibit increased cocaine taking compared to controls, and this increase is associated with escalated dopaminergic responses in the NAcSh. PMID:25216798

  17. Choline Transporter Hemizygosity Results in Diminished Basal Extracellular Dopamine Levels in Nucleus Accumbens and Blunts Dopamine Elevations Following Cocaine or Nicotine

    PubMed Central

    Dong, Yu; Dani, John A.; Blakely, Randy D.

    2015-01-01

    Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/−), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically-imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD). PMID:23939187

  18. Ozone depletion by hydrofluorocarbons

    NASA Astrophysics Data System (ADS)

    Hurwitz, Margaret M.; Fleming, Eric L.; Newman, Paul A.; Li, Feng; Mlawer, Eli; Cady-Pereira, Karen; Bailey, Roshelle

    2015-10-01

    Atmospheric concentrations of hydrofluorocarbons (HFCs) are projected to increase considerably in the coming decades. Chemistry climate model simulations forced by current projections show that HFCs will impact the global atmosphere increasingly through 2050. As strong radiative forcers, HFCs increase tropospheric and stratospheric temperatures, thereby enhancing ozone-destroying catalytic cycles and modifying the atmospheric circulation. These changes lead to a weak depletion of stratospheric ozone. Simulations with the NASA Goddard Space Flight Center 2-D model show that HFC-125 is the most important contributor to HFC-related atmospheric change in 2050; its effects are comparable to the combined impacts of HFC-23, HFC-32, HFC-134a, and HFC-143a. Incorporating the interactions between chemistry, radiation, and dynamics, ozone depletion potentials (ODPs) for HFCs range from 0.39 × 10-3 to 30.0 × 10-3, approximately 100 times larger than previous ODP estimates which were based solely on chemical effects.

  19. Habenula lesions alter synaptic plasticity within the fimbria-accumbens pathway in the rat.

    PubMed

    Lecourtier, L; Deschaux, O; Arnaud, C; Chessel, A; Kelly, P H; Garcia, R

    2006-08-25

    Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

  20. Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and Amygdala Abnormalities in Young Adult Recreational Users

    PubMed Central

    Gilman, Jodi M.; Kuster, John K.; Lee, Sang; Lee, Myung Joo; Kim, Byoung Woo; Makris, Nikos; van der Kouwe, Andre; Blood, Anne J.

    2014-01-01

    Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization. PMID:24741043

  1. Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats.

    PubMed

    Liang, Jing; Marty, Vincent N; Mulpuri, Yatendra; Olsen, Richard W; Spigelman, Igor

    2014-07-01

    The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

  2. Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure.

    PubMed

    Watson, Corey T; Szutorisz, Henrietta; Garg, Paras; Martin, Qammarah; Landry, Joseph A; Sharp, Andrew J; Hurd, Yasmin L

    2015-12-01

    Drug exposure during critical periods of development is known to have lasting effects, increasing one's risk for developing mental health disorders. Emerging evidence has also indicated the possibility for drug exposure to even impact subsequent generations. Our previous work demonstrated that adolescent exposure to Δ(9)-tetrahydrocannabinol (THC), the main psychoactive component of marijuana (Cannabis sativa), in a Long-Evans rat model affects reward-related behavior and gene regulation in the subsequent (F1) generation unexposed to the drug. Questions, however, remained regarding potential epigenetic consequences. In the current study, using the same rat model, we employed Enhanced Reduced Representation Bisulfite Sequencing to interrogate the epigenome of the nucleus accumbens, a key brain area involved in reward processing. This analysis compared 16 animals with parental THC exposure and 16 without to characterize relevant systems-level changes in DNA methylation. We identified 1027 differentially methylated regions (DMRs) associated with parental THC exposure in F1 adults, each represented by multiple CpGs. These DMRs fell predominantly within introns, exons, and intergenic intervals, while showing a significant depletion in gene promoters. From these, we identified a network of DMR-associated genes involved in glutamatergic synaptic regulation, which also exhibited altered mRNA expression in the nucleus accumbens. These data provide novel insight into drug-related cross-generational epigenetic effects, and serve as a useful resource for investigators to explore novel neurobiological systems underlying drug abuse vulnerability.

  3. Tank depletion flow controller

    DOEpatents

    Georgeson, Melvin A.

    1976-10-26

    A flow control system includes two bubbler tubes installed at different levels within a tank containing such as radioactive liquid. As the tank is depleted, a differential pressure transmitter monitors pressure differences imparted by the two bubbler tubes at a remote, shielded location during uniform time intervals. At the end of each uniform interval, balance pots containing a dense liquid are valved together to equalize the pressures. The resulting sawtooth-shaped signal generated by the differential pressure transmitter is compared with a second sawtooth signal representing the desired flow rate during each time interval. Variations in the two signals are employed by a control instrument to regulate flow rate.

  4. Microinjections of acetaldehyde or salsolinol into the posterior ventral tegmental area increase dopamine release in the nucleus accumbens shell

    PubMed Central

    Deehan, Gerald A.; Engleman, Eric A.; Ding, Zheng-Ming; McBride, William J.; Rodd, Zachary A.

    2014-01-01

    Background Published findings indicate that acetaldehyde (ACD; the first metabolite of EtOH) and salsolinol (SAL; formed through the non-enzymatic condensation of ACD and dopamine) can be formed following ethanol (EtOH) consumption. Both ACD and SAL exhibit reinforcing properties within the posterior ventral tegmental area (pVTA) and both exhibit an inverted “U-shaped” dose-response curve. The current study was undertaken to examine the dose-response effects of microinjections of ACD or SAL into the pVTA on DA efflux in the nucleus accumbens shell (AcbSh). Methods For the first experiment, separate groups of male Wistar rats received pulse microinjections of aCSF or 12, 23 or 90 µM ACD into the pVTA while extracellular DA levels were concurrently measured in the AcbSh. The second experiment was similarly conducted, except rats were given microinjections of aCSF or 0.03, 0.3, 1.0 or 3.0 µM SAL, while extracellular levels of DA were measured in the AcbSh. Results Both ACD and SAL produced a dose-dependent inverted “U-shaped” response on DA release in the AcbSh, with 23 µM ACD (200% baseline) and 0.3 µM SAL (300% baseline) producing maximal peak responses with higher concentrations of ACD (90 µM) and SAL (3.0 µM) producing significantly lower DA efflux. Conclusions The findings from the current study indicate that local application of intermediate concentrations of ACD and SAL stimulated DA neurons in the pVTA, whereas higher concentrations may be having secondary effects within the pVTA that inhibit DA neuronal activity. The present results parallel studies on the reinforcing effects of ACD and SAL in the pVTA and support the idea that the reinforcing effects of ACD and SAL within the pVTA are mediated by activating DA neurons. PMID:23278868

  5. A thalamic input to the nucleus accumbens mediates opiate dependence

    PubMed Central

    Zhu, Yingjie; Wienecke, Carl F.R.; Nachtrab, Gregory; Chen, Xiaoke

    2016-01-01

    Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both rewarding effects of drug and the desire to avoid withdrawal symptoms motivate continued drug use1-3, and the nucleus accumbens (NAc) is important for orchestrating both processes4,5. While multiple inputs to the NAc regulate reward6-9, little is known about the NAc circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus (PVT) as a prominent input to the NAc mediating the expression of opiate withdrawal induced physical signs and aversive memory. Activity in the PVT to NAc pathway is necessary and sufficient to mediate behavioral aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the PVT and D2-receptor-expressing medium spiny neurons (D2-MSNs) via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at PVT→D2-MSNs synapses and robustly suppresses morphine withdrawal symptoms. These results link morphine-evoked pathway- and cell type-specific plasticity in the PVT→NAc circuit to opiate dependence, and suggest that reprogramming this circuit holds promise for treating opiate addiction. PMID:26840481

  6. Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

    PubMed

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

    2016-08-01

    Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties. PMID:27139934

  7. Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

    PubMed

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

    2016-08-01

    Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties.

  8. Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards

    PubMed Central

    Cameron, Courtney M.; Wightman, R. Mark; Carelli, Regina M.

    2014-01-01

    Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n=8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. PMID:25174553

  9. Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards.

    PubMed

    Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M

    2014-11-01

    Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n = 8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. PMID:25174553

  10. Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards.

    PubMed

    Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M

    2014-11-01

    Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n = 8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors.

  11. Ozone Depletion by Hydrofluorocarbons

    NASA Astrophysics Data System (ADS)

    Hurwitz, M.; Fleming, E. L.; Newman, P. A.; Li, F.; Mlawer, E. J.; Cady-Pereira, K. E.; Bailey, R.

    2015-12-01

    Hydrofluorocarbons (HFCs) are second-generation replacements for the chlorofluorocarbons (CFCs), halons and other substances that caused the 'ozone hole'. Atmospheric concentrations of HFCs are projected to increase dramatically in the coming decades. Coupled chemistry-climate simulations forced by these projections show that HFCs will impact the global atmosphere in 2050. As strong radiative forcers, HFCs modulate atmospheric temperature, thereby changing ozone-destroying catalytic cycles and enhancing the stratospheric circulation. These changes lead to a weak depletion of stratospheric ozone. Sensitivity simulations with the NASA Goddard Space Flight Center (GSFC) 2D model show that HFC-125 is the most important contributor to atmospheric change in 2050, as compared with HFC-23, HFC-32, HFC-134a and HFC-143a. Incorporating the interactions between chemistry, radiation and dynamics, for a likely 2050 climate, ozone depletion potentials (ODPs) for HFCs range from 4.3x10-4 to 3.5x10-2; previously HFCs were assumed to have negligible ODPs since these species lack chlorine or bromine atoms. The ozone impacts of HFCs are further investigated with the Goddard Earth Observing System Chemistry-Climate Model (GEOSCCM). The GEOSCCM is a three-dimensional, fully coupled ocean-atmosphere model with interactive stratospheric chemistry. Sensitivity simulations in which CO2, CFC-11 and HCFC-22 are enhanced individually are used as proxies for the atmospheric response to the HFC concentrations expected by the mid-21st century. Sensitivity simulations provide quantitative estimates of the impacts of these greenhouse gases on global total ozone, and can be used to assess their effects on the recovery of Antarctic ozone.

  12. Relationship of Dopamine of the Nucleus Accumbens with Intra-infralimbic Apomorphine Microinjection

    PubMed Central

    Alimoradian, Abbas; Sajedianfard, Javad; Baha-aldini Beigy, Faegheh; Panjehshahin, Mohammad Reza; Owji, Ali Akbar

    2013-01-01

    Objective(s): The dopamine level of the nucleus accumbens changes during some stereotyped behaviors. To study dopamine level of the nucleus accumbens in intra infralimbic apomorphine-induced climbing, microdialysis probes were implanted into the nucleus accumbens shell of male Sprague Dawley rats weighting 275–400 g. Materials and Methods: The rats were divided into two groups (apomorphine and control) of least eleven rats in each group. Apomorphine at dose of 5 μg/0.5 μl or its vehicle was microinjected into the infralimbic in apomorphine and control groups respectively. Then, changes in dopamine levels in the nucleus accumbens shell were monitored. The concentration of dopamine was measured by High-Performance Liquid Chromatography-Electochemical (HPLC-ECD). Finally, the stereotyped behaviors were recorded. Results: The mean of dopamine levels for all of after microinjection period in control and drug groups were 450% and 150% respectively compared to those of before microinjection period. However, there was no significant difference between groups of apomorphine and control. In addition, the return of dopamine level to the baseline was faster in apomorphine group than the control group. Conclusion: The intra infralimbic apomorphine -induced climbing at dose of 5 μg/0.5 μl was not modulated via the increase of dopamine level in the nucleus accumbens area. PMID:23997899

  13. ΔJunD overexpression in the nucleus accumbens prevents sexual reward in female Syrian hamsters.

    PubMed

    Been, L E; Hedges, V L; Vialou, V; Nestler, E J; Meisel, R L

    2013-08-01

    Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ΔFosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli.

  14. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.

    PubMed

    Dölen, Gül; Darvishzadeh, Ayeh; Huang, Kee Wui; Malenka, Robert C

    2013-09-12

    Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism. PMID:24025838

  15. Medial accumbens lesions attenuate testosterone-dependent aggression in male rats.

    PubMed

    Albert, D J; Petrovic, D M; Walsh, M L; Jonik, R H

    1989-10-01

    Male hooded rats were castrated and implanted with testosterone-filled Silastic tubes appropriate for maintaining a normal average serum testosterone concentration. They were then given lesions of the medial accumbens nucleus or sham lesions. Twenty-four hours postoperatively each male was housed with a female. Beginning 7 days following pairing and continuing once each week for 4 weeks, each lesioned or sham-lesioned male was observed for aggression toward an unfamiliar male intruder. On the day following each test of aggression toward an unfamiliar male, each lesioned and sham-lesioned male was assessed for defensiveness toward an experimenter. Rats with medial accumbens lesions displayed significantly less aggression toward an unfamiliar male intruder during each of the weekly tests than did sham-lesioned animals. The attenuation was most pronounced in animals with lesions damaging the posterior part of the medial accumbens nucleus (also designated as anterior portion of the bed nucleus of the stria terminalis) in the region of the crossover of the anterior commissure. Although medial accumbens lesions are known to make individually housed rats hyperdefensive toward an experimenter, lesion-induced hyperdefensiveness was not observed in the pair-housed animals in the present experiment. It is argued that the medial accumbens/bed nucleus of the stria terminalis area is an important region in the anterior forebrain for the modulation of hormone-dependent aggression.

  16. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors.

  17. Dissociated Accumbens and Hippocampal Structural Abnormalities across Obesity and Alcohol Dependence

    PubMed Central

    Mak, Elijah; Chien, Yee; Voon, Valerie

    2016-01-01

    Background: Processing of food and drug rewards involves specific neurocircuitry, and emerging evidence implicates subcortical abnormalities, particularly the nucleus accumbens and hippocampus. We specifically hypothesized that these 2 established regions in addiction neurocircuitry are associated with distinctive in vivo structural abnormalities in obesity and alcohol dependence. Methods: To specifically investigate anatomically discrete volumetric changes associated with overconsumption of different rewards, we acquired T1 MRI data from 118 subjects in 3 groups comprising obesity (n=42), alcohol dependence (n=32), and healthy volunteer controls (n=44). To exploit novel methods of automated hippocampal subfield segmentation, we used Freesurfer software to generate volumetric data in subject groups for the hippocampal subiculum and its major striatal efferent target, the nucleus accumbens. Hypothesis-led, selective group difference comparisons were analyzed. Results: We found markedly greater accumbens volumes (P=.002) and relatively preserved hippocampal subfield volumes in obesity. Conversely, in alcohol dependence, we found preserved accumbens volumes but atrophy of specific ventral hippocampal subfields, the subiculum and presubiculum. Smaller global subcortical gray-matter volume was found in the alcohol dependence group only. Conclusions: Reward neurocircuitry including the accumbens and ventral hippocampus may show key structural abnormalities in disorders involving processing of both food and drug rewards, although the foci of disruption may vary as a function of reward modality. Structural differences may subserve altered reward and motivational processes in obesity and alcohol dependence and represent a potential biomarker for therapeutic targeting in key public health disorders. PMID:27207916

  18. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. PMID:27421228

  19. Depleted zinc: Properties, application, production.

    PubMed

    Borisevich, V D; Pavlov, A V; Okhotina, I A

    2009-01-01

    The addition of ZnO, depleted in the Zn-64 isotope, to the water of boiling water nuclear reactors lessens the accumulation of Co-60 on the reactor interior surfaces, reduces radioactive wastes and increases the reactor service-life because of the inhibitory action of zinc on inter-granular stress corrosion cracking. To the same effect depleted zinc in the form of acetate dihydrate is used in pressurized water reactors. Gas centrifuge isotope separation method is applied for production of depleted zinc on the industrial scale. More than 20 years of depleted zinc application history demonstrates its benefits for reduction of NPP personnel radiation exposure and combating construction materials corrosion.

  20. 12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM CASTING OPERATIONS CEASED IN 1988. (11/14/57) - Rocky Flats Plant, Non-Nuclear Production Facility, South of Cottonwood Avenue, west of Seventh Avenue & east of Building 460, Golden, Jefferson County, CO

  1. Behavioral Flexibility Is Increased by Optogenetic Inhibition of Neurons in the Nucleus Accumbens Shell during Specific Time Segments

    ERIC Educational Resources Information Center

    Aquili, Luca; Liu, Andrew W.; Shindou, Mayumi; Shindou, Tomomi; Wickens, Jeffery R.

    2014-01-01

    Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus-reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity…

  2. Histone arginine methylation in cocaine action in the nucleus accumbens.

    PubMed

    Damez-Werno, Diane M; Sun, HaoSheng; Scobie, Kimberly N; Shao, Ningyi; Rabkin, Jaclyn; Dias, Caroline; Calipari, Erin S; Maze, Ian; Pena, Catherine J; Walker, Deena M; Cahill, Michael E; Chandra, Ramesh; Gancarz, Amy; Mouzon, Ezekiell; Landry, Joseph A; Cates, Hannah; Lobo, Mary-Kay; Dietz, David; Allis, C David; Guccione, Ernesto; Turecki, Gustavo; Defilippi, Paola; Neve, Rachael L; Hurd, Yasmin L; Shen, Li; Nestler, Eric J

    2016-08-23

    Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. PMID:27506785

  3. Rapid feedback processing in human nucleus accumbens and motor thalamus.

    PubMed

    Schüller, Thomas; Gruendler, Theo O J; Jocham, Gerhard; Klein, Tilmann A; Timmermann, Lars; Visser-Vandewalle, Veerle; Kuhn, Jens; Ullsperger, Markus

    2015-04-01

    The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event-related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316. PMID:25726897

  4. Encoding of aversion by dopamine and the nucleus accumbens.

    PubMed

    McCutcheon, James E; Ebner, Stephanie R; Loriaux, Amy L; Roitman, Mitchell F

    2012-01-01

    Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward. PMID:23055953

  5. Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.

    PubMed

    Winters, Bradley D; Krüger, Juliane M; Huang, Xiaojie; Gallaher, Zachary R; Ishikawa, Masago; Czaja, Krzysztof; Krueger, James M; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2012-10-01

    Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. Here, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Using these mice, we demonstrated that tdT-positive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were electrically coupled with each other, and thus may help synchronize populations/ensembles of NAc neurons. CB1-expressing FSIs also form GABAergic synapses on adjacent medium spiny neurons (MSNs), providing feed-forward inhibition of NAc output. Furthermore, the membrane excitability of tdT-positive FSIs in the NAc was up-regulated after withdrawal from cocaine exposure, an effect that might increase FSI-to-MSN inhibition. Taken together with our previous findings that the membrane excitability of NAc MSNs is decreased during cocaine withdrawal, the present findings suggest that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms. As such, CB1-expressing FSIs are targeted by cocaine exposure to influence the overall functional output of the NAc. PMID:23012412

  6. A case of musical preference for Johnny Cash following deep brain stimulation of the nucleus accumbens

    PubMed Central

    Mantione, Mariska; Figee, Martijn; Denys, Damiaan

    2014-01-01

    Music is among all cultures an important part of the live of most people. Music has psychological benefits and may generate strong emotional and physiological responses. Recently, neuroscientists have discovered that music influences the reward circuit of the nucleus accumbens (NAcc), even when no explicit reward is present. In this clinical case study, we describe a 60-year old patient who developed a sudden and distinct musical preference for Johnny Cash following deep brain stimulation (DBS) targeted at the NAcc. This case report substantiates the assumption that the NAcc is involved in musical preference, based on the observation of direct stimulation of the accumbens with DBS. It also shows that accumbens DBS can change musical preference without habituation of its rewarding properties. PMID:24834035

  7. Neurons in the Nucleus Accumbens Promote Selection Bias for Nearer Objects

    PubMed Central

    Morrison, Sara E.

    2014-01-01

    Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level. PMID:25319709

  8. Depleted Uranium in Repositories

    SciTech Connect

    Haire, M.J.; Croff, A.G.

    1997-12-31

    For uranium to be useful in most fission nuclear reactors, it must be enriched (i.e. the concentration of the fissile isotope 235U must be increased). Therefore, depleted uranium (DU)-uranium which has less than naturally occurring concentrations of 235U-is a co-product of the enrichment process. Four to six tons of DU exist for every ton of fresh light water reactor fuel. There were 407,006 MgU 407,000 metric tons (t) of DU stored on U.S. Department of Energy (DOE) sites as of July 1993. If this DU were to be declared surplus, converted to a stable oxide form, and emplaced in a near surface disposal facility, the costs are estimated to be several billion dollars. However, the U.S. Nuclear Regulatory Commission has stated that near surface disposal of large quantities of DU tails is not appropriate. Thus, there is the possibility that disposition via disposal will be in a deep geological repository. One alternative that may significantly reduce the cost of DU disposition is to use it beneficially. In fact, DOE has begun the Beneficial Uses of DU Project to identify large scale uses of DU and to encourage its reuse. Several beneficial uses, many of which involve applications in the repository per se or in managing the wastes to go into the repository, are discussed in this report.

  9. Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus)

    PubMed Central

    Gray, C.L.; Norvelle, A.; Larkin, T.; Huhman, K.L..

    2015-01-01

    Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Exp. 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 μg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24 hr later in response to a non-aggressive intruder. In Exp. 2, infusion of 3.75 μg cis(z)flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Exp. 3, we found that the effect of cis(z)flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat. PMID:25721736

  10. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

    PubMed

    Salti, Ahmad; Kummer, Kai K; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2015-12-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens.

  11. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats

    PubMed Central

    Salti, Ahmad; Kummer, Kai K.; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2016-01-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens. PMID:26300300

  12. Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

    PubMed

    Salti, Ahmad; Kummer, Kai K; Sadangi, Chinmaya; Dechant, Georg; Saria, Alois; El Rawas, Rana

    2015-12-01

    We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens. PMID:26300300

  13. Differential involvement of the shell and core subterritories of the nucleus accumbens in latent inhibition and amphetamine-induced activity.

    PubMed

    Weiner, I; Gal, G; Rawlins, J N; Feldon, J

    1996-11-01

    Latent inhibition (LI) consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In view of findings that LI is disrupted in acute schizophrenic patients and evidence from animal experiments pointing to the involvement of the mesolimbic dopamine (DA) system in this phenomenon, the present study investigated the effects of electrolytic lesions to the shell and core subterritories of the nucleus accumbens on LI in rats (Expt. 1). LI was indexed by the amount of suppression of drinking in the presence of a tone that was either pre-exposed or not prior to its pairing with reinforcement (a foot shock). Expt.2 tested the effects of the DA antagonist, haloperidol, on LI in shell- and core-lesioned animals. Expt. 3 tested the effects of shell and core lesions on spontaneous and amphetamine-induced locomotion. In Expt. 1, LI, i.e., lower suppression of drinking in the pre-exposed as compared to the non-pre-exposed animals, was obtained in the sham-operated condition. Core and shell lesions produced distinct effects on LI. Animals with core lesions developed LI, but exhibited an overall lower suppression of drinking in comparison to the sham-operated animals. In contrast, shell lesions led to a disappearance of LI. Expt. 2 replicated the differential effects of shell and core lesions on LI, although in this experiment, core lesion did not attenuate suppression of drinking. Haloperidol prevented shell-induced abolition of LI. In Expt. 3, shell- but not core-lesioned animals were more active than sham controls following amphetamine administration. These results provide evidence for functional differences between the shell and core subregions, as well as for the involvement of the mesolimbic DA system in LI. PMID:8950008

  14. Ego depletion impairs implicit learning.

    PubMed

    Thompson, Kelsey R; Sanchez, Daniel J; Wesley, Abigail H; Reber, Paul J

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent.

  15. Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences.

    PubMed

    Kerfoot, Erin C; Chattillion, Elizabeth A; Williams, Cedric L

    2008-01-01

    The shell division of the nucleus accumbens receives noradrenergic input from neurons in the nucleus of the solitary tract (NTS) that transmit information regarding fluctuations in peripheral hormonal and autonomic activity. Accumbens shell neurons also receive converging inputs from limbic areas such as the hippocampus and amygdala that process newly acquired information. However, few studies have explored whether peripheral information regarding changes in emotional arousal contributes to memory processing in the accumbens. The beneficial effects on memory produced by emotional arousal and the corresponding activation of NTS neurons may be mediated through influences on neuronal activity in the accumbens shell during memory encoding. To explore this putative relationship, Experiment 1 examined interactions between the NTS and the accumbens shell in modulating memory for responses acquired after footshock training in a water-motivated inhibitory avoidance task. Memory for the noxious shock was significantly improved by posttraining excitation of noradrenergic NTS neurons. The enhanced retention produced by activating NTS neurons was attenuated by suppressing neuronal activity in the accumbens shell with bupivacaine (0.25%/0.5 microl). Experiment 2 examined the direct involvement of accumbens shell noradrenergic activation in the modulation of memory for psychologically arousing events such as a reduction in perceived reward value. Noradrenergic activation of the accumbens shell with phenylephrine (1.0 microg/0.5 microl) produced an enhancement in memory for the frustrating experience relative to control injections as evidenced by runway performance on an extended seven-day retention test. These findings demonstrate a functional relationship between NTS neurons and the accumbens shell in modulating memory following physiological arousal and identifies a role of norepinephrine in modulating synaptic activity in the accumbens shell to facilitate this process.

  16. Stratospheric ozone depletion.

    PubMed

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules.

  17. Stratospheric ozone depletion

    PubMed Central

    Rowland, F. Sherwood

    2006-01-01

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290–320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime—the ‘Antarctic ozone hole’. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  18. Stratospheric ozone depletion.

    PubMed

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  19. Testing fully depleted CCD

    NASA Astrophysics Data System (ADS)

    Casas, Ricard; Cardiel-Sas, Laia; Castander, Francisco J.; Jiménez, Jorge; de Vicente, Juan

    2014-08-01

    The focal plane of the PAU camera is composed of eighteen 2K x 4K CCDs. These devices, plus four spares, were provided by the Japanese company Hamamatsu Photonics K.K. with type no. S10892-04(X). These detectors are 200 μm thick fully depleted and back illuminated with an n-type silicon base. They have been built with a specific coating to be sensitive in the range from 300 to 1,100 nm. Their square pixel size is 15 μm. The read-out system consists of a Monsoon controller (NOAO) and the panVIEW software package. The deafualt CCD read-out speed is 133 kpixel/s. This is the value used in the calibration process. Before installing these devices in the camera focal plane, they were characterized using the facilities of the ICE (CSIC- IEEC) and IFAE in the UAB Campus in Bellaterra (Barcelona, Catalonia, Spain). The basic tests performed for all CCDs were to obtain the photon transfer curve (PTC), the charge transfer efficiency (CTE) using X-rays and the EPER method, linearity, read-out noise, dark current, persistence, cosmetics and quantum efficiency. The X-rays images were also used for the analysis of the charge diffusion for different substrate voltages (VSUB). Regarding the cosmetics, and in addition to white and dark pixels, some patterns were also found. The first one, which appears in all devices, is the presence of half circles in the external edges. The origin of this pattern can be related to the assembly process. A second one appears in the dark images, and shows bright arcs connecting corners along the vertical axis of the CCD. This feature appears in all CCDs exactly in the same position so our guess is that the pattern is due to electrical fields. Finally, and just in two devices, there is a spot with wavelength dependence whose origin could be the result of a defectous coating process.

  20. The Role of the Nucleus Accumbens in Knowing when to Respond

    ERIC Educational Resources Information Center

    Singh, Teghpal; McDannald, Michael A.; Takahashi, Yuji K.; Haney, Richard Z.; Cooch, Nisha K.; Lucantonio, Federica; Schoenbaum, Geoffrey

    2011-01-01

    While knowing what to expect is important, it is equally important to know when to expect it and to respond accordingly. This is apparent even in simple Pavlovian training situations in which animals learn to respond more strongly closer to reward delivery. Here we report that the nucleus accumbens core, an area well-positioned to represent…

  1. Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release.

    PubMed

    Lecourtier, Lucas; Defrancesco, Alicia; Moghaddam, Bita

    2008-04-01

    Conditions of increased cognitive or emotional demand activate dopamine release in a regionally selective manner. Whereas the brief millisecond response of dopamine neurons to salient stimuli suggests that dopamine's influence on behaviour may be limited to signalling certain cues, the prolonged availability of dopamine in regions such as the prefrontal cortex and nucleus accumbens is consistent with the well described role of dopamine in maintaining motivation states, associative learning and working memory. The behaviourally elicited terminal release of dopamine is generally attributed to increased excitatory drive on dopamine neurons. Our findings here, however, indicate that this increase may involve active removal of a tonic inhibitory control on dopamine neurons exerted by the lateral habenula (LHb). Inhibition of LHb in behaving animals transiently increased dopamine release in the prefrontal cortex, nucleus accumbens and dorsolateral striatum. The inhibitory influence was more pronounced in the nucleus accumbens and striatum than in the prefrontal cortex. This pattern of regional dopamine activation after LHb inhibition mimicked conditions of reward availability but not increased cognitive demand. Electrical or chemical stimulation of LHb produced minimal reduction of extracellular dopamine, suggesting that in an awake brain the inhibition associated with tonic LHb activity represents a near-maximal influence on dopamine neurotransmission. These data indicate that LHb may be critical for functional differences in dopamine neurons by preferentially modulating dopamine neurons that project to the nucleus accumbens over those neurons that primarily project to the prefrontal cortex.

  2. Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it.

    PubMed

    Rada, P V; Hoebel, B G

    2001-01-01

    Hypothalamic electrodes can generate positive reinforcement, as shown by self-stimulation, and negative reinforcement shown by stimulation-escape. It was hypothesized that acetylcholine (ACh) is released in the nucleus accumbens during the aversive state that underlies stimulation-escape. If this is correct, escape behavior should lower extracellular ACh. Rats were prepared with microdialysis probes in the accumbens (posterior shell region) and electrodes in the perifornical lateral hypothalamus. Animals learned to press a lever for 0.5 s trains of stimulation (typically 3600 responses/h). Then they were given automatic stimulation to determine which animals would also learn to press a lever to turn stimulation off for 5 s at a time (typically 75 responses/h). Accumbens microdialysis showed that automatic stimulation caused extracellular ACh to double, but only in the rats that were motivated to learn stimulation-escape. When allowed to escape stimulation, these animals lowered extracellular ACh significantly. It is concluded that ACh release in the accumbens is related to the neural state that animals work to escape.

  3. Excitant amino acid projections from rat amygdala and thalamus to nucleus accumbens

    SciTech Connect

    Robinson, T.G.; Beart, P.M.

    1988-04-01

    High affinity uptake of D-(/sup 3/H)aspartate, (/sup 3/H)choline and (/sup 3/H)GABA was examined in synaptosomal-containing preparations of rat nucleus accumbens septi 7 to 10 days after unilateral or bilateral N-methyl-D-aspartate lesions confined to the parataenial nucleus of the thalamus or the basolateral nucleus of the amygdala. Uptake of both D-(/sup 3/H)aspartate and (/sup 3/H)choline was significantly reduced (11% and 14% less than control, respectively) by unilateral lesion of the thalamus, whereas (/sup 3/H)GABA uptake was unaffected. Bilateral thalamic lesions significantly reduced D-(/sup 3/H)aspartate uptake (11% less than control) into homogenates of the nucleus accumbens, whilst (/sup 3/H)GABA uptake was unaltered. D-(/sup 3/H)aspartate uptake was significantly reduced (26% less than control) following unilateral lesion of the amygdala, whereas both (/sup 3/H)GABA and (/sup 3/H)choline uptake were unaffected. Bilateral amygdaloid lesions significantly increased D-(/sup 3/H)aspartate uptake (39% greater than control), whilst uptake of (/sup 3/H)GABA was not affected. The results implicate glutamate and/or aspartate as putative neurotransmitters in afferent projections from the basolateral amygdala and the parataenial thalamus to the nucleus accumbens. Thalamic afferents to the nucleus accumbens may also utilize acetylcholine as their transmitter.

  4. Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens.

    PubMed

    McGinty, Vincent B; Lardeux, Sylvie; Taha, Sharif A; Kim, James J; Nicola, Saleem M

    2013-06-01

    A key function of the nucleus accumbens is to promote vigorous reward seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here, we study cued flexible approach behavior, a form of reward seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and the speed of subsequent flexible approach responses, but not those of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subject's proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion. PMID:23764290

  5. Hedonic and Nucleus Accumbens Neural Responses to a Natural Reward Are Regulated by Aversive Conditioning

    ERIC Educational Resources Information Center

    Roitman, Mitchell F.; Wheeler, Robert A.; Tiesinga, Paul H. E.; Roitman, Jamie D.; Carelli, Regina M.

    2010-01-01

    The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli. Learning can alter the hedonic valence of a given stimulus, and it remains unclear how the NAc encodes this shift. The present study examined whether the population response of NAc neurons to a taste stimulus is plastic using a conditioned taste aversion (CTA)…

  6. Individual Differences in Dopamine Efflux in Nucleus Accumbens Shell and Core during Instrumental Learning

    ERIC Educational Resources Information Center

    Cheng, Jingjun; Feenstra, Matthijs G. P.

    2006-01-01

    Combined activation of dopamine D1- and NMDA-glutamate receptors in the nucleus accumbens has been strongly implicated in instrumental learning, the process in which an individual learns that a specific action has a wanted outcome. To assess dopaminergic activity, we presented rats with two sessions (30 trials each) of a one-lever appetitive…

  7. Good Vibrations: Cross-Frequency Coupling in the Human Nucleus Accumbens during Reward Processing

    ERIC Educational Resources Information Center

    Cohen, Michael X.; Axmacher, Nikolai; Lenartz, Doris; Elger, Christian E.; Sturm, Volker; Schlaepfer, Thomas E.

    2009-01-01

    The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to "gate" the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of…

  8. Invigoration of reward-seeking by cue and proximity encoding in the nucleus accumbens

    PubMed Central

    McGinty, Vincent B.; Lardeux, Sylvie; Taha, Sharif A.; Kim, James J.; Nicola, Saleem M.

    2014-01-01

    Summary A key function of the nucleus accumbens is to promote vigorous reward-seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here we study cued flexible approach behavior, a form of reward-seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and speed of subsequent flexible approach responses, but not of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subject’s proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion. PMID:23764290

  9. Accumbens Shell AMPA Receptors Mediate Expression of Extinguished Reward Seeking through Interactions with Basolateral Amygdala

    ERIC Educational Resources Information Center

    Millan, E. Zayra; McNally, Gavan P.

    2011-01-01

    Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B).…

  10. Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens

    PubMed Central

    Hadar, R; Vengeliene, V; Barroeta Hlusicke, E; Canals, S; Noori, H R; Wieske, F; Rummel, J; Harnack, D; Heinz, A; Spanagel, R; Winter, C

    2016-01-01

    Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse. PMID:27327255

  11. Origin of Enthalpic Depletion Forces.

    PubMed

    Sapir, Liel; Harries, Daniel

    2014-04-01

    Solutes excluded from macromolecules or colloids are known to drive depletion attractions. The established Asakura-Oosawa model, as well as subsequent theories aimed at explaining the effects of macromolecular crowding, attribute depletion forces to diminished hard-core excluded volume upon compaction, and hence predict depletion forces dominated by entropy. However, recent experiments measuring the effect of preferentially excluded solutes on protein folding and macromolecular association find these forces can also be enthalpic. We use simulations of macromolecular association in explicit binary cosolute-solvent mixtures, with solvent and cosolute intermolecular interactions that go beyond hard-cores, to show that not all cosolutes conform to the established entropically dominated model. We further demonstrate how the enthalpically dominated depletion forces that we find can be well described within an Asakura-Oosawa like model provided that the hard-core macromolecule-cosolute potential of mean force is augmented by a "soft" step-like repulsion.

  12. Ego depletion impairs implicit learning.

    PubMed

    Thompson, Kelsey R; Sanchez, Daniel J; Wesley, Abigail H; Reber, Paul J

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent. PMID:25275517

  13. Spatially selective reward site responses in tonically active neurons of the nucleus accumbens in behaving rats.

    PubMed

    Mulder, A B; Shibata, R; Trullier, O; Wiener, S I

    2005-05-01

    To study how hippocampal output signals conveying spatial and other contextual information might be integrated in the nucleus accumbens, tonically active accumbens neurons were recorded in three unrestrained rats as they performed spatial orientation tasks on an elevated round rotatable platform with four identical reward boxes symmetrically placed around the edge. The partially water-deprived rats were required to shuttle either between the pair of reward boxes indicated by beacon cues (lights in the boxes) or between the pair of boxes occupying particular locations in relation to environmental landmark cues. In 43/82 neurons, behaviorally correlated phasic modulations in discharge activity occurred, primarily prior to or after water was provided at the reward boxes. Twenty-two had inhibitory modulation, 12 excitatory, and nine were mixed excitatory and inhibitory. Although tonically active neurons (TANs) have rarely been reported in the rodent, the inhibitory and mixed responses correspond to previously reports in the macaque accumbens of tonically active neurons with activity correlated with reward delivery and, following conditioning, to sensory stimuli associated with rewards. Eighteen of the 43 tonically active accumbens neurons showed spatial selectivity, i.e., behaviorally correlated increases or decreases in firing rate were of different magnitudes at the respective reward boxes. This is the first demonstration that the configuration of environmental sensory cues associated with reward sites are also an effective stimulus for these neurons and that different neurons are selective for different places. These results are consistent with a role for the nucleus accumbens in the initiation of goal-directed displacement behaviors.

  14. Role of nucleus accumbens glutamatergic plasticity in drug addiction

    PubMed Central

    Quintero, Gabriel C

    2013-01-01

    Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance’s effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca2+-permeable AMPA receptors (CP-AMPARs) at the level of the NAc

  15. Role of nucleus accumbens glutamatergic plasticity in drug addiction

    PubMed Central

    Quintero, Gabriel C

    2013-01-01

    Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance’s effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca2+-permeable AMPA receptors (CP-AMPARs) at the level of the NAc

  16. Depletion-mediated red blood cell aggregation in polymer solutions.

    PubMed

    Neu, Björn; Meiselman, Herbert J

    2002-11-01

    Polymer-induced red blood cell (RBC) aggregation is of current basic science and clinical interest, and a depletion-mediated model for this phenomenon has been suggested; to date, however, analytical approaches to this model are lacking. An approach is thus described for calculating the interaction energy between RBC in polymer solutions. The model combines electrostatic repulsion due to RBC surface charge with osmotic attractive forces due to polymer depletion near the RBC surface. The effects of polymer concentration and polymer physicochemical properties on depletion layer thickness and on polymer penetration into the RBC glycocalyx are considered for 40 to 500 kDa dextran and for 18 to 35 kDa poly (ethylene glycol). The calculated results are in excellent agreement with literature data for cell-cell affinities and with RBC aggregation-polymer concentration relations. These findings thus lend strong support to depletion interactions as the basis for polymer-induced RBC aggregation and suggest the usefulness of this approach for exploring interactions between macromolecules and the RBC glycocalyx. PMID:12414682

  17. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    PubMed

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs.

  18. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

    PubMed

    Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J; Bowles, Dawn E; Meyer, Rebecca C; Hall, Randy A; Ko, Daijin; Paladini, Carlos A; Weinshenker, David

    2016-01-01

    Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs. PMID:25123018

  19. Depleting depletion: Polymer swelling in poor solvent mixtures

    NASA Astrophysics Data System (ADS)

    Mukherji, Debashish; Marques, Carlos; Stuehn, Torsten; Kremer, Kurt

    A polymer collapses in a solvent when the solvent particles dislike monomers more than the repulsion between monomers. This leads to an effective attraction between monomers, also referred to as depletion induced attraction. This attraction is the key factor behind standard polymer collapse in poor solvents. Strikingly, even if a polymer exhibits poor solvent condition in two different solvents, it can also swell in mixtures of these two poor solvents. This collapse-swelling-collapse scenario is displayed by poly(methyl methacrylate) (PMMA) in aqueous alcohol. Using molecular dynamics simulations of a thermodynamically consistent generic model and theoretical arguments, we unveil the microscopic origin of this phenomenon. Our analysis suggests that a subtle interplay of the bulk solution properties and the local depletion forces reduces depletion effects, thus dictating polymer swelling in poor solvent mixtures.

  20. Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats: monoaminergic correlates.

    PubMed

    Espejo, E F; Serrano, M I; Caillé, S; Stinus, L

    2001-08-01

    The objective of this study was to establish the effects of prefrontocortical dopamine depletion on opiate withdrawal and prefrontocortical neurochemical changes elicited by morphine dependence and withdrawal. The dopaminergic content was also measured in the nucleus accumbens during withdrawal, in order to detect reactive changes induced by prefrontocortical lesion. Withdrawal was induced by naloxone in morphine-dependent rats. Monoamine levels were analyzed post-mortem by high performance liquid cromatography. The results showed that chronic morphine dependence did not modify basal levels of monoamines in sham rats, revealing neuroadaptation of prefrontocortical dopamine, noradrenaline and serotonin systems to chronic morphine. The neuroadaptive phenomenon remained after prefrontocortical lesion (> 79% dopamine depletion). On the other hand, a strong increase of dopamine, noradrenaline, and serotonin contents in the medial prefrontal cortex of sham rats was detected during opiate withdrawal. However, in lesioned rats, the increase of prefrontocortical dopamine and serotonin content, but not that of noradrenaline, was much lower. In the nucleus accumbens, prefrontocortical lesion reactively enhanced the dopaminergic tone and, although opiate withdrawal reduced dopaminergic activity in both sham and lesioned rats, this reduction was less intense in the latter group. At a behavioral level, some symptoms of physical opiate withdrawal were exacerbated in lesioned rats (writhing, mastication, teeth-chattering, global score) and exploration was reduced. The findings hence indicate that: (i) prefrontocortical monoaminergic changes play a role in the behavioral expression of opiate withdrawal; (ii) the severity of some withdrawal signs are related to the dopaminergic and serotonergic tone of the medial prefrontal cortex rather than to the noradrenergic one, and (iii) an inverse relationship between mesocortical and mesolimbic dopaminergic systems exists.

  1. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.

    PubMed

    Kupchik, Yonatan M; Brown, Robyn M; Heinsbroek, Jasper A; Lobo, Mary Kay; Schwartz, Danielle J; Kalivas, Peter W

    2015-09-01

    It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

  2. Fully depleted back illuminated CCD

    DOEpatents

    Holland, Stephen Edward

    2001-01-01

    A backside illuminated charge coupled device (CCD) is formed of a relatively thick high resistivity photon sensitive silicon substrate, with frontside electronic circuitry, and an optically transparent backside ohmic contact for applying a backside voltage which is at least sufficient to substantially fully deplete the substrate. A greater bias voltage which overdepletes the substrate may also be applied. One way of applying the bias voltage to the substrate is by physically connecting the voltage source to the ohmic contact. An alternate way of applying the bias voltage to the substrate is to physically connect the voltage source to the frontside of the substrate, at a point outside the depletion region. Thus both frontside and backside contacts can be used for backside biasing to fully deplete the substrate. Also, high resistivity gaps around the CCD channels and electrically floating channel stop regions can be provided in the CCD array around the CCD channels. The CCD array forms an imaging sensor useful in astronomy.

  3. Directed Communication between Nucleus Accumbens and Neocortex in Humans Is Differentially Supported by Synchronization in the Theta and Alpha Band

    PubMed Central

    Horschig, Jörn M.; Smolders, Ruud; Bonnefond, Mathilde; Schoffelen, Jan-Mathijs; van den Munckhof, Pepijn; Schuurman, P. Richard; Cools, Roshan; Denys, Damiaan; Jensen, Ole

    2015-01-01

    Here, we report evidence for oscillatory bi-directional interactions between the nucleus accumbens and the neocortex in humans. Six patients performed a demanding covert visual attention task while we simultaneously recorded brain activity from deep-brain electrodes implanted in the nucleus accumbens and the surface electroencephalogram (EEG). Both theta and alpha oscillations were strongly coherent with the frontal and parietal EEG during the task. Theta-band coherence increased during processing of the visual stimuli. Granger causality analysis revealed that the nucleus accumbens was communicating with the neocortex primarily in the theta-band, while the cortex was communicating the nucleus accumbens in the alpha-band. These data are consistent with a model, in which theta- and alpha-band oscillations serve dissociable roles: Prior to stimulus processing, the cortex might suppress ongoing processing in the nucleus accumbens by modulating alpha-band activity. Subsequently, upon stimulus presentation, theta oscillations might facilitate the active exchange of stimulus information from the nucleus accumbens to the cortex. PMID:26394404

  4. Ketamine induces dopamine-dependent depression of evoked hippocampal activity in the nucleus accumbens in freely moving rats.

    PubMed

    Hunt, Mark J; Kessal, Karima; Garcia, Rene

    2005-01-12

    Noncompetitive NMDA receptor antagonists, such as ketamine, induce a transient schizophrenia-like state in healthy individuals and exacerbate psychosis in schizophrenic patients. In rodents, noncompetitive NMDA receptor antagonists induce a behavioral syndrome that represents an experimentally valid model of schizophrenia. Current experimental evidence has implicated the nucleus accumbens in the pathophysiology of schizophrenia and the psychomimetic actions of ketamine. In this study, we have demonstrated that acute systemic administration of ketamine, at a dose known to produce hyperlocomotion and stereotypy, depressed the amplitude of the monosynaptic component of fimbria-evoked field potentials recorded in the nucleus accumbens. A similar effect was observed using the more selective antagonist dizocilpine maleate, indicating the depression was NMDA receptor dependent. Paired-pulse facilitation was enhanced concomitantly with, and in proportion to, ketamine-induced depressed synaptic efficacy, indicative of a presynaptic mechanism of action. Notably, the depression of field potentials recorded in the nucleus accumbens was markedly reduced after a focal 6-hydroxydopamine lesioning procedure in the nucleus accumbens. More specifically, pretreatment with the D2/D4 antagonist haloperidol, but not the D1 antagonist SCH23390 blocked ketamine-induced depression of nucleus accumbens responses. Our findings provide supporting evidence for the contemporary theory of schizophrenia as aberrant excitatory neurotransmission at the level of the nucleus accumbens.

  5. Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin.

    PubMed

    Suyama, Julie A; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A; Lazenka, Matthew F; Negus, S Stevens; Banks, Matthew L

    2016-01-01

    Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = -0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

  6. Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

    PubMed Central

    Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

    2015-01-01

    Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

  7. Targeted disruption of cocaine-activated accumbens neurons prevents context-specific sensitization

    PubMed Central

    Koya, Eisuke; Golden, Sam A.; Harvey, Brandon K.; Guez, Danielle H.; Berkow, Alexander; Simmons, Danielle E.; Bossert, Jennifer M.; Nair, Sunila G.; Uejima, Jamie L.; Marin, Marcelo T.; Mitchell, Timothy; Farquhar, David; Ghosh, Sukhen; Mattson, Brandi J.; Hope, Bruce T.

    2009-01-01

    Learned associations between effects of abused drugs and the drug administration environment play important roles in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations between accumbens neuronal activity and responsivity to drugs and drug cues have been observed, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a novel method, termed ‘Daun02-inactivation method’, that selectively inactivates a minority of neurons activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool to study causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors. PMID:19620976

  8. Endocannabinoid-Mediated Plasticity in Nucleus Accumbens Controls Vulnerability to Anxiety after Social Defeat Stress.

    PubMed

    Bosch-Bouju, Clémentine; Larrieu, Thomas; Linders, Louisa; Manzoni, Olivier J; Layé, Sophie

    2016-08-01

    Chronic social defeat stress (CSDS) is a clinically relevant model of mood disorders. The relationship between the CSDS model and a physiologically pertinent paradigm of synaptic plasticity is not known. Here, we found that cluster analysis of the emotional behavior states of mice exposed to CSDS allowed their segregation into anxious and non-anxious groups. Endocannabinoid-mediated spike-timing dependent plasticity (STDP) in the nucleus accumbens was attenuated in non-anxious mice and abolished in anxious mice. Anxiety-like behavior in stressed animals was specifically correlated with their ability to produce STDP. Pharmacological enhancement of 2-arachidonoyl glycerol (2-AG) signaling in the nucleus accumbens normalized the anxious phenotype and STDP in anxious mice. These data reveal that endocannabinoid modulation of synaptic efficacy in response to a naturalistic activity pattern is both a molecular correlate of behavioral adaptability and a crucial factor in the adaptive response to chronic stress. PMID:27452462

  9. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Reinstatement through Local and Antidromic Activation

    PubMed Central

    White, Samantha L.; Hopkins, Thomas J.; Guercio, Leonardo A.; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D.; Pierce, R. Christopher

    2013-01-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  10. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation.

    PubMed

    Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J; Guercio, Leonardo A; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D; Pierce, R Christopher

    2013-09-01

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents. PMID:24005296

  11. The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain

    PubMed Central

    Ren, Wenjie; Centeno, Maria Virginia; Berger, Sara; Wu, Ying; Na, Xiaodong; Liu, Xianguo; Kondapalli, Jyothisri; Apkarian, A Vania; Martina, Marco; Surmeier, D James

    2016-01-01

    We examined adaptations in nucleus accumbens (NAc) neurons in mouse and rat peripheral nerve injury models of neuropathic pain. Injury selectively increased excitability of NAc shell indirect pathway spiny projection neurons (iSPNs) and altered their synaptic connectivity. Moreover, injury-induced tactile allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, indicating that they not only participated in the central representation of pain, but gated activity in ascending nociceptive pathways. PMID:26691834

  12. α2δ-1 Signaling in Nucleus Accumbens Is Necessary for Cocaine-Induced Relapse

    PubMed Central

    Brown, Robyn M.; Quintero, Gabriel C.; Kupchik, Yonatan M.; Thomas, Charles A.; Reissner, Kathryn J.; Kalivas, Peter W.

    2014-01-01

    Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy. PMID:24948814

  13. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    PubMed

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project. PMID:21704383

  14. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    PubMed

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.

  15. Injection of Cocaine-Amphetamine Regulated Transcript (CART) peptide into the nucleus accumbens does not inhibit caffeine-induced locomotor activity: Implications for CART peptide mechanism.

    PubMed

    Job, Martin O

    2016-09-01

    Much evidence suggests that intra-nucleus accumbens (NAc) CART peptide (CART 55-102) injection inhibits locomotor activity (LMA) when there is an increase in the release and activity of dopamine (DA) in the NAc. However, this hypothesis has not been fully tested. One way to examine this is to determine if there is a lack of effect of intra-NAc CART peptide on LMA that does not involve increases in DA release in the NAc. Several studies have suggested that caffeine-induced LMA does not involve extracellular DA release in the NAc core. Therefore, in this study, we have examined the effect of injections of CART peptide (2.5μg) into the NAc core on the locomotor effects of caffeine in male Sprague-Dawley rats. Several LMA relevant doses of caffeine were used (0, 10, 20mg/kg i.p.), and an inverted U response curve was found as expected. We determined, in the same animals, that intra-NAc CART peptide had no effect on caffeine-induced LMA whereas it blunted cocaine-mediated LMA, as shown by other reports. We also extended a previous observation in mice by showing that at a LMA activating dose of caffeine there is no alteration of CART peptide levels in the NAc of rats. Our study supports the hypothesis that the inhibitory effects of CART peptide in the NAc may be exerted only under conditions of increased extracellular DA release and activity in this region. Our results also suggest that intra-NAc CART 55-102 does not generally inhibit increases in LMA due to all drugs, but has a more specific inhibitory effect on dopaminergic neurotransmission. PMID:27168116

  16. Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell.

    PubMed

    Pisanu, Augusta; Lecca, Daniele; Valentini, Valentina; Bahi, Amine; Dreyer, Jean-Luc; Cacciapaglia, Fabio; Scifo, Andrea; Piras, Giovanna; Cadoni, Cristina; Di Chiara, Gaetano

    2015-02-01

    Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement. PMID:25446574

  17. Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

    PubMed

    Hildebrand, B E; Nomikos, G G; Hertel, P; Schilström, B; Svensson, T H

    1998-01-01

    Mesolimbocortical dopamine (DA) neurotransmission is important in the mediation of the dependence-producing actions of nicotine and other drugs of abuse. Withdrawal from chronic treatment with various types of addictive drugs, including amphetamine, cocaine, ethanol and morphine is associated with a decrease in dopaminergic output in the nucleus accumbens (NAC), whereas the effects of withdrawal from these drugs on dopaminergic output in the medial prefrontal cortex (PFC), as yet, remain largely unknown. This study examined putative changes in the extracellular levels of dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC and in the PFC of rats displaying behavioral signs of nicotine withdrawal. Rats were infused for 7 days with nicotine via subcutaneously implanted minipumps, whereas control animals carried saline-containing pumps. On the fifth day of infusion a microdialysis probe was implanted in the NAC or the PFC of the rats. Forty-eight hours later the levels of DA and the monoamine metabolites were assessed in the dialysate. The behavioral and biochemical effects of a saline injection and a subsequent challenge with the nicotinic receptor antagonist mecamylamine (1 mg/kg s.c.) were determined. Following mecamylamine challenge in nicotine-treated animals, the levels of DA, DOPAC and HVA in the NAC, but not in the PFC, decreased below pre-injection levels and in relation to control animals. The score of abstinence signs increased in the nicotine-treated rats, as compared both to the score after saline and to that in control animals. The decreased DA output in the NAC in animals displaying nicotine withdrawal signs is similar to that seen after withdrawal of several other drugs of abuse, and may have bearing on motivational deficits associated with the abstinence reactions. PMID:9473676

  18. Thermophoretic depletion follows Boltzmann distribution.

    PubMed

    Duhr, Stefan; Braun, Dieter

    2006-04-28

    Thermophoresis, also termed thermal diffusion or the Soret effect, moves particles along temperature gradients. For particles in liquids, the effect lacks a theoretical explanation. We present experimental results at moderate thermal gradients: (i) Thermophoretic depletion of 200 nm polystyrene spheres in water follows an exponential distribution over 2 orders of magnitude in concentration; (ii) Soret coefficients scale linearly with the sphere's surface area. Based on the experiments, it is argued that local thermodynamic equilibrium is a good starting point to describe thermophoresis.

  19. Ozone depletion, paradigms, and politics

    SciTech Connect

    Iman, R.L.

    1993-10-01

    The destruction of the Earth`s protective ozone layer is a prime environmental concern. Industry has responded to this environmental problem by: implementing conservation techniques to reduce the emission of ozone-depleting chemicals (ODCs); using alternative cleaning solvents that have lower ozone depletion potentials (ODPs); developing new, non-ozone-depleting solvents, such as terpenes; and developing low-residue soldering processes. This paper presents an overview of a joint testing program at Sandia and Motorola to evaluate a low-residue (no-clean) soldering process for printed wiring boards (PWBs). Such processes are in widespread use in commercial applications because they eliminate the cleaning operation. The goal of this testing program was to develop a data base that could be used to support changes in the mil-specs. In addition, a joint task force involving industry and the military has been formed to conduct a follow-up evaluation of low-residue processes that encompass the concerns of the tri-services. The goal of the task force is to gain final approval of the low-residue technology for use in military applications.

  20. Ozone Depletion from Nearby Supernovae

    NASA Technical Reports Server (NTRS)

    Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan; Bhartia, P. K. (Technical Monitor)

    2002-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made also in theoretical modeling of supernovae and of the resultant gamma ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma rays and cosmic rays. We find that for the combined ozone depletion from these effects roughly to double the 'biologically active' UV flux received at the surface of the Earth, the supernova must occur at approximately or less than 8 parsecs.

  1. Issues in Stratospheric Ozone Depletion.

    NASA Astrophysics Data System (ADS)

    Lloyd, Steven Andrew

    Following the announcement of the discovery of the Antarctic ozone hole in 1985 there have arisen a multitude of questions pertaining to the nature and consequences of polar ozone depletion. This thesis addresses several of these specific questions, using both computer models of chemical kinetics and the Earth's radiation field as well as laboratory kinetic experiments. A coupled chemical kinetic-radiative numerical model was developed to assist in the analysis of in situ field measurements of several radical and neutral species in the polar and mid-latitude lower stratosphere. Modeling was used in the analysis of enhanced polar ClO, mid-latitude diurnal variation of ClO, and simultaneous measurements of OH, HO_2, H_2 O and O_3. Most importantly, such modeling was instrumental in establishing the link between the observed ClO and BrO concentrations in the Antarctic polar vortex and the observed rate of ozone depletion. The principal medical concern of stratospheric ozone depletion is that ozone loss will lead to the enhancement of ground-level UV-B radiation. Global ozone climatology (40^circS to 50^ circN latitude) was incorporated into a radiation field model to calculate the biologically accumulated dosage (BAD) of UV-B radiation, integrated over days, months, and years. The slope of the annual BAD as a function of latitude was found to correspond to epidemiological data for non-melanoma skin cancers for 30^circ -50^circN. Various ozone loss scenarios were investigated. It was found that a small ozone loss in the tropics can provide as much additional biologically effective UV-B as a much larger ozone loss at higher latitudes. Also, for ozone depletions of > 5%, the BAD of UV-B increases exponentially with decreasing ozone levels. An important key player in determining whether polar ozone depletion can propagate into the populated mid-latitudes is chlorine nitrate, ClONO_2 . As yet this molecule is only indirectly accounted for in computer models and field

  2. Tickling increases dopamine release in the nucleus accumbens and 50 kHz ultrasonic vocalizations in adolescent rats.

    PubMed

    Hori, Miyo; Shimoju, Rie; Tokunaga, Ryota; Ohkubo, Masato; Miyabe, Shigeki; Ohnishi, Junji; Murakami, Kazuo; Kurosawa, Mieko

    2013-03-27

    Adolescent rats emit 50 kHz ultrasonic vocalizations, a marker of positive emotion, during rough-and-tumble play or on tickling stimulation. The emission of 50 kHz ultrasonic vocalizations in response to tickling is suggested to be mediated by dopamine release in the nucleus accumbens; however, there is no direct evidence supporting this hypothesis. The present study aimed to elucidate whether play behavior (tickling) in adolescent rats can trigger dopamine release in the nucleus accumbens with hedonic 50 kHz ultrasonic vocalizations. The effect of tickling stimulation was compared with light-touch stimulation, as a discernible stimulus. We examined 35-40-day-old rats, which corresponds to the period of midadolescence. Tickling stimulation for 5 min significantly increased dopamine release in the nucleus accumbens (118±7% of the prestimulus control value). Conversely, light-touch stimulation for 5 min did not significantly change dopamine release. In addition, 50 kHz ultrasonic vocalizations were emitted during tickling stimulation but not during light-touch stimulation. Further, tickling-induced 50 kHz ultrasonic vocalizations were significantly blocked by the direct application of SCH23390 (D1 receptor antagonist) and raclopride (D2/D3 receptor antagonist) into the nucleus accumbens. Our study demonstrates that tickling stimulation in adolescent rats increases dopamine release in the nucleus accumbens, leading to the generation of 50 kHz ultrasonic vocalizations.

  3. Evidence for a nucleus accumbens CCK2 receptor regulation of rat ventral pallidal GABA levels: a dual probe microdialysis study.

    PubMed

    Ferraro, L; O'Connor, W T; Glennon, J; Tomasini, M C; Bebe, B W; Tanganelli, S; Antonelli, T

    2000-12-22

    We employed dual probe microdialysis in the nucleus accumbens and ipsilateral ventral pallidum of the halothane anaesthetized rat to investigate the effect of intra-accumbens perfusion with the sulphated octapeptide cholecystokinin (CCK-8S, 10-1000 nM, 60 min) alone and in the presence of the selective CCK1 and CCK2 receptor antagonists L-364,718 (10 and 100 nM) and PD134308 (10 nM), tetrodotoxin (TTX, 1000 nM) and the GABA(A) receptor antagonist bicuculline (1000 nM), on dialysate GABA levels in the ventral pallidum. Intra-accumbens perfusion with the 100 and 1000 nM concentration of CCK-8S was associated with a significant decrease (-16+/-3% and -23+/-3% vs basal, respectively) in ventral pallidum GABA levels. The CCK-8S (1000 nM) induced decrease in ventral pallidal dialysate GABA levels was abolished when PD134308, TTX and bicuculline, but not L-364,718, were included into the perfusion medium of the accumbens probe. The data indicate that nucleus accumbens CCK-8S exerts a CCK2 receptor mediated inhibition of ventral pallidal GABA levels. Furthermore, the TTX and bicuculline sensitivity of this effect suggests that this is possibly mediated via CCK2 receptors probably located on local GABA interneurons.

  4. The Case of Ozone Depletion

    NASA Technical Reports Server (NTRS)

    Lambright, W. Henry

    2005-01-01

    While the National Aeronautics and Space Administration (NASA) is widely perceived as a space agency, since its inception NASA has had a mission dedicated to the home planet. Initially, this mission involved using space to better observe and predict weather and to enable worldwide communication. Meteorological and communication satellites showed the value of space for earthly endeavors in the 1960s. In 1972, NASA launched Landsat, and the era of earth-resource monitoring began. At the same time, in the late 1960s and early 1970s, the environmental movement swept throughout the United States and most industrialized countries. The first Earth Day event took place in 1970, and the government generally began to pay much more attention to issues of environmental quality. Mitigating pollution became an overriding objective for many agencies. NASA's existing mission to observe planet Earth was augmented in these years and directed more toward environmental quality. In the 1980s, NASA sought to plan and establish a new environmental effort that eventuated in the 1990s with the Earth Observing System (EOS). The Agency was able to make its initial mark via atmospheric monitoring, specifically ozone depletion. An important policy stimulus in many respects, ozone depletion spawned the Montreal Protocol of 1987 (the most significant international environmental treaty then in existence). It also was an issue critical to NASA's history that served as a bridge linking NASA's weather and land-resource satellites to NASA s concern for the global changes affecting the home planet. Significantly, as a global environmental problem, ozone depletion underscored the importance of NASA's ability to observe Earth from space. Moreover, the NASA management team's ability to apply large-scale research efforts and mobilize the talents of other agencies and the private sector illuminated its role as a lead agency capable of crossing organizational boundaries as well as the science-policy divide.

  5. Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking

    PubMed Central

    Graf, Evan N.; Wheeler, Robert A.; Baker, David A.; Ebben, Amanda L.; Hill, Jonathan E.; McReynolds, Jayme R.; Robble, Mykel A.; Vranjkovic, Oliver; Wheeler, Daniel S.; Mantsch, John R.

    2013-01-01

    Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake2-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake. PMID:23864669

  6. Variability in nucleus accumbens activity mediates age-related suboptimal financial risk taking

    PubMed Central

    Samanez-Larkin, Gregory R.; Kuhnen, Camelia M.; Yoo, Daniel J.; Knutson, Brian

    2010-01-01

    As human life expectancy continues to rise, financial decisions of aging investors may have an increasing impact on the global economy. In this study, we examined age differences in financial decisions across the adult life span by combining functional neuroimaging with a dynamic financial investment task. During the task, older adults made more suboptimal choices than younger adults when choosing risky assets. This age-related effect was mediated by a neural measure of temporal variability in nucleus accumbens activity. These findings reveal a novel neural mechanism by which aging may disrupt rational financial choice. PMID:20107069

  7. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.

    PubMed

    Smith-Roe, S L; Kelley, A E

    2000-10-15

    The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

  8. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking.

    PubMed

    Bossert, Jennifer M; Stern, Anna L; Theberge, Florence R M; Marchant, Nathan J; Wang, Hui-Ling; Morales, Marisela; Shaham, Yavin

    2012-04-01

    In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse. PMID:22492053

  9. The 1988 Antarctic ozone depletion: Comparison with previous year depletions

    SciTech Connect

    Schoeberl, M.R.; Stolarski, R.S.; Krueger, A.J. )

    1989-05-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15% during September 1988 compared to nearly 50% during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30{degree}-60{degree}S. The standard deviation also correlates with the QBO cycling of the tropical winds. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  10. The 1988 Antarctic ozone depletion - Comparison with previous year depletions

    NASA Technical Reports Server (NTRS)

    Schoeberl, Mark R.; Stolarski, Richard S.; Krueger, Arlin J.

    1989-01-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15 percent during September 1988, compared to nearly 50 percent during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30-60 deg S. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  11. Type 2-depleted fungal laccase.

    PubMed Central

    Hanna, P M; McMillin, D R; Pasenkiewicz-Gierula, M; Antholine, W E; Reinhammar, B

    1988-01-01

    Although copper is quantitatively removed from fungal laccase (Polyporus versicolor) by extended dialysis against high concentrations of cyanide, we have been unable to reconstitute the protein by addition of Cu(I) ions. However, two new methods for reversibly removing the type 2 Cu centre have been developed. The visible absorption at 610 nm, which is attributable to type 1 Cu, is unaffected by the procedure, but the absorbance of the type 3 Cu at 330 nm is decreased by 60 +/- 10%. The decrease is due, at least in part, to partial reduction of the binuclear type 3 centre, although there may be some change in the molar absorptivity of the oxidized chromophore as well. The change in the c.d. spectrum that occurs at approx. 350 nm may be explained in the same way, but it may also reflect the loss of a signal due to the type 2 Cu. Upon removal of the type 2 Cu an absorbance increase appears at approx. 435 nm, and it is assigned to the semi-reduced form of the type 3 pair. In the e.p.r. spectrum of the type 2-depleted enzyme the type 1 Cu signal exhibits well-resolved ligand hyperfine splitting, which can be simulated on the basis of contributions from two N and two H nuclei (AH congruent to AN congruent to 25 MHz). The H atoms are assumed to be attached to the beta-carbon of the covalently bonded cysteine ligand. A signal from a semi-reduced form(s) of the type 3 site can also be resolved in the spectrum of the type 2-depleted enzyme, and on the basis of the second integral of the e.p.r. spectrum 40% of the type 3 pairs are believed to be in a partially reduced state. The semi-reduced type 3 site is remarkably stable and is not readily oxidized by H2O2 or IrCl6(2-) or reduced by Fe(CN)6(4-). Intramolecular electron transfer is apparently quite slow in at least some forms of the type 2-depleted enzyme, and this may explain why the activity is at best 5% of that of the native enzyme. Full activity returns when type 2 copper is restored. PMID:2845923

  12. Accumbens cholinergic interneurons play a role in the regulation of body weight and metabolism.

    PubMed

    Hajnal, A; Székely, M; Gálosi, R; Lénárd, L

    The aims of the present study were (1) to determine whether selective lesions of the accumbens cholinergic interneurons impair feeding and body weight regulation, and (2) to characterize the nature of disturbances using motivational and metabolic challenges. Rats with bilateral cholinotoxic (AF64A) lesions in the nucleus accumbens showed a significant and lasting lag in body weight gain in comparison to the sham-operated controls. This failure to gain weight was not due to a decrease in feeding because lesioned rats actually ate more food and drank more water than controls under basal conditions. Lesion-induced deficits were also exposed when the rats were challenged with food deprivation or cold exposure. Lesioned rats ate less than controls when 24 h food deprived and maintained both a higher core temperature and a higher metabolic rate than controls following either 24-h food deprivation or exposure to cold. Thyroid hormones, insulin, and blood glucose levels were, however, within the physiological range, and no sensory and motor disturbances were observed. The results suggest that the altered body weight regulation is partly due to the enhanced metabolic responsiveness to stress. Possible explanations for the effects of the lesions are also discussed in the context of motivational alterations, including possible dopamine-acetylcholine interactions.

  13. Acute drug-induced spine changes in the nucleus accumbens are dependent on β-adducin.

    PubMed

    Engmann, Olivia; Giralt, Albert; Girault, Jean-Antoine

    2016-11-01

    Chronic modifications of dopamine transmission alter striatal dendritic spines. Here, we show that spine density and length are increased in the nucleus accumbens 24 h after a single injection of caffeine or quinpirole, a dopamine D2/D3 dopamine receptors agonist, whereas the dopamine antagonist haloperidol has opposite effects. These effects are absent in mice lacking β-adducin, a protein that stabilizes actin/spectrin cortical cytoskeleton and modulates synaptic plasticity. Phosphorylation of adducin (Ser713 in β-adducin), which disrupts actin/spectrin interaction, is increased by quinpirole, haloperidol, or caffeine. We previously demonstrated that DARPP-32 interacts with β-adducin and facilitates its phosphorylation. Quinpirole increased DARPP-32 phosphorylation at Thr75 and haloperidol at Ser97, two modifications that can have similar consequences on adducin phosphorylation through distinct mechanisms. Experiments in DARPP-32 mutant mice confirmed that the apparently paradoxical similar effects of quinpirole and haloperidol on adducin phosphorylation may result from differential effects of these drugs on DARPP-32 phosphorylation at Thr75 and Ser97. Our data provide novel insights on how a single dose of widely used psychoactive drugs can affect spine plasticity in the nucleus accumbens, a component of the reward system. PMID:27480796

  14. Understanding the Role α7 Nicotinic Receptors Play in Dopamine Efflux in Nucleus Accumbens

    PubMed Central

    2015-01-01

    Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction. PMID:25147933

  15. Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents.

    PubMed

    Karoly, Hollis C; Bryan, Angela D; Weiland, Barbara J; Mayer, Andrew; Dodd, Andrew; Feldstein Ewing, Sarah W

    2015-12-01

    Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol). Due to the role of the nucleus accumbens (NAcc) in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID) task. Adolescents (ages 14-18; 66% male) were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n=14), tobacco-only (n=34), alcohol-only (n=12), cannabis+tobacco (n=17), cannabis+tobacco+alcohol (n=17), and non-using controls (n=38). All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc) activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.

  16. Depleted Argon from Underground Sources

    SciTech Connect

    Back, H. O.; Galbiati, C.; Goretti, A.; Loer, B.; Montanari, D.; Mosteiro, P.; Alexander, T.; Alton, A.; Rogers, H.; Kendziora, C.; Pordes, S.

    2011-04-27

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however {sup 39}Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in {sup 39}Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO{sub 2} well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO{sub 2}. We first concentrate the argon locally to 3% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation, and then the N{sub 2} and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO{sub 2} facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  17. Depleted Argon from Underground Sources

    NASA Astrophysics Data System (ADS)

    Back, H. O.; Alexander, T.; Alton, A.; Galbiati, C.; Goretti, A.; Kendziora, C.; Loer, B.; Montanari, D.; Mosteiro, P.; Pordes, S.; Rogers, H.

    2011-04-01

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however 39Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in 39Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO2 well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO2. We first concentrate the argon locally to 3% in an Ar, N2, and He mixture, from the CO2 through chromatographic gas separation, and then the N2 and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO2 facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  18. Depleted uranium disposal options evaluation

    SciTech Connect

    Hertzler, T.J.; Nishimoto, D.D.; Otis, M.D.

    1994-05-01

    The Department of Energy (DOE), Office of Environmental Restoration and Waste Management, has chartered a study to evaluate alternative management strategies for depleted uranium (DU) currently stored throughout the DOE complex. Historically, DU has been maintained as a strategic resource because of uses for DU metal and potential uses for further enrichment or for uranium oxide as breeder reactor blanket fuel. This study has focused on evaluating the disposal options for DU if it were considered a waste. This report is in no way declaring these DU reserves a ``waste,`` but is intended to provide baseline data for comparison with other management options for use of DU. To PICS considered in this report include: Retrievable disposal; permanent disposal; health hazards; radiation toxicity and chemical toxicity.

  19. Dust-acoustic shock waves in an electron depleted nonextensive dusty plasma

    NASA Astrophysics Data System (ADS)

    Ferdousi, M.; Miah, M. R.; Sultana, S.; Mamun, A. A.

    2015-12-01

    A theoretical study of dust-acoustic (DA) shock waves has been carried out in an unmagnetized electron depleted dusty plasma containing inertial negatively charged dust grains and nonextensive positively charged ions. The normal mode analysis is used to examine the linear properties of DA waves. The reductive perturbation technique is employed in order to derive the nonlinear Burgers equation. The basic features (viz. polarity, amplitude, width, etc.) of the DA shock waves are investigated. Both polarity (positive and negative potential) shock waves are found to exists in the plasma under consideration in this manuscript. The findings of this investigation may be used in understanding the wave propagation in laboratory and space plasmas.

  20. High-voltage-compatible, fully depleted CCDs

    SciTech Connect

    Holland, Stephen E.; Bebek, Chris J.; Dawson, Kyle S.; Emes, JohnE.; Fabricius, Max H.; Fairfield, Jessaym A.; Groom, Don E.; Karcher, A.; Kolbe, William F.; Palaio, Nick P.; Roe, Natalie A.; Wang, Guobin

    2006-05-15

    We describe charge-coupled device (CCD) developmentactivities at the Lawrence Berkeley National Laboratory (LBNL).Back-illuminated CCDs fabricated on 200-300 mu m thick, fully depleted,high-resistivity silicon substrates are produced in partnership with acommercial CCD foundry.The CCDs are fully depleted by the application ofa substrate bias voltage. Spatial resolution considerations requireoperation of thick, fully depleted CCDs at high substrate bias voltages.We have developed CCDs that are compatible with substrate bias voltagesof at least 200V. This improves spatial resolution for a given thickness,and allows for full depletion of thicker CCDs than previously considered.We have demonstrated full depletion of 650-675 mu m thick CCDs, withpotential applications in direct x-ray detection. In this work we discussthe issues related to high-voltage operation of fully depleted CCDs, aswell as experimental results on high-voltage-compatible CCDs.

  1. 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

  2. Microstructural Abnormality in Left Nucleus Accumbens Predicts Dysfunctional Beliefs in Treatment-Resistant Obsessive-Compulsive Disorder

    PubMed Central

    Li, Zhongchun; Ji, Weidong; Li, Deqiang; Li, Xujuan; Feng, Wei

    2014-01-01

    Background The aim of this study was to determine whether dysfunctional beliefs might predict treatment-resistance and to examine the relationship between fractional anisotropy (FA) in diffusion tensor imaging (DTI) and cognitive biases for optimal treatment choice. Material/Methods We recruited 11 non-resistant obsessive-compulsive disorder (OCD) patients, 11 resistant OCD patients, and 11 healthy subjects. Results OCD patients had higher Obsessive Beliefs Questionnaire (OBQ-87) subscale scores than subjects in non-resistant and resistant groups. A significant difference was found between non-resistant and resistant OCD patients in R-Scale and I-Scale. A significant decrease in FA was found in left dorsal frontal gyrus and left inferior parietal lobule in the non-resistant group as compared to the control group. FA also decreased significantly in left anterior cingulate cortex, putamen, and nucleus accumbens in the resistant group as compared to the control group. There was a significant decrease in FA in nucleus accumbens in the resistant group as compared to the non-resistant group. Reduced FA in left nucleus accumbens was negatively associated with OBQ-87 factor R and I and the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Conclusions Abnormalities in cortical-striatal white matter networks may contribute to the dysfunctional beliefs in patients with treatment-resistant OCD, and the left nucleus accumbens may be an important and promising target for the treatment of OCD. PMID:25393961

  3. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use

    PubMed Central

    Meshi, Dar; Morawetz, Carmen; Heekeren, Hauke R.

    2013-01-01

    Our reputation is important to us; we've experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one's character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one's degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior. PMID:24009567

  4. The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Bradfield, Laura A.; McNally, Gavan P.

    2010-01-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning…

  5. A Study on the Role of the Dorsal Striatum and the Nucleus Accumbens in Allocentric and Egocentric Spatial Memory Consolidation

    ERIC Educational Resources Information Center

    De Leonibus, Elvira; Oliverio, Alberto; Mele, Andrea

    2005-01-01

    There is now accumulating evidence that the striatal complex in its two major components, the dorsal striatum and the nucleus accumbens, contributes to spatial memory. However, the possibility that different striatal subregions might modulate specific aspects of spatial navigation has not been completely elucidated. Therefore, in this study, two…

  6. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    ERIC Educational Resources Information Center

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  7. Neural encoding of psychomotor activation in the nucleus accumbens core, but not the shell, requires cannabinoid receptor signaling

    PubMed Central

    Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

    2010-01-01

    The current study aimed to further elucidate the role of endocannabinoid signaling in methamphetamine-induced psychomotor activation. Rats were treated with bilateral, intracranial microinjections of the cannabinoid CB1 receptor antagonists rimonabant (1 μg; 1 μl) or AM251 (1 μg; 1 μl), or vehicle (1 μl), followed by intravenous methamphetamine (3 mg/kg). Antagonist pretreatment in the nucleus accumbens core, but not shell, attenuated methamphetamine-induced stereotypy, while treatment in either brain region had no effect on drug-induced locomotion. In a parallel experiment, we recorded multiple single-units in the nucleus accumbens of behaving rats treated with intravenous rimonabant (0.3 mg/kg) or vehicle, followed by methamphetamine (0.01, 0.1, 1, 3 mg/kg; cumulative dosing). We observed robust, phasic changes in neuronal firing time-locked to the onset of methamphetamine-induced locomotion and stereotypy. Stereotypy encoding was observed in the core and was attenuated by CB1 receptor antagonism, while locomotor correlates were observed uniformly across the accumbens and were not affected by rimonabant. Psychomotor activation encoding was expressed predominantly by putative fast-spiking interneurons. We therefore propose that endocannabinoid modulation of psychomotor activation is preferentially driven by CB1 receptor-dependent interneuron activity in the nucleus accumbens core. PMID:20371830

  8. Microinjections of D-Ala2-Met5-enkephalinamide placed into nucleus accumbens suppress hypothalamically elicited hissing in the cat.

    PubMed

    Brutus, M; Zuabi, S; Siegel, A

    1989-04-01

    The effects of D-Ala2-Met5-enkephalinamide (DAME) upon the hissing component of hypothalamically elicited affective defense behavior in the cat were examined in this study. Microinjections of DAME placed into the nucleus accumbens significantly suppressed this response in a dose and time dependent manner. This dose dependent suppression of affective defense decreased toward baseline levels at 60 and 90 min following delivery of 1 and 10 micrograms/0.5 microliters of DAME, respectively. Similar injections placed into the caudate nucleus had no effects upon this response. Neither vehicle control nor naloxone placed into nucleus accumbens was found to significantly alter latencies for hissing. Naloxone injected into nucleus accumbens prior to administration of either a 1-microgram or a 10-micrograms dose of DAME blocked the suppressive effects of DAME that were observed when this drug was administered alone. These findings suggest that opioid receptors in the nucleus accumbens play an important role in the regulation of the hissing component of hypothalamically elicited affective defense behavior in the cat. PMID:2924870

  9. Nucleus accumbens response to gains in reputation for the self relative to gains for others predicts social media use.

    PubMed

    Meshi, Dar; Morawetz, Carmen; Heekeren, Hauke R

    2013-01-01

    Our reputation is important to us; we've experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one's character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one's degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior.

  10. CO depletion in the Gould Belt clouds

    NASA Astrophysics Data System (ADS)

    Christie, H.; Viti, S.; Yates, J.; Hatchell, J.; Fuller, G. A.; Duarte-Cabral, A.; Sadavoy, S.; Buckle, J. V.; Graves, S.; Roberts, J.; Nutter, D.; Davis, C.; White, G. J.; Hogerheijde, M.; Ward-Thompson, D.; Butner, H.; Richer, J.; Di Francesco, J.

    2012-05-01

    We present a statistical comparison of CO depletion in a set of local molecular clouds within the Gould Belt using Sub-millimetre Common User Bolometer Array (SCUBA) and Heterodyne Array Receiver Programme (HARP) data. This is the most wide-ranging study of depletion thus far within the Gould Belt. We estimate CO column densities assuming local thermodynamic equilibrium and, for a selection of sources, using the radiative transfer code RADEX in order to compare the two column density estimation methods. High levels of depletion are seen in the centres of several dust cores in all the clouds. We find that in the gas surrounding protostars, levels of depletion are somewhat lower than for starless cores with the exception of a few highly depleted protostellar cores in Serpens and NGC 2024. There is a tentative correlation between core mass and core depletion, particularly in Taurus and Serpens. Taurus has, on average, the highest levels of depletion. Ophiuchus has low average levels of depletion which could perhaps be related to the anomalous dust grain size distribution observed in this cloud. High levels of depletion are often seen around the edges of regions of optical emission (Orion) or in more evolved or less dynamic regions such as the bowl of L1495 in Taurus and the north-western region of Serpens.

  11. Ego depletion increases risk-taking.

    PubMed

    Fischer, Peter; Kastenmüller, Andreas; Asal, Kathrin

    2012-01-01

    We investigated how the availability of self-control resources affects risk-taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk-taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings. PMID:22931000

  12. Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

    PubMed Central

    Shin, Jung Hoon; Adrover, Martín F.; Wess, Jürgen; Alvarez, Veronica A.

    2015-01-01

    Cholinergic transmission in the striatum functions as a key modulator of dopamine (DA) transmission and synaptic plasticity, both of which are required for reward and motor learning. Acetylcholine (ACh) can elicit striatal DA release through activation of nicotinic ACh receptors (nAChRs) on DA axonal projections. However, it remains controversial how muscarinic ACh receptors (mAChRs) modulate striatal DA release, with studies reporting both potentiation and depression of striatal DA transmission by mAChR agonists. This study investigates the mAChR-mediated regulation of release from three types of midbrain neurons that project to striatum: DA, DA/glutamate, and glutamate neurons. We found that M5 mAChRs potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain. We also show that M2/M4 mAChRs depress the nAChR-dependent mechanism of DA release in the striatum. These results suggest that M5 receptors on DA neuron terminals enhance DA release, whereas M2/M4 autoreceptors on cholinergic terminals inhibit ACh release and subsequent nAChR-dependent DA release. Our findings clarify the mechanisms of mAChR-dependent modulation of DA and glutamate transmission in the striatum. PMID:26080439

  13. Dual effects of limbic seizures on psychosis-relevant behaviors shown by nucleus accumbens kindling in rats

    PubMed Central

    Ma, Jingyi; Leung, L. Stan

    2016-01-01

    Background A paradox in epilepsy and psychiatry is that temporal lobe epilepsy is often predisposed to schizophrenic-like psychosis, whereas convulsive therapy can relieve schizophrenic symptoms. We have previously demonstrated that the nucleus accumbens is a key structure in mediating postictal psychosis induced by a hippocampal electrographic seizure. Objective/Hypothesis The purpose of this study is to test a hypothesis that accumbens kindling cumulating in a single (1-time) or repeated (5-times) convulsive seizures have different effects on animal models of psychosis. Methods Electrical stimulation at 60 Hz was applied to nucleus accumbens to evoke afterdischarges until one, or five, convulsive seizures that involved the hind limbs (stage 5 seizures) were attained. Behavioral tests, performed at 3 days after the last seizure, included gating of hippocampal auditory evoked potentials (AEP) and prepulse inhibition to an acoustic startle response (PPI), tested without drug injection or after ketamine (3 mg/kg s.c.) injection, as well as locomotion induced by ketamine or methamphetamine (1 mg/kg i.p.). Results Compared to non-kindled control rats, 1-time, but not 5-times, convulsive seizures induced PPI deficit and decreased gating of hippocampal AEP, without drug injection. Compared to non-kindled rats, 5-times, but not 1-time, convulsive seizures antagonized ketamine-induced hyperlocomotion, ketamine-induced PPI deficit and AEP gating decrease. However, both 1- and 5-times convulsive seizures, significantly enhanced methamphetamine-induced locomotion as compared to non-kindled rats. Conclusions Accumbens kindling ending with 1 convulsive seizure may induce schizophrenic-like behaviors, while repeated (≥ 5) convulsive seizures induced by accumbens kindling may have therapeutic effects on dopamine independent psychosis. PMID:27267861

  14. Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

    PubMed

    Bull, Cecilia; Freitas, Kelen C C; Zou, Shiping; Poland, Ryan S; Syed, Wahab A; Urban, Daniel J; Minter, Sabrina C; Shelton, Keith L; Hauser, Kurt F; Negus, S Stevens; Knapp, Pamela E; Bowers, M Scott

    2014-11-01

    Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with

  15. Dopaminergic effects of histamine administration in the nucleus accumbens and the impact of H1-receptor blockade.

    PubMed

    Galosi, R; Lenard, L; Knoche, A; Haas, H; Huston, J P; Schwarting, R K

    2001-03-01

    The mesolimbic dopamine system is thought to play a critical role in reward-related processes. A number of studies have shown that lesion or inhibition of histaminergic neurons acting through H1 receptors can potentiate the effects of drug-induced reward (e.g., psychostimulants and opioids) and can enhance the reinforcing effects of electrical stimulation of the brain. Since dopamine transmission in the nucleus accumbens is thought to provide a crucial link in these histaminergic actions, we examined the effects of local histamine application (0.1, 1.0 and 10.0 micromol/l) on dopamine and its metabolites in the nucleus accumbens of anesthetized rats by means of unilateral reverse dialysis. To study the influence of H1 receptors, we also applied the H1-receptor antagonist pyrilamine (10.0 and 20.0 mg/kg, intraperitoneally) 20 min before histamine administration (1 mmol/l). Finally, pyrilamine (0.1, 1.0 and 10.0 micromol/l) was locally administered into the nucleus accumbens. The data show that histamine can enhance extracellular dopamine levels in the nucleus accumbens in a dose-dependent way. This increase was partially antagonized by prior peripheral administration of 10 mg/kg, and was completely blocked by 20 mg/kg, of pyrilamine. Finally, intra-accumbens administration of pyrilamine locally decreased dopamine and increased dihydroxyphenylacetic acid and homovanillic acid levels. These data are discussed with respect to the possible interactions between dopaminergic and histaminergic mechanisms in the mesolimbic system and their relation to mechanisms of reinforcement. PMID:11249972

  16. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats

    PubMed Central

    Vassoler, F.M.; Schmidt, H.D.; Gerard, M.E.; Famous, K.R.; Ciraulo, D.A.; Kornetsky, C.; Knapp, C.M.; Pierce, R.C.

    2008-01-01

    Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 hours daily for 21 days and then cocaine seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 μAmps. DBS began immediately after a priming injection of cocaine (0, 5, 10 or 20 mg/kg, i.p.) and continued throughout each 2-hour reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer-specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Taken together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction. PMID:18753374

  17. D1 receptors in the nucleus accumbens-shell, but not the core, are involved in mediating ethanol-seeking behavior of alcohol-preferring (P) rats.

    PubMed

    Hauser, S R; Deehan, G A; Dhaher, R; Knight, C P; Wilden, J A; McBride, W J; Rodd, Z A

    2015-06-01

    Clinical and preclinical research suggest that activation of the mesolimbic dopamine (DA) system is involved in mediating the rewarding actions of drugs of abuse, as well as promoting drug-seeking behavior. Inhibition of DA D1 receptors in the nucleus accumbens (Acb) can reduce ethanol (EtOH)-seeking behavior of non-selective rats triggered by environmental context. However, to date, there has been no research on the effects of D1 receptor agents on EtOH- seeking behavior of high alcohol-preferring (P) rats following prolonged abstinence. The objective of the present study was to examine the effects of microinjecting the D1 antagonist SCH 23390 or the D1 agonist A-77636 into the Acb shell or Acb core on spontaneous recovery of EtOH-seeking behavior. After 10 weeks of concurrent access to EtOH and water, P rats underwent seven extinction sessions (EtOH and water withheld), followed by 2 weeks in their home cages without access to EtOH or operant sessions. In the 2nd week of the home cage phase, rats were bilaterally implanted with guide cannula aimed at the Acb shell or Acb core; rats were allowed 7d ays to recover before EtOH-seeking was assessed by the Pavlovian Spontaneous Recovery (PSR) model. Administration of SCH23390 (1μg/side) into the Acb shell inhibited responding on the EtOH lever, whereas administration of A-77636 (0.125μg/side) increased responding on the EtOH lever. Microinfusion of D1 receptor agents into the Acb core did not alter responding on the EtOH lever. Responses on the water lever were not altered by any of the treatments. The results suggest that activation of D1 receptors within the Acb shell, but not Acb core, are involved in mediating PSR of EtOH-seeking behavior of P rats.

  18. D1 Receptors in the Nucleus Accumbens-Shell, but not the Core, are Involved in Mediating Ethanol-Seeking Behavior of Alcohol-Preferring (P) Rats

    PubMed Central

    Hauser, Sheketha R.; Deehan, Gerald A.; Dhaher, Ronnie; Knight, Christopher P.; Wilden, Jessica A.; McBride, William J.; Rodd, Zachary A.

    2015-01-01

    Clinical and preclinical research suggest that activation of the mesolimbic dopamine (DA) system is involved in mediating the rewarding actions of drugs of abuse, as well as promoting drug-seeking behavior. Inhibition of DA D1 receptors in the nucleus accumbens (Acb) can reduce ethanol (EtOH)-seeking behavior of non-selective rats triggered by environmental context. However, to date, there has been no research on the effects D1 receptor agen ts on EtOH-seeking behavior of high alcohol preferring (P) rats following prolonged abstinence. The objective of the present study was to examine the effects of microinjecting the D1 antagonist SCH 23390 or the D1 agonist A-77636 into the Acb shell or Acb core on spontaneous recovery of EtOH-seeking behavior. After 10 weeks of concurrent access to EtOH and water, P rats underwent 7 extinction sessions (EtOH and water withheld), followed by 2 weeks in their home cages without access to EtOH or operant sessions. In the 2nd week of the home cage phase, rats were bilaterally implanted with guide cannula aimed at the Acb shell or Acb core; rats were allowed 7 days to recover before EtOH-seeking was assessed by the Pavlovian spontaneous recovery (PSR) model. Administration of SCH23390 (1 μg/side) into the Acb shell inhibited responding on the EtOH lever, whereas administration of A-77636 (0.125 μg/side) increased responding on the EtOH lever. Microinfusion of D1 receptor agents into the Acb core did not alter responding on the EtOH lever. Responses on the water lever were not altered by any of the treatments. The results suggest that activation of D1 receptors within the Acb shell, but not Acb core, are involved in mediating PSR of EtOH-seeking behavior of P rats. PMID:25813708

  19. Depleted argon from underground sources

    SciTech Connect

    Back, H.O.; Alton, A.; Calaprice, F.; Galbiati, C.; Goretti, A.; Kendziora, C.; Loer, B.; Montanari, D.; Mosteiro, P.; Pordes, S.; /Fermilab

    2011-09-01

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic {sup 39}Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in {sup 39}Ar. In Cortez Colorado a CO{sub 2} well has been discovered to contain approximately 500ppm of argon as a contamination in the CO{sub 2}. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation. The N{sub 2} and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  20. Depleted Argon from Underground Sources

    NASA Astrophysics Data System (ADS)

    Back, H. O.; Alton, A.; Calaprice, F.; Galbiati, C.; Goretti, A.; Kendziora, C.; Loer, B.; Montanari, D.; Mosteiro, P.; Pordes, S.

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic 39Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in 39Ar. In Cortez Colorado a CO2 well has been discovered to contain approximately 500 ppm of argon as a contamination in the CO2. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N2, and He mixture, from the CO2 through chromatographic gas separation. The N2 and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  1. Beneficial Uses of Depleted Uranium

    SciTech Connect

    Brown, C.; Croff, A.G.; Haire, M. J.

    1997-08-01

    Naturally occurring uranium contains 0.71 wt% {sup 235}U. In order for the uranium to be useful in most fission reactors, it must be enriched the concentration of the fissile isotope {sup 235}U must be increased. Depleted uranium (DU) is a co-product of the processing of natural uranium to produce enriched uranium, and DU has a {sup 235}U concentration of less than 0.71 wt%. In the United States, essentially all of the DU inventory is in the chemical form of uranium hexafluoride (UF{sub 6}) and is stored in large cylinders above ground. If this co-product material were to be declared surplus, converted to a stable oxide form, and disposed, the costs are estimated to be several billion dollars. Only small amounts of DU have at this time been beneficially reused. The U.S. Department of Energy (DOE) has begun the Beneficial Uses of DU Project to identify large-scale uses of DU and encourage its reuse for the primary purpose of potentially reducing the cost and expediting the disposition of the DU inventory. This paper discusses the inventory of DU and its rate of increase; DU disposition options; beneficial use options; a preliminary cost analysis; and major technical, institutional, and regulatory issues to be resolved.

  2. Tritium transport vessel using depleted uranium

    SciTech Connect

    Heung, L.K.

    1995-01-01

    A tritium transport vessel using depleted uranium was tested in the laboratory using deuterium and protium. The vessel contains 0.5 kg of depleted uranium and can hold up to 18 grams of tritium. The conditions for activation, tritium loading and tritium unloading were defined. The safety aspects that included air-ingress, tritium diffusion, temperature and pressure potentials were evaluated.

  3. Satiating effects of cocaine are controlled by dopamine actions in the nucleus accumbens core

    PubMed Central

    Suto, Nobuyoshi; Wise, Roy A.

    2012-01-01

    Intravenous cocaine intake in laboratory animals is characterized by periods of apparent drug satiety between regularly spaced earned injections. The reinforcing properties of cocaine are linked primarily to dopaminergic neurotransmission in the shell and not the core of nucleus accumbens. To determine if the satiating effects of cocaine are similarly mediated, we perfused dopamine receptor agonists into the core or the shell during intravenous cocaine self-administrations by rats. Neither D1-type (SKF38393) nor D2-type (quinpirole) agonist was effective when given alone. However, a combination of the two agonists perfused into the core but not the shell significantly increased the time between cocaine self-injections, decreasing the amount of earned intake. Together with previous findings, the current data suggest that the satiating and reinforcing effects of cocaine are mediated by different ventral striatal output neurons. PMID:22159106

  4. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation

    PubMed Central

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J.

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1–D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  5. A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

    PubMed

    McCairn, Kevin W; Nagai, Yuji; Hori, Yukiko; Ninomiya, Taihei; Kikuchi, Erika; Lee, Ju-Young; Suhara, Tetsuya; Iriki, Atsushi; Minamimoto, Takafumi; Takada, Masahiko; Isoda, Masaki; Matsumoto, Masayuki

    2016-01-20

    Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

  6. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.

    PubMed

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1-D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  7. Emotional environments retune the valence of appetitive versus fearful functions in nucleus accumbens

    PubMed Central

    Reynolds, Sheila M; Berridge, Kent C

    2009-01-01

    The nucleus accumbens mediates both appetitive motivation for rewards and fearful motivation toward threats, which are generated in part by glutamate-related circuits organized in a keyboard fashion. At rostral sites of the medial shell, localized glutamate disruptions typically generate intense appetitive behaviors in rats, but the disruption incrementally generates fearful behaviors as microinjection sites move more caudally. We found that exposure to stressful environments caused caudal fear-generating zones to expand rostrally, filling ~90% of the shell. Conversely, a preferred home environment caused fear-generating zones to shrink and appetitive-generating zones to expand caudally, filling ~90% of the shell. Thus, the emotional environments retuned the generation of motivation in corticolimbic circuits. PMID:18344996

  8. Ventral-striatal/nucleus-accumbens sensitivity to prediction errors during classification learning.

    PubMed

    Rodriguez, P F; Aron, A R; Poldrack, R A

    2006-04-01

    A prominent theory in neuroscience suggests reward learning is driven by the discrepancy between a subject's expectation of an outcome and the actual outcome itself. Furthermore, it is postulated that midbrain dopamine neurons relay this mismatch to target regions including the ventral striatum. Using functional MRI (fMRI), we tested striatal responses to prediction errors for probabilistic classification learning with purely cognitive feedback. We used a version of the Rescorla-Wagner model to generate prediction errors for each subject and then entered these in a parametric analysis of fMRI activity. Activation in ventral striatum/nucleus-accumbens (Nacc) increased parametrically with prediction error for negative feedback. This result extends recent neuroimaging findings in reward learning by showing that learning with cognitive feedback also depends on the same circuitry and dopaminergic signaling mechanisms.

  9. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

    PubMed Central

    Mohammadi, Milad; Fendt, Markus

    2015-01-01

    Background and Purpose Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning. Experimental Approach The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested. Key Results Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections. Conclusion and Implication The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory. PMID:25572550

  10. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

    PubMed

    LaPlant, Quincey; Vialou, Vincent; Covington, Herbert E; Dumitriu, Dani; Feng, Jian; Warren, Brandon L; Maze, Ian; Dietz, David M; Watts, Emily L; Iñiguez, Sergio D; Koo, Ja Wook; Mouzon, Ezekiell; Renthal, William; Hollis, Fiona; Wang, Hui; Noonan, Michele A; Ren, Yanhua; Eisch, Amelia J; Bolaños, Carlos A; Kabbaj, Mohamed; Xiao, Guanghua; Neve, Rachael L; Hurd, Yasmin L; Oosting, Ronald S; Fan, Gouping; Morrison, John H; Nestler, Eric J

    2010-09-01

    Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

  11. Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice.

    PubMed

    Heshmati, Mitra; Golden, Sam A; Pfau, Madeline L; Christoffel, Daniel J; Seeley, Elena L; Cahill, Michael E; Khibnik, Lena A; Russo, Scott J

    2016-02-01

    Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors.

  12. Sulpiride infused into the nucleus accumbens posttraining impairs memory of spatial water maze training.

    PubMed

    Setlow, B; McGaugh, J L

    1998-06-01

    A variety of nucleus accumbens (NA) manipulations induce deficits in spatial learning and memory tasks. It is not known, however, if these deficits reflect influences on memory or on other processes affecting performance. The experiments in this article were undertaken to examine the involvement of the NA in memory consolidation in a spatial task. Rats were given 1 training session in a spatial water maze immediately followed by intra-NA infusions of sulpiride or saline vehicle. A probe test 2 days later revealed an impairing effect of sulpiride on several retention measures. Sulpiride infused into the NA either 2 hr posttraining in the spatial task or immediately posttraining in a cued water maze task did not affect retention performance. These findings suggest that the impairing effects of immediate posttraining sulpiride in the spatial task are due to interference with spatial water maze-specific consolidation processes involving the NA.

  13. Cocaine exposure reorganizes cell type- and input-specific connectivity in the nucleus accumbens.

    PubMed

    MacAskill, Andrew F; Cassel, John M; Carter, Adam G

    2014-09-01

    Repeated exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we used whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine exposure alters connectivity in the mouse NAc medial shell. Cocaine selectively enhanced amygdala innervation of MSNs expressing D1 dopamine receptors (D1-MSNs) relative to D2-MSNs. We also found that amygdala activity was required for cocaine-induced changes to behavior and connectivity. Finally, we established how heightened amygdala innervation can explain the structural and functional changes evoked by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell type- and input-specific connectivity in the NAc.

  14. Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward

    PubMed Central

    Al-Hasani, Ream; McCall, Jordan G.; Shin, Gunchul; Gomez, Adrian M.; Schmitz, Gavin P.; Bernardi, Julio M.; Pyo, Chang-O.; Park, Sung Il; Marcinkiewcz, Catherine M.; Crowley, Nicole A.; Krashes, Michael J.; Lowell, Bradford B.; Kash, Thomas L.; Rogers, John A.; Bruchas, Michael R.

    2015-01-01

    SUMMARY The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and were positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease. PMID:26335648

  15. Cocaine Exposure Reorganizes Cell-Type and Input-Specific Connectivity in the Nucleus Accumbens

    PubMed Central

    MacAskill, Andrew F.; Cassel, John M.; Carter, Adam G.

    2014-01-01

    Exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the Nucleus Accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we use whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine alters connectivity in the mouse NAc medial shell. We first determine that cocaine selectively enhances amygdala innervation of D1-MSNs relative to D2-MSNs. We then show that amygdala activity is required for cocaine-induced changes to behavior and connectivity. Finally, we establish how heightened amygdala innervation can explain the structural and functional changes induced by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell-type and input-specific connectivity in the NAc. PMID:25108911

  16. Specification for the VERA Depletion Benchmark Suite

    SciTech Connect

    Kim, Kang Seog

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  17. High homocysteine induces betaine depletion.

    PubMed

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J

    2015-04-28

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

  18. Gulf war depleted uranium risks.

    PubMed

    Marshall, Albert C

    2008-01-01

    US and British forces used depleted uranium (DU) in armor-piercing rounds to disable enemy tanks during the Gulf and Balkan Wars. Uranium particulate is generated by DU shell impact and particulate entrained in air may be inhaled or ingested by troops and nearby civilian populations. As uranium is slightly radioactive and chemically toxic, a number of critics have asserted that DU exposure has resulted in a variety of adverse health effects for exposed veterans and nearby civilian populations. The study described in this paper used mathematical modeling to estimate health risks from exposure to DU during the 1991 Gulf War for both US troops and nearby Iraqi civilians. The analysis found that the risks of DU-induced leukemia or birth defects are far too small to result in an observable increase in these health effects among exposed veterans or Iraqi civilians. The analysis indicated that only a few ( approximately 5) US veterans in vehicles accidentally targeted by US tanks received significant exposure levels, resulting in about a 1.4% lifetime risk of DU radiation-induced fatal cancer (compared with about a 24% risk of a fatal cancer from all other causes). These veterans may have also experienced temporary kidney damage. Iraqi children playing for 500 h in DU-destroyed vehicles are predicted to incur a cancer risk of about 0.4%. In vitro and animal tests suggest the possibility of chemically induced health effects from DU internalization, such as immune system impairment. Further study is needed to determine the applicability of these findings for Gulf War exposure to DU. Veterans and civilians who did not occupy DU-contaminated vehicles are unlikely to have internalized quantities of DU significantly in excess of normal internalization of natural uranium from the environment.

  19. Serotonergic antidepressants decrease hedonic signals but leave learning signals in the nucleus accumbens unaffected.

    PubMed

    Graf, Heiko; Metzger, Coraline D; Walter, Martin; Abler, Birgit

    2016-01-01

    Investigating the effects of serotonergic antidepressants on neural correlates of visual erotic stimulation revealed decreased reactivity within the dopaminergic reward network along with decreased subjective sexual functioning compared with placebo. However, a global dampening of the reward system under serotonergic drugs is not intuitive considering clinical observations of their beneficial effects in the treatment of depression. Particularly, learning signals as coded in prediction error processing within the dopaminergic reward system can be assumed to be rather enhanced as antidepressant drugs have been demonstrated to facilitate the efficacy of psychotherapeutic interventions relying on learning processes. Within the same study sample, we now explored the effects of serotonergic and dopaminergic/noradrenergic antidepressants on prediction error signals compared with placebo by functional MRI. A total of 17 healthy male participants (mean age: 25.4 years) were investigated under the administration of paroxetine, bupropion and placebo for 7 days each within a randomized, double-blind, within-subject cross-over design. During functional MRI, we used an established monetary incentive task to explore neural prediction error signals within the bilateral nucleus accumbens as region of interest within the dopaminergic reward system. In contrast to diminished neural activations and subjective sexual functioning under the serotonergic agent paroxetine under visual erotic stimulation, we revealed unaffected or even enhanced neural prediction error processing within the nucleus accumbens under this antidepressant along with unaffected behavioural processing. Our study provides evidence that serotonergic antidepressants facilitate prediction error signalling and may support suggestions of beneficial effects of these agents on reinforced learning as an essential element in behavioural psychotherapy. PMID:26555033

  20. The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.

    PubMed

    Barrot, M; Marinelli, M; Abrous, D N; Rougé-Pont, F; Le Moal, M; Piazza, P V

    2000-03-01

    The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos-like proteins selectively in the shell in response to cocaine. However, the induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain. PMID:10762327

  1. Alterations in ethanol-induced accumbal transmission after acute and long-term zinc depletion.

    PubMed

    Morud, Julia; Adermark, Louise; Ericson, Mia; Söderpalm, Bo

    2015-01-01

    Alcoholism is subject to extensive research, but the role of changes in metabolism caused by alcohol consumption has been poorly investigated. Zinc (Zn(2+) ) deficiency is a common metabolic aberration among alcoholics and Zn(2+) influences the function of ligand-gated ion channels, known pharmacological targets of ethanol (EtOH). Here, we investigate whether manipulation of extracellular levels of Zn(2+) modulates EtOH-induced increases of dopamine (DA) output, as measured by in vivo microdialysis in the rat, and whether voluntary EtOH consumption is altered by Zn(2+) deficiency. Our findings show that the Zn(2+) -chelating agent tricine slowly raises DA levels when perfused in the nucleus accumbens (nAc), whereas the more potent Zn(2+) chelator TPEN reduces DA levels. We also show that pre-treatment with either tricine or TPEN blocks the EtOH-induced DA elevation. Chronic Zn(2+) deficiency induced by a Zn(2+) -free diet did not affect EtOH consumption, but excitatory transmission, assessed by striatal field-potential recordings in the nAc shell, was significantly modulated both by Zn(2+) -free diet and by EtOH consumption, as compared with the EtOH naïve controls. The present study indicates that Zn(2+) influences EtOH's interaction with the brain reward system, possibly by interfering with glycine receptor and GABAA receptor function. This also implies that Zn(2+) deficiency among alcoholics may be important to correct in order to normalize important aspects of brain function.

  2. Mesocortical dopamine depletion and anxiety-related behavior in the rat: sex and hemisphere differences.

    PubMed

    Sullivan, R M; Dufresne, M M; Siontas, D; Chehab, S; Townsend, J; Laplante, F

    2014-10-01

    The mesocortical dopamine (DA) system of the rat plays an important role in prefrontal cortex (PFC) regulation of stress and emotion and exhibits functional hemispheric asymmetry for such processing. Since few studies examine sex differences in this context, we compared the effects of left vs. right unilateral PFC DA depletion in males and females in several behavioral situations associated with anxiety or aversion. Adult rats received unilateral injections of 6-hydroxydopamine (6-OHDA) or vehicle in the ventromedial (vm) PFC. Behavioral tests included a predator odor burying test, elevated plus maze and sucrose consumption with simple taste aversion. Tissue analysis confirmed that vmPFCs injected with 6-OHDA were depleted of DA (75-85%) compared to controls. Burying behavior and sucrose consumption were affected only by left lesions, similarly in both sexes. However, risk assessment behaviors were affected by right lesions in opposite directions in males and females. Behaviors modified preferentially by the left cortex thus showed less evidence of sex differences than those modulated by the right. While mesocortical DA depletion effects are lateralized, the nature of these effects can vary with sex and specific behavior. Such findings may be clinically significant, given the large gender differences in the incidence of mood and anxiety disorders, which also show many lateralized prefrontal abnormalities. PMID:24819821

  3. A parallel algorithm for implicit depletant simulations

    NASA Astrophysics Data System (ADS)

    Glaser, Jens; Karas, Andrew S.; Glotzer, Sharon C.

    2015-11-01

    We present an algorithm to simulate the many-body depletion interaction between anisotropic colloids in an implicit way, integrating out the degrees of freedom of the depletants, which we treat as an ideal gas. Because the depletant particles are statistically independent and the depletion interaction is short-ranged, depletants are randomly inserted in parallel into the excluded volume surrounding a single translated and/or rotated colloid. A configurational bias scheme is used to enhance the acceptance rate. The method is validated and benchmarked both on multi-core processors and graphics processing units for the case of hard spheres, hemispheres, and discoids. With depletants, we report novel cluster phases in which hemispheres first assemble into spheres, which then form ordered hcp/fcc lattices. The method is significantly faster than any method without cluster moves and that tracks depletants explicitly, for systems of colloid packing fraction ϕc < 0.50, and additionally enables simulation of the fluid-solid transition.

  4. Fully Depleted Charge-Coupled Devices

    SciTech Connect

    Holland, Stephen E.

    2006-05-15

    We have developed fully depleted, back-illuminated CCDs thatbuild upon earlier research and development efforts directed towardstechnology development of silicon-strip detectors used inhigh-energy-physics experiments. The CCDs are fabricated on the same typeof high-resistivity, float-zone-refined silicon that is used for stripdetectors. The use of high-resistivity substrates allows for thickdepletion regions, on the order of 200-300 um, with corresponding highdetection efficiency for near-infrared andsoft x-ray photons. We comparethe fully depleted CCD to thep-i-n diode upon which it is based, anddescribe the use of fully depleted CCDs in astronomical and x-ray imagingapplications.

  5. Possible ozone depletions following nuclear explosions

    NASA Technical Reports Server (NTRS)

    Whitten, R. C.; Borucki, W. J.; Turco, R. P.

    1975-01-01

    The degree of depletion of the ozone layer ensuing after delivery of strategic nuclear warheads (5000 and 10,000 Mton) due to production of nitrogen oxides is theoretically assessed. Strong depletions are calculated for 16-km and 26-km altitudes, peaking 1-2 months after detonation and lasting for three years, while a significant depletion at 36 km would peak after one year. Assuming the explosions occur between 30 and 70 deg N, these effects should be much more pronounced in this region than over the Northern Hemisphere as a whole. It is concluded that Hampson's concern on this matter (1974) is well-founded.-

  6. In Vivo Depletion of T Lymphocytes.

    PubMed

    Laky, Karen; Kruisbeek, Ada M

    2016-01-01

    In vivo depletion of T lymphocytes is a means of studying the role of specific T cell populations during defined phases of in vivo immune responses. In this unit, a protocol is provided for injecting monoclonal antibodies (mAbs) into wild-type adult mice. Depletion of the appropriate subset of cells is verified by flow cytometry analysis of lymph node and spleen cell suspensions in pilot experiments. Once conditions have been established, depleted mice can be used to study the impact of T cell subsets on a variety of in vivo immune responses. The depleted condition may be maintained by repeated injections of the monoclonal antibody, or reversed by normal thymopoiesis following discontinuation of antibody administration. PMID:27038463

  7. A definition of depletion of fish stocks

    USGS Publications Warehouse

    Van Oosten, John

    1949-01-01

    Attention was focused on the need of a common and better understanding of the term depletion as applied to the fisheries in order to eliminate if possible the existing inexactness of thought on the subject. Depletion has been confused at various times with at least ten different ideas associated with it but which, as has has heen pointed out, are not synonymous at all. In defining depletion we must recognize that the term represents a condition and must not he confounded with the cause (overfishing) that leads to this condition or with the symptoms that identify it. Depletion was defined as a reduction, through overfishing, in the level of abundance of the exploitable segment of a stock that prevents the realization of the maximum productive capacity.

  8. Silicon Depletion in the Interstellar Medium

    NASA Astrophysics Data System (ADS)

    Haris, U.; Parvathi, V. S.; Gudennavar, S. B.; Bubbly, S. G.; Murthy, J.; Sofia, U. J.

    2016-06-01

    We report interstellar silicon (Si) depletion and dust-phase column densities of Si along 131 Galactic sight lines using archival observations. The data were corrected for differences in the assumed oscillator strength. This is a much larger sample than previous studies but confirms the majority of results, which state that the depletion of Si is correlated with the average density of hydrogen along the line of sight (< n({{H}})> ) as well as the fraction of hydrogen in molecular form (f(H2)). We also find that the linear part of the extinction curve is independent of Si depletion. Si depletion is correlated with the bump strength (c3/RV) and the FUV curvature (c4/RV) suggesting that silicon plays a significant role in both the 2175 Å bump and the FUV rise.

  9. Polar stratospheric clouds and ozone depletion

    NASA Technical Reports Server (NTRS)

    Toon, Owen B.; Turco, Richard P.

    1991-01-01

    A review is presented of investigations into the correlation between the depletion of ozone and the formation of polar stratospheric clouds (PSCs). Satellite measurements from Nimbus 7 showed that over the years the depletion from austral spring to austral spring has generally worsened. Approximately 70 percent of the ozone above Antarctica, which equals about 3 percent of the earth's ozone, is lost during September and October. Various hypotheses for ozone depletion are discussed including the theory suggesting that chlorine compounds might be responsible for the ozone hole, whereby chlorine enters the atmosphere as a component of chlorofluorocarbons produced by humans. The three types of PSCs, nitric acid trihydrate, slowly cooling water-ice, and rapidly cooling water-ice clouds act as important components of the Antarctic ozone depletion. It is indicated that destruction of the ozone will be more severe each year for the next few decades, leading to a doubling in area of the Antarctic ozone hole.

  10. The NMDA receptor antagonist CPP suppresses long-term potentiation in the rat hippocampal-accumbens pathway in vivo.

    PubMed

    Feasey-Truger, K J; ten Bruggencate, G

    1994-08-01

    Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (N1) with a peak latency of 8-10 ms, followed by a second negative-going peak (N2) with a latency of 22-24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by approximately 20 and 50% respectively. Administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45-60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7981867

  11. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.

    PubMed

    Nealey, Kathryn A; Smith, Alexander W; Davis, Seth M; Smith, Daniel G; Walker, Brendan M

    2011-01-01

    Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable

  12. Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens

    PubMed Central

    Rose, Jamie H.; Karkhanis, Anushree N.; Chen, Rong; Gioia, Dominic; Lopez, Marcelo F.; Becker, Howard C.; McCool, Brian A.

    2016-01-01

    Background: Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Methods: Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. Results: Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. Conclusions: These data suggest that the chronic intermittent ethanol-induced increase

  13. Excessive disgust caused by brain lesions or temporary inactivations: Mapping hotspots of nucleus accumbens and ventral pallidum

    PubMed Central

    Ho, Chao-Yi; Berridge, Kent C.

    2014-01-01

    Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense ‘disgust reactions’ (e.g., gapes) to a normally pleasant sensation such as sweetness. Here we aimed to map forebrain candidates more precisely to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol-baclofen microinjections) caused rats to emit excessive sensory disgust reactions to sucrose. Our study compared subregions of nucleus accumbens shell, ventral pallidum, lateral hypothalamus and adjacent extended amygdala. Results indicated the posterior half of ventral pallidum to be the only forebrain site where intense sensory disgust gapes to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness ‘liking’). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust but lesions never did at any site. Further, even inactivations failed to induce disgust in the rostral half of accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior versus rostral halves of medial shell. PMID:25229197

  14. A theoretical model of atmospheric ozone depletion

    NASA Astrophysics Data System (ADS)

    Midya, S. K.; Jana, P. K.; Lahiri, T.

    1994-01-01

    A critical study on different ozone depletion and formation processes has been made and following important results are obtained: (i) From analysis it is shown that O3 concentration will decrease very minutely with time for normal atmosphere when [O], [O2] and UV-radiation remain constant. (ii) An empirical equation is established theoretically between the variation of ozone concentration and time. (iii) Special ozone depletion processes are responsible for the dramatic decrease of O3-concentration at Antarctica.

  15. Depleted uranium: A DOE management guide

    SciTech Connect

    1995-10-01

    The U.S. Department of Energy (DOE) has a management challenge and financial liability in the form of 50,000 cylinders containing 555,000 metric tons of depleted uranium hexafluoride (UF{sub 6}) that are stored at the gaseous diffusion plants. The annual storage and maintenance cost is approximately $10 million. This report summarizes several studies undertaken by the DOE Office of Technology Development (OTD) to evaluate options for long-term depleted uranium management. Based on studies conducted to date, the most likely use of the depleted uranium is for shielding of spent nuclear fuel (SNF) or vitrified high-level waste (HLW) containers. The alternative to finding a use for the depleted uranium is disposal as a radioactive waste. Estimated disposal costs, utilizing existing technologies, range between $3.8 and $11.3 billion, depending on factors such as applicability of the Resource Conservation and Recovery Act (RCRA) and the location of the disposal site. The cost of recycling the depleted uranium in a concrete based shielding in SNF/HLW containers, although substantial, is comparable to or less than the cost of disposal. Consequently, the case can be made that if DOE invests in developing depleted uranium shielded containers instead of disposal, a long-term solution to the UF{sub 6} problem is attained at comparable or lower cost than disposal as a waste. Two concepts for depleted uranium storage casks were considered in these studies. The first is based on standard fabrication concepts previously developed for depleted uranium metal. The second converts the UF{sub 6} to an oxide aggregate that is used in concrete to make dry storage casks.

  16. Dopamine, Behavioral Economics, and Effort

    PubMed Central

    Salamone, John D.; Correa, Merce; Farrar, Andrew M.; Nunes, Eric J.; Pardo, Marta

    2009-01-01

    There are numerous problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements). Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders. PMID:19826615

  17. Dopamine, behavioral economics, and effort.

    PubMed

    Salamone, John D; Correa, Merce; Farrar, Andrew M; Nunes, Eric J; Pardo, Marta

    2009-01-01

    There are numerous problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements). Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders. PMID:19826615

  18. Dopamine, behavioral economics, and effort.

    PubMed

    Salamone, John D; Correa, Merce; Farrar, Andrew M; Nunes, Eric J; Pardo, Marta

    2009-01-01

    There are numerous problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements). Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders.

  19. The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens.

    PubMed

    Velázquez-Sánchez, Clara; García-Verdugo, José M; Murga, Juan; Canales, Juan J

    2013-07-01

    Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been postulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psychomotor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimulant abuse. The results indicated that JHW007 did not produce sensitized locomotor activity when given alone but prevented the sensitized motor behavior induced by chronic AMPH administration. Morphological analysis of medium spiny neurons of the nucleus accumbens revealed that JHW 007 prevented the neuroadaptations induced by chronic AMPH exposure, including increments in dendritic arborization, lengthening of dendritic processes and increases in spine density. Furthermore, data revealed that AMPH produced an increase in the density of asymmetric, possibly glutamatergic synapses in the nucleus accumbens, an effect that was also blocked by JHW007 pretreatment. The present observations demonstrate that JHW007 is able to prevent not only AMPH-induced behavioral sensitization but also the long-term structural changes induced by chronic AMPH in the nucleus accumbens. Such findings support the development and evaluation of BZT derivatives as possible leads for treatment in stimulant addiction.

  20. Intra-accumbens injection of a dopamine aptamer abates MK-801-induced cognitive dysfunction in a model of schizophrenia.

    PubMed

    Holahan, Matthew R; Madularu, Dan; McConnell, Erin M; Walsh, Ryan; DeRosa, Maria C

    2011-01-01

    Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

  1. GSK-3β inhibitors reverse cocaine-induced synaptic transmission dysfunction in the nucleus accumbens.

    PubMed

    Zhao, Rui; Chen, Jiaojiao; Ren, Zhaoxiang; Shen, Hui; Zhen, Xuechu

    2016-11-01

    Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion. PMID:27377051

  2. Nucleus Accumbens Core and Shell Differentially Encode Reward-Associated Cues after Reinforcer Devaluation

    PubMed Central

    West, Elizabeth A.

    2016-01-01

    Nucleus accumbens (NAc) neurons encode features of stimulus learning and action selection associated with rewards. The NAc is necessary for using information about expected outcome values to guide behavior after reinforcer devaluation. Evidence suggests that core and shell subregions may play dissociable roles in guiding motivated behavior. Here, we recorded neural activity in the NAc core and shell during training and performance of a reinforcer devaluation task. Long–Evans male rats were trained that presses on a lever under an illuminated cue light delivered a flavored sucrose reward. On subsequent test days, each rat was given free access to one of two distinctly flavored foods to consume to satiation and were then immediately tested on the lever pressing task under extinction conditions. Rats decreased pressing on the test day when the reinforcer earned during training was the sated flavor (devalued) compared with the test day when the reinforcer was not the sated flavor (nondevalued), demonstrating evidence of outcome-selective devaluation. Cue-selective encoding during training by NAc core (but not shell) neurons reliably predicted subsequent behavioral performance; that is, the greater the percentage of neurons that responded to the cue, the better the rats suppressed responding after devaluation. In contrast, NAc shell (but not core) neurons significantly decreased cue-selective encoding in the devalued condition compared with the nondevalued condition. These data reveal that NAc core and shell neurons encode information differentially about outcome-specific cues after reinforcer devaluation that are related to behavioral performance and outcome value, respectively. SIGNIFICANCE STATEMENT Many neuropsychiatric disorders are marked by impairments in behavioral flexibility. Although the nucleus accumbens (NAc) is required for behavioral flexibility, it is not known how NAc neurons encode this information. Here, we recorded NAc neurons during a training

  3. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor.

    PubMed

    Zernig, Gerald; Pinheiro, Barbara S

    2015-09-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  4. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor

    PubMed Central

    Pinheiro, Barbara S.

    2015-01-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  5. Age Moderates the Effect of Acute Dopamine Depletion on Passive Avoidance Learning

    PubMed Central

    Kelm, Mary Katherine; Boettiger, Charlotte Ann

    2015-01-01

    Despite extensive links between reinforcement-based learning and dopamine (DA), studies to date have not found consistent effects of acute DA reduction on reinforcement learning in both men and women. Here, we tested the effects of reducing DA on reward- and punishment-based learning using the deterministic passive avoidance learning (PAL) task We tested 16 (5 female) adults (ages 22–40) in a randomized, cross-over design to determine whether reducing global DA by administering an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[−]), would affect performance on the PAL task. We found that P/T[−] beverage effects on PAL performance were modulated by age. In particular, we found that P/T depletion significantly improved learning from punishment with increasing participant age. Participants committed 1.49 fewer passive avoidance errors per additional year of age (95% CI, −0.71 – −2.27, r=−0.74, p=0.001). Moreover, in this small sample, P/T depletion improved learning from punishment in adults (ages 26–40) while it impaired learning from punishment in emerging adults (ages 22–25). We observed similar, but non-significant trends in learning from reward. While there was no overall effect of P/T-depletion on reaction time (RT), there was a relationship between the effect of P/T depletion on PAL performance and RT; those who responded more slowly on the P/T[−] beverage also made more errors on the P/T[−] beverage. When P/T-depletion slowed RT after a correct response, there was a worsening of PAL task performance; there was no similar relationship for the RT after an incorrect response and PAL task performance. Moreover, among emerging adults, changes in mood on the P/T[−] beverage negatively correlated with learning from reward on the P/T[−] beverage. Together, we found that both reward- and punishment-based learning are sensitive to central catecholamine levels, and that these effects of acute DA reduction vary

  6. Nucleus accumbens deep brain stimulation in a rat model of binge eating

    PubMed Central

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a ‘chronic BE' model as well as in a ‘relapse to chronic BE' model. Male Sprague–Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5–7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior. PMID:26670280

  7. Differential Dopamine Regulation of Ca2+ Signaling and Its Timing Dependence in the Nucleus Accumbens

    PubMed Central

    Swapna, Immani; Bondy, Brian; Morikawa, Hitoshi

    2016-01-01

    SUMMARY Dopamine action in the nucleus accumbens (NAc) is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs) of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR)-induced Ca2+ signaling dependent on the Ca2+- releasing messenger inositol 1,4,5-triphosphate (IP3) plays a critical role in controlling neuronal excitability and synaptic plasticity. Here, we show that transient dopamine application facilitates mGluR/IP3-induced Ca2+ signals within a time window of ~2–10 s in a subpopulation of MSNs in the NAc core. Dopamine facilitation of IP3-induced Ca2+ signaling is mediated by D1 dopamine receptors. In dopamine-insensitive MSNs, activation of A2A adenosine receptors causes enhancement of IP3-evoked Ca2+ signals, which is reversed by D2 dopamine receptor activation. These results show that dopamine differentially regulates Ca2+ signaling on the order of seconds in two distinct MSN subpopulations. PMID:27068462

  8. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    NASA Astrophysics Data System (ADS)

    Albaugh, Daniel L.; Salzwedel, Andrew; van den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-09-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action.

  9. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit.

    PubMed

    Ramaekers, J G; Evers, E A; Theunissen, E L; Kuypers, K P C; Goulas, A; Stiers, P

    2013-09-01

    Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.

  10. Effects of nucleus accumbens core and shell lesions on autoshaped lever-pressing

    PubMed Central

    Chang, Stephen E.; Holland, Peter C.

    2013-01-01

    Certain Pavlovian conditioned stimuli (CSs) paired with food unconditioned stimuli (USs) come to elicit approach and even consumption-like behaviors in rats (sign-tracking). We investigated the effects of lesions of the nucleus accumbens core (ACbC) or shell (ACbS) on the acquisition of sign-tracking in a discriminative autoshaping procedure in which presentation of one lever CS was followed by delivery of sucrose, and another was not. Although we previously found that bilateral lesions of the whole ACb disrupted the initial acquisition of sign-tracking, neither ACbC or ACbS lesions affected the rate or percentage of trials in which rats pressed the CS+. In addition, detailed video analysis showed no effect of either lesion on the topography of the sign-tracking conditioned response (CR). These and other results from lesion studies of autoshaping contrast with those from previous sign-tracking experiments that used purely visual cues (Parkinson, Robbins, and Everitt, 2000a; Parkinson, Willoughby, Robbins, and Everitt, 2000b), suggesting that the neural circuitry involved in assigning incentive value depends upon the nature of the CS. PMID:23933141

  11. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    PubMed Central

    Albaugh, Daniel L.; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  12. Phasic dopamine release in the rat nucleus accumbens symmetrically encodes a reward prediction error term.

    PubMed

    Hart, Andrew S; Rutledge, Robb B; Glimcher, Paul W; Phillips, Paul E M

    2014-01-15

    Making predictions about the rewards associated with environmental stimuli and updating those predictions through feedback is an essential aspect of adaptive behavior. Theorists have argued that dopamine encodes a reward prediction error (RPE) signal that is used in such a reinforcement learning process. Recent work with fMRI has demonstrated that the BOLD signal in dopaminergic target areas meets both necessary and sufficient conditions of an axiomatic model of the RPE hypothesis. However, there has been no direct evidence that dopamine release itself also meets necessary and sufficient criteria for encoding an RPE signal. Further, the fact that dopamine neurons have low tonic firing rates that yield a limited dynamic range for encoding negative RPEs has led to significant debate about whether positive and negative prediction errors are encoded on a similar scale. To address both of these issues, we used fast-scan cyclic voltammetry to measure reward-evoked dopamine release at carbon fiber electrodes chronically implanted in the nucleus accumbens core of rats trained on a probabilistic decision-making task. We demonstrate that dopamine concentrations transmit a bidirectional RPE signal with symmetrical encoding of positive and negative RPEs. Our findings strengthen the case that changes in dopamine concentration alone are sufficient to encode the full range of RPEs necessary for reinforcement learning.

  13. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression

    PubMed Central

    Bagot, Rosemary C.; Parise, Eric M.; Peña, Catherine J.; Zhang, Hong-Xing; Maze, Ian; Chaudhury, Dipesh; Persaud, Brianna; Cachope, Roger; Bolaños-Guzmán, Carlos A.; Cheer, Joseph; Deisseroth, Karl; Han, Ming-Hu; Nestler, Eric J.

    2015-01-01

    Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression. PMID:25952660

  14. Influence of olfactory bulbectomy on maternal behavior and dopaminergic function in nucleus accumbens in mice.

    PubMed

    Sato, Atsushi; Nakagawasai, Osamu; Tan-No, Koichi; Onogi, Hiroshi; Niijima, Fukie; Tadano, Takeshi

    2010-12-20

    Olfactory bulbectomy (OBX) induces behavioral, physiological, and neurochemical alterations resembling clinical depression and is widely used as an animal model of depression. It has been reported that depression is a critical cause of child abuse and neglect and that maternal behavior involves dopaminergic neurons of the mesolimbic pathway. In a previous study we found that OBX mice show maternal behavior deficits which are improved by administration of apomorphine, a non-selective dopamine agonist. Therefore, in this study, we investigated the effect of l-3,4-dihydroxyphenylalanine (l-DOPA) on maternal behavior deficits to examine the influence of pre-synaptic dopaminergic function in OBX mice. Furthermore, we measured tyrosine hydroxylase (TH) levels using microphotometry and quantified dopamine D1- and D2-like receptors using autoradiography in the nucleus accumbens (NAc). As a result, 25mg/kg l-DOPA with 12.5mg/kg benserazide improved disrupted maternal behavior in OBX mice and there are no changes in TH levels or number of D1- and D2-like receptors between sham and OBX mothers. The behavioral data support the hypothesis that changed dopaminergic function may contribute to maternal behavior deficits in OBX mice. However, our findings concerning dopaminergic function suggest that the deficits in OBX mice are not simply due to changes in TH levels or dopamine receptor number in the NAc. PMID:20638419

  15. Selecting danger signals: dissociable roles of nucleus accumbens shell and core glutamate in predictive fear learning.

    PubMed

    Li, Susan S Y; McNally, Gavan P

    2015-06-01

    Conditioned stimuli (CSs) vary in their reliability as predictors of danger. Animals must therefore select among CSs those that are appropriate to enter into an association with the aversive unconditioned stimulus (US). The actions of prediction error instruct this stimulus selection so that when prediction error is large, attention to the CS is maintained and learning occurs but when prediction is small attention to the CS is withdrawn and learning is prevented. Here we studied the role of glutamate acting at rat nucleus accumbens shell (AcbSh) and core (AcbC) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in this selection of danger signals. Using associative blocking and unblocking designs in rats, we show that antagonizing AcbSh AMPA receptors via infusions of 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX; 0.5 μg) prevents the unblocking of fear learning, whereas antagonizing AcbC AMPA receptors via infusions of NBQX (0.5 μg) prevents both the blocking and unblocking of fear learning. These results identify dissociable but complementary roles for AcbSh and AcbC glutamate acting at AMPA receptors in selecting danger signals: AcbSh AMPA receptors upregulate attention and learning to CSs that signal surprising USs, whereas AcbC AMPA receptors encode the predicted outcome of each trial.

  16. Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

    PubMed

    Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M

    2014-10-01

    Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior.

  17. Activation in the VTA and Nucleus Accumbens Increases in Anticipation of Both Gains and Losses

    PubMed Central

    Carter, R. McKell; MacInnes, Jeff J.; Huettel, Scott A.; Adcock, R. Alison

    2009-01-01

    To represent value for learning and decision making, the brain must encode information about both the motivational relevance and affective valence of anticipated outcomes. The nucleus accumbens (NAcc) and ventral tegmental area (VTA) are thought to play key roles in representing these and other aspects of valuation. Here, we manipulated the valence (i.e., monetary gain or loss) and personal relevance (i.e., self-directed or charity-directed) of anticipated outcomes within a variant of the monetary incentive delay task. We scanned young-adult participants using functional magnetic resonance imaging (fMRI), utilizing imaging parameters targeted for the NAcc and VTA. For both self-directed and charity-directed trials, activation in the NAcc and VTA increased to anticipated gains, as predicted by prior work, but also increased to anticipated losses. Moreover, the magnitude of responses in both regions was positively correlated for gains and losses, across participants, while an independent reward-sensitivity covariate predicted the relative difference between and gain- and loss-related activation on self-directed trials. These results are inconsistent with the interpretation that these regions reflect anticipation of only positive-valence events. Instead, they indicate that anticipatory activation in reward-related regions largely reflects the motivational relevance of an upcoming event. PMID:19753142

  18. Prefrontal cortex modulates desire and dread generated by nucleus accumbens glutamate disruption

    PubMed Central

    Richard, Jocelyn M.; Berridge, Kent. C

    2012-01-01

    Background Corticolimbic circuits, including direct projections from prefrontal cortex to nucleus accumbens (NAc), permit “top-down” control of intense motivations generated by subcortical circuits. In rats, localized disruptions of glutamate signaling within medial shell of NAc generate desire or dread, anatomically organized along a rostrocaudal gradient analogous to a limbic “keyboard”. At rostral locations in shell these disruptions generate appetitive eating, but at caudal locations the disruptions generate progressively fearful behaviors (distress vocalizations, escape attempts and antipredator reactions). Here we asked whether medial prefrontal cortex can modulate intense motivations generated by subcortical NAc disruptions. Methods We used simultaneous microinjections in medial prefrontal cortex regions and in NAc shell to examine whether the desire or dread generated by NAc shell disruptions is modulated by activation/inhibition of three specific regions of prefrontal cortex: medial orbitofrontal cortex, infralimbic cortex (homologous to area 25 or subgenual anterior cingulate in the human), or prelimbic cortex (midventral anterior cingulate). Results We found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by amplifying generation of eating behavior by middle to caudal NAc disruptions, without altering fear. In contrast, activation of infralimbic prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by NAc shell disruptions. Conclusions These results suggest that corticolimbic projections from discrete prefrontal regions can either bias motivational valence or generally suppress subcortically-generated intense motivations of desire or fear. PMID:22981656

  19. Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

    SciTech Connect

    Goeders, N.E.; Kuhar, M.J.

    1987-01-01

    A variety of clinical and animal data suggest that the repeated administration of cocaine and related psychomotor stimulants may be associated with a behavioral sensitization whereby the same dose of the drug results in increasing behavioral pathology. This investigation was designed to determine the effects of chronic cocaine administration on the binding of (/sup 3/H)sulpiride, a relatively specific ligand for D2 dopaminergic receptors, in the rat brain using in vitro homogenate binding and light microscopic quantitative autoradiographic methodologies. Chronic daily injections of cocaine (10 mg/kg, i.p.) for 15 days resulted in a significant decrease in the maximum concentration of sulpiride binding sites in the striatum and a significant increase in the maximum number of these binding sites in the nucleus accumbens. No significant differences in binding affinity were observed in either brain region. These data suggest that chronic cocaine administration may result in differential effects on D2 receptors in the nigro-striatal and mesolimbic dopaminergic systems.

  20. Nucleus accumbens associated 1 is recruited within the promyelocytic leukemia nuclear body through SUMO modification

    PubMed Central

    Tatemichi, Yoshinori; Shibazaki, Masahiko; Yasuhira, Shinji; Kasai, Shuya; Tada, Hiroshi; Oikawa, Hiroki; Suzuki, Yuji; Takikawa, Yasuhiro; Masuda, Tomoyuki; Maesawa, Chihaya

    2015-01-01

    Nucleus accumbens associated 1 (NACC1) is a cancer-associated BTB/POZ (pox virus and zinc finger/bric-a-brac tramtrack broad complex) gene, and is involved in several cellular functions in neurons, cancer and stem cells. Some of the BTB/POZ proteins associated with cancer biology are SUMOylated, which appears to play an important role in transcription regulation. We show that NACC1 is SUMOylated on a phylogenetically conserved lysine (K167) out of three consensus SUMOylation motif sites. Amino acid substitution in the SIM sequence (SIM/M) within the BTB/POZ domain partially reduced K167 SUMOylation activity of NACC1. Overexpression of GFP-NACC1 fusion protein leads to formation of discrete nuclear foci similar to promyelocytic leukemia nuclear bodies (PML-NB), which colocalized with SUMO paralogues (SUMO1/2/3). Both NACC1 nuclear body formation and colocalization with SUMO paralogues were completely suppressed in the GFP-NACC1-SIM/M mutant, whereas they were partially maintained in the NACC1 K167R mutant. Confocal immunofluorescence analysis showed that endogenous and exogenous NACC1 proteins colocalized with endogenous PML protein. A pull-down assay revealed that the consensus motifs of the SUMO acceptor site at K167 and the SIM within the BTB/POZ domain were both necessary for efficient binding to PML protein. Our study demonstrates that NACC1 can be modified by SUMO paralogues, and cooperates with PML protein. PMID:25891951

  1. AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization.

    PubMed

    Zhu, Yongsheng; Xing, Bo; Dang, Wei; Ji, Yuanyuan; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Lai, Jianghua

    2016-10-01

    Autism susceptibility candidate 2 (AUTS2) is a gene associated with autism and mental retardation. Recent studies have suggested an association of the AUTS2 gene with heroin dependence, and reduced AUTS2 gene expression may confer increased susceptibility to heroin dependence. However, the functional role of the AUTS2 protein in regulating enduring neuroadaptations in response to heroin exposure has not been established. Here, we investigated the effects of acute and chronic heroin exposure on AUTS2 mRNA and protein expression in the nucleus accumbens (NAc) and caudate-putamen (CPu) to determine whether changes in AUTS2 expression are associated with heroin-induced locomotor sensitization in mice. Moreover, we explored whether AUST2 knockdown affects heroin-induced locomotor sensitization. AUTS2 mRNA and protein expression in the NAc, but not the CPu, was decreased after chronic heroin (1mg/kg) administration. In the NAc, the expression of heroin-induced locomotor sensitization was enhanced through the lentiviral-AUTS2-shRNA-mediated knockdown of AUTS2, while the overexpression of AUTS2 attenuated the locomotor-stimulant effects of heroin. Together, these results indicate that AUTS2 in the NAc, but not the CPu, suppresses the initiation and expression of heroin-induced behavioral sensitization, suggesting that AUST2 may be a potential target for the treatment of heroin dependence. PMID:27423627

  2. Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior

    PubMed Central

    du Hoffmann, Johann; Nicola, Saleem M.

    2016-01-01

    Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety. PMID:27471453

  3. Nucleus accumbens deep brain stimulation in a rat model of binge eating.

    PubMed

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5-7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior. PMID:26670280

  4. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

    PubMed

    Trifilieff, P; Feng, B; Urizar, E; Winiger, V; Ward, R D; Taylor, K M; Martinez, D; Moore, H; Balsam, P D; Simpson, E H; Javitch, J A

    2013-09-01

    A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc. PMID:23711983

  5. Reduced nucleus accumbens reactivity and adolescent depression following early-life stress.

    PubMed

    Goff, B; Gee, D G; Telzer, E H; Humphreys, K L; Gabard-Durnam, L; Flannery, J; Tottenham, N

    2013-09-26

    Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention. PMID:23262241

  6. Nucleus Accumbens Mediates Relative Motivation for Rewards in the Absence of Choice

    PubMed Central

    Clithero, John A.; Reeck, Crystal; Carter, R. McKell; Smith, David V.; Huettel, Scott A.

    2011-01-01

    To dissociate a choice from its antecedent neural states, motivation associated with the expected outcome must be captured in the absence of choice. Yet, the neural mechanisms that mediate behavioral idiosyncrasies in motivation, particularly with regard to complex economic preferences, are rarely examined in situations without overt decisions. We employed functional magnetic resonance imaging in a large sample of participants while they anticipated earning rewards from two different modalities: monetary and candy rewards. An index for relative motivation toward different reward types was constructed using reaction times to the target for earning rewards. Activation in the nucleus accumbens (NAcc) and anterior insula (aINS) predicted individual variation in relative motivation between our reward modalities. NAcc activation, however, mediated the effects of aINS, indicating the NAcc is the likely source of this relative weighting. These results demonstrate that neural idiosyncrasies in reward efficacy exist even in the absence of explicit choices, and extend the role of NAcc as a critical brain region for such choice-free motivation. PMID:21941472

  7. Reduced Nucleus Accumbens Reactivity and Adolescent Depression following Early-life Stress

    PubMed Central

    Goff, Bonnie; Gee, Dylan G.; Telzer, Eva H.; Humphreys, Kathryn L.; Gabard-Durnam, Laurel; Flannery, Jessica; Tottenham, Nim

    2013-01-01

    Depression is a common outcome for those having experienced early life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youth without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, fMRI results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention. PMID:23262241

  8. Resting state functional connectivity of the nucleus accumbens in youth with a family history of alcoholism

    PubMed Central

    Cservenka, Anita; Casimo, Kaitlyn; Fair, Damien; Nagel, Bonnie

    2014-01-01

    Adolescents with a family history of alcoholism (FHP) are at heightened risk for developing alcohol use disorders (AUDs). The nucleus accumbens (NAcc), a key brain region for reward processing, is implicated in the development of AUDs. Thus, functional connectivity of the NAcc may be an important marker of risk in FHP youth. Resting state functional magnetic resonance imaging (rs-fcMRI) was used to examine the intrinsic connectivity of the NAcc in 47 FHP and 50 family history negative (FHN) youth, ages 10–16 years old. FHP and FHN adolescents showed significant group differences in resting state synchrony between the left NAcc and bilateral inferior frontal gyri and the left postcentral gyrus (PG). Additionally, FHP youth differed from FHN youth in right NAcc functional connectivity with the left orbitofrontal cortex (OFC), left superior temporal gyrus, right cerebellum, left PG, and right occipital cortex. These results indicate that FHP youth have less segregation between the NAcc and executive functioning brain regions, and less integration with reward-related brain areas, such as the OFC. The findings of the current study highlight that premorbid atypical connectivity of appetitive systems, in the absence of heavy alcohol use, may be a risk marker in FHP adolescents. PMID:24440571

  9. Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

    PubMed

    Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M

    2014-10-01

    Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior. PMID:25244086

  10. Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

    PubMed

    Mátyás, Ferenc; Watanabe, Masahiko; Mackie, Ken; Katona, István; Freund, Tamás F

    2007-03-30

    Several abused drugs are known to alter glutamatergic signaling in reward pathways of the brain, and these plastic changes may contribute to the establishment of addiction-related behaviour. Glutamatergic synapses of the prefrontal cortical projections to the nucleus accumbens (nAcb)--which are suggested to be under endocannabinoid (eCB) control - play a central role in the addiction process. The most abundant eCB in the brain is 2-arachi-donoyl-glycerol (2-AG). It is synthesized by diacylglycerol lipase alpha (DGL-alpha), and exerts its action via type 1 cannabinoid receptors (CB1). However, the precise localization of DGL-alpha and CB1 - i.e. the sites of synthesis and action of 2AG - is still unknown. At the light microscopic level, immunocytochemistry revealed a granular pattern of DGL-alpha distribution in the core of the nAcb. Electron microscopic analysis confirmed that these granules corresponded to the heads of dendritic spines. On the other hand, presynaptic axon terminals forming excitatory synapses on these spineheads were found to express CB1 receptors. Our results demonstrate that the molecular constituents for a retrograde endocannabinoid control of glutamatergic transmission are available in the core of the nAcb, and their relative subcellular location is consistent with a role of 2-AG in addiction-related plasticity of cortical excitatory synapses in this reward area.

  11. Bidirectional modulation of cocaine-expectancy by phasic glutamate fluctuations in the nucleus accumbens

    PubMed Central

    Suto, Nobuyoshi; Elmer, Greg I.; Wang, Bin; You, Zhi-Bing; Wise, Roy A.

    2013-01-01

    While glutamate in the nucleus accumbens (NAS) contributes to the promotion of drug-seeking by drug-predictive cues, it also appears to play a role in the inhibition of drug-seeking following extinction procedures. Thus we measured extracellular fluctuations of NAS glutamate in response to discriminative stimuli that signaled either cocaine availability or cocaine omission. We trained rats to self-administer intravenous cocaine and then to recognize discriminative odor cues that predicted either sessions where cocaine was available or alternating sessions where it was not (saline substituted for cocaine). Whereas responding in cocaine availability sessions remained stable, responding in cocaine omission sessions progressively declined to chance levels. We then determined the effects of each odor cue on extracellular glutamate in the core and shell subregions of NAS preceding and accompanying lever-pressing under an extinction condition. Glutamate levels were elevated in both core and shell by the availability odor and depressed in the core but not the shell by the omission odor. Infusion of kynurenic acid (an antagonist for ionotropic glutamate receptors) into core but not shell suppressed responding associated with the availability odor, but had no effect on the suppression associated with the omission odor. Thus cocaine-predictive cues appear to promote cocaine-seeking in part by elevating glutamatergic neurotransmission in the core of NAS, whereas cocaine-omission cues appear to suppress cocaine-seeking in part by depressing glutamatergic receptor activation in the same region. PMID:23699516

  12. Differential contributions of infralimbic prefrontal cortex and nucleus accumbens during reward-based learning and extinction.

    PubMed

    Francois, Jennifer; Huxter, John; Conway, Michael W; Lowry, John P; Tricklebank, Mark D; Gilmour, Gary

    2014-01-01

    Using environmental cues for the prediction of future events is essential for survival. Such cue-outcome associations are thought to depend on mesolimbic circuitry involving the nucleus accumbens (NAc) and prefrontal cortex (PFC). Several studies have identified roles for both NAc and PFC in the expression of stable goal-directed behaviors, but much remains unknown about their roles during learning of such behaviors. To further address this question, we used in vivo oxygen amperometry, a proxy for blood oxygen level-dependent (BOLD) signal measurement in human functional magnetic resonance imaging, in rats performing a cued lever-pressing task requiring discrimination between a rewarded and nonrewarded cue. Simultaneous oxygen recordings were obtained from infralimbic PFC (IFC) and NAc throughout both acquisition and extinction of this task. Activation of NAc was specifically observed following rewarded cue onset during the entire acquisition phase and also during the first days of extinction. In contrast, IFC activated only during the earliest periods of acquisition and extinction, more specifically to the nonrewarded cue. Thus, in vivo oxygen amperometry permits a novel, stable form of longitudinal analysis of brain activity in behaving animals, allowing dissociation of the roles of different brain regions over time during learning of reward-driven instrumental action. The present results offer a unique temporal perspective on how NAc may promote actions directed toward anticipated positive outcome throughout learning, while IFC might suppress actions that no longer result in reward, but only during critical periods of learning. PMID:24403158

  13. Nucleus accumbens deep brain stimulation in a rat model of binge eating.

    PubMed

    Doucette, W T; Khokhar, J Y; Green, A I

    2015-01-01

    Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for the initial chronic BE experiments. After testing in the chronic BE state, rats did not engage in binge sessions for 1 month, and then resumed binge sessions (relapse to chronic BE) with active or sham stimulation (N=5-7 per group). A significant effect of intervention group was observed on binge size in the chronic BE state, but no significant difference between intervention groups was observed in the relapse to chronic BE experiments. This research, making use of both a chronic BE model as well as a relapse to chronic BE model, provides data supporting the hypothesis that DBS of the NAc core can decrease BE. Further research will be needed to learn how to increase the effect size and decrease deep brain stimulation-treatment outcome variability across the continuum of BE behavior.

  14. Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis.

    PubMed

    Zhang, Yi; Cheng, Yan; Ren, Xingcong; Hori, Tsukasa; Huber-Keener, Kathryn J; Zhang, Li; Yap, Kai Lee; Liu, David; Shantz, Lisa; Qin, Zheng-Hong; Zhang, Suping; Wang, Jianrong; Wang, Hong-Gang; Shih, Ie-Ming; Yang, Jin-Ming

    2012-08-15

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1-/- cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment.

  15. Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens

    PubMed Central

    du Hoffmann, Johann

    2014-01-01

    Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior. PMID:25339748

  16. HIV-1 Transgenic Female Rat: Synaptodendritic Alterations of Medium Spiny Neurons in the Nucleus Accumbens

    PubMed Central

    Roscoe, Robert F.; Mactutus, Charles F.

    2015-01-01

    HIV-1 associated neurocognitive deficits are increasing in prevalence, although the neuronal basis for these deficits is unclear. HIV-1 Tg rats constitutively express 7 of 9 HIV-associated proteins, and may be useful for studying the neuropathological substrates of HIV-1 associated neurocognitive disorders (HAND). In this study, adult female HIV-1 Tg rats and F344 control rats had similar growth rates, estrous cyclicity and startle reflex inhibition to a visual prepulse stimulus. Medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) were ballistically-labeled utilizing the indocarbocyanine dye DiI. The branching complexity of MSNs in the NAcc was significantly decreased in HIV-1 Tg rats, relative to controls; moreover, the shorter length and decreased volume of dendritic spines, but unchanged head diameter, in HIV-1 Tg rats suggested a reduction of longer spines and an increase in shorter, less projected spines, indicating a population shift to a more immature spine phenotype. Collectively, these results from HIV-1 Tg female rats indicated significant synaptodendritic alterations of MSNs in the NAcc occur as a consequence of chronic, low-level, exposure to HIV-1 associated proteins. PMID:25037595

  17. Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens.

    PubMed

    Dong, Zhifang; Han, Huili; Wang, Meina; Xu, Lin; Hao, Wei; Cao, Jun

    2006-01-01

    Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus and nucleus accumbens (NAc). The underlying mechanisms are not fully understood. Here, we examined whether glucocorticoid receptors (GRs) of hippocampus and NAc influenced the formation of morphine CPP in Sprague Dawley rats. We found that systemic or intrahippocampal infused DMSO vehicle (DMSO 20% in saline) 30 min before daily morphine (10 mg/kg, s.c.) conditioning did not affect the formation of morphine CPP. In contrast, systemic administration (5 mg/kg, s.c.) or intrahippocampal infusion (0, 0.1, 1.0, 10, 20 microg per side) of the GR antagonist RU38486 blocked or impaired the formation of CPP in a dose-dependent manner, respectively. Furthermore, intra-NAc infused RU38486 (10 microg per side) but not DMSO vehicle also prevented the formation of CPP. These results demonstrate that both the GRs of hippocampus and NAc are necessary for the formation of morphine CPP, suggesting a neural network function of the GRs in forming the opiate-associated memory.

  18. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens.

    PubMed

    Albaugh, Daniel L; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action.

  19. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens.

    PubMed

    Albaugh, Daniel L; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  20. Individual Variations in Nucleus Accumbens Responses Associated with Major Depressive Disorder Symptoms

    PubMed Central

    Misaki, Masaya; Suzuki, Hideo; Savitz, Jonathan; Drevets, Wayne C.; Bodurka, Jerzy

    2016-01-01

    Abnormal reward-related responses in the nucleus accumbens (NAcc) have been reported for major depressive disorder (MDD) patients. However, variability exists in the reported results, which could be due to heterogeneity in neuropathology of depression. To parse the heterogeneity of MDD we investigated variation of NAcc responses to gain and loss anticipations using fMRI. We found NAcc responses to monetary gain and loss were significantly variable across subjects in both MDD and healthy control (HC) groups. The variations were seen as a hyperactive response subtype that showed elevated activation to the anticipation of both gain and loss, an intermediate response with greater activation to gain than loss, and a suppressed-activity with reduced activation to both gain and loss compared to a non-monetary condition. While these response variability were seen in both MDD and HC subjects, specific symptoms were significantly associated with the right NAcc variation in MDD. Both the hyper- and suppressed-activity subtypes of MDD patients had severe suicidal ideation and anhedonia symptoms. The intermediate subjects had less severity in these symptoms. These results suggest that differing propensities in reward responsiveness in the NAcc may affect the development of specific symptoms in MDD. PMID:26880358

  1. Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone.

    PubMed

    Rougé-Pont, F; Deroche, V; Le Moal, M; Piazza, P V

    1998-12-01

    Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress-induced dopamine release in intact rats and in rats in which stress-induced corticosterone secretion was experimentally blocked. Ten-minute tail-pinch was used as a stressor and dopamine release estimated in the nucleus accumbens by using the microdialysis technique. Individual differences were also taken into account by comparing rats identified as either predisposed (HRs) or resistant (LRs) to develop self-administration of drugs of abuse, on the basis of their locomotor response to novelty. It was found that suppression of stress-induced corticosterone secretion significantly decreased stress-induced dopamine release. However, such an effect greatly differed between HR and LR rats. When corticosterone secretion was intact HR animals had a higher and longer dopamine release in response to stress than LRs. The blockade of stress-induced corticosterone secretion selectively reduced the dopaminergic response of HRs that did not differ from LRs anymore. These findings strength the idea that glucocorticoids could be involved in determining propensity to develop drug self-administration. In particular, these hormones could play a role in determining the higher dopaminergic activity that characterizes drug proned individuals. PMID:9875367

  2. Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior.

    PubMed

    du Hoffmann, Johann; Nicola, Saleem M

    2016-01-01

    Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety. PMID:27471453

  3. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

    PubMed Central

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J.; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-01-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens-glutamatergic pathway remains unknown. Here, we report that nAcc photoactivation of mesoaccumbens-glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens-glutamate-fibers lack GABA, the aversion evoked by their photoactivation depends on glutamate and GABA receptor signaling, and not on dopamine receptor signaling. We found that mesoaccumbens-glutamatergic-fibers establish multiple asymmetric synapses on single parvalbumin-GABAergic interneurons, and that nAcc photoactivation of these fibers drives AMPA-mediated cellular firing of parvalbumin-GABAergic interneurons. These parvalbumin-GABAergic-interneurons, in turn, inhibit nAcc medium spiny output neurons, as such, controlling inhibitory neurotransmission within nAcc. The mesoaccumbens-glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion, instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin-GABAergic interneurons. PMID:27019014

  4. Subsecond dopamine release in the nucleus accumbens predicts conditioned punishment and its successful avoidance.

    PubMed

    Oleson, Erik B; Gentry, Ronny N; Chioma, Vivian C; Cheer, Joseph F

    2012-10-17

    The mesolimbic dopamine system is believed to be a pathway that processes rewarding information. While previous studies have also implicated a general role for dopamine in punishment and its avoidance, the precise nature of subsecond dopamine release during these phenomena remains unknown. Here, we used fast-scan cyclic voltammetry to investigate whether subsecond dopamine release events in the nucleus accumbens encode cues predicting the avoidance of punishment during behavior maintained in a signaled footshock avoidance procedure. In this task, rats could initiate an avoidance response by pressing a lever within a warning period, preventing footshock. Alternatively, once footshocks commenced, animals could initiate an escape response by pressing the lever, terminating footshock. This design allowed us to assess subsecond dopamine release events during the presentation of a warning signal, safety periods, and two distinct behavioral responses. We found that release consistently increased upon presentation of the warning signal in a manner that reliably predicted successful punishment avoidance. We also observed subsecond dopamine release during the safety period, as occurs following the receipt of reward. Conversely, we observed a decrease in release at the warning signal during escape responses. Because of this finding, we next assessed dopamine release in a conditioned fear model. As seen during escape responses, we observed a time-locked decrease in dopamine release upon presentation of a cue conditioned to inescapable footshock. Together, these data show that subsecond fluctuations in mesolimbic dopamine release predict when rats will successfully avoid punishment and differentially encode cues related to aversive outcomes.

  5. The New MCNP6 Depletion Capability

    SciTech Connect

    Fensin, Michael Lorne; James, Michael R.; Hendricks, John S.; Goorley, John T.

    2012-06-19

    The first MCNP based inline Monte Carlo depletion capability was officially released from the Radiation Safety Information and Computational Center as MCNPX 2.6.0. Both the MCNP5 and MCNPX codes have historically provided a successful combinatorial geometry based, continuous energy, Monte Carlo radiation transport solution for advanced reactor modeling and simulation. However, due to separate development pathways, useful simulation capabilities were dispersed between both codes and not unified in a single technology. MCNP6, the next evolution in the MCNP suite of codes, now combines the capability of both simulation tools, as well as providing new advanced technology, in a single radiation transport code. We describe here the new capabilities of the MCNP6 depletion code dating from the official RSICC release MCNPX 2.6.0, reported previously, to the now current state of MCNP6. NEA/OECD benchmark results are also reported. The MCNP6 depletion capability enhancements beyond MCNPX 2.6.0 reported here include: (1) new performance enhancing parallel architecture that implements both shared and distributed memory constructs; (2) enhanced memory management that maximizes calculation fidelity; and (3) improved burnup physics for better nuclide prediction. MCNP6 depletion enables complete, relatively easy-to-use depletion calculations in a single Monte Carlo code. The enhancements described here help provide a powerful capability as well as dictate a path forward for future development to improve the usefulness of the technology.

  6. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    PubMed

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion.

  7. Global Warming: Lessons from Ozone Depletion

    NASA Astrophysics Data System (ADS)

    Hobson, Art

    2010-11-01

    My teaching and textbook have always covered many physics-related social issues, including stratospheric ozone depletion and global warming. The ozone saga is an inspiring good-news story that's instructive for solving the similar but bigger problem of global warming. Thus, as soon as students in my physics literacy course at the University of Arkansas have developed a conceptual understanding of energy and of electromagnetism, including the electromagnetic spectrum, I devote a lecture (and a textbook section) to ozone depletion and another lecture (and section) to global warming. Humankind came together in 1986 and quickly solved, to the extent that humans can solve it, ozone depletion. We could do the same with global warming, but we haven't and as yet there's no sign that we will. The parallel between the ozone and global warming cases, and the difference in outcomes, are striking and instructive.

  8. Self-regulation, ego depletion, and inhibition.

    PubMed

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it.

  9. Ozone depletion and chlorine loading potentials

    NASA Technical Reports Server (NTRS)

    Pyle, John A.; Wuebbles, Donald J.; Solomon, Susan; Zvenigorodsky, Sergei; Connell, Peter; Ko, Malcolm K. W.; Fisher, Donald A.; Stordal, Frode; Weisenstein, Debra

    1991-01-01

    The recognition of the roles of chlorine and bromine compounds in ozone depletion has led to the regulation or their source gases. Some source gases are expected to be more damaging to the ozone layer than others, so that scientific guidance regarding their relative impacts is needed for regulatory purposes. Parameters used for this purpose include the steady-state and time-dependent chlorine loading potential (CLP) and the ozone depletion potential (ODP). Chlorine loading potentials depend upon the estimated value and accuracy of atmospheric lifetimes and are subject to significant (approximately 20-50 percent) uncertainties for many gases. Ozone depletion potentials depend on the same factors, as well as the evaluation of the release of reactive chlorine and bromine from each source gas and corresponding ozone destruction within the stratosphere.

  10. Neutral depletion and the helicon density limit

    SciTech Connect

    Magee, R. M.; Galante, M. E.; Carr, J. Jr.; Lusk, G.; McCarren, D. W.; Scime, E. E.

    2013-12-15

    It is straightforward to create fully ionized plasmas with modest rf power in a helicon. It is difficult, however, to create plasmas with density >10{sup 20} m{sup −3}, because neutral depletion leads to a lack of fuel. In order to address this density limit, we present fast (1 MHz), time-resolved measurements of the neutral density at and downstream from the rf antenna in krypton helicon plasmas. At the start of the discharge, the neutral density underneath the antenna is reduced to 1% of its initial value in 15 μs. The ionization rate inferred from these data implies that the electron temperature near the antenna is much higher than the electron temperature measured downstream. Neutral density measurements made downstream from the antenna show much slower depletion, requiring 14 ms to decrease by a factor of 1/e. Furthermore, the downstream depletion appears to be due to neutral pumping rather than ionization.

  11. No effect of dopamine depletion on the binding of the high-affinity D 2/3 radiotracer [11C]FLB 457 in the human cortex.

    PubMed

    Frankle, W Gordon; Mason, N Scott; Rabiner, Eugenii A; Ridler, Khanum; May, Maureen A; Asmonga, Deanna; Chen, Chi-Min; Kendro, Steve; Cooper, Thomas B; Mathis, Chester A; Narendran, Rajesh

    2010-12-01

    The use of PET and SPECT endogenous competition-binding techniques has contributed to the understanding of the role of dopamine (DA) in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of changes in synaptic DA have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal-to-noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than that in the striatum. Recently, we published a comparison study of the ability of two high-affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. Our findings support the use of [(11)C]FLB 457 to measure changes in cortical synaptic DA induced by amphetamine. The goal of this study is to examine the effects of DA depletion with α-methyl-para-tyrosine (α-MPT) on [(11)C]FLB 457 binding in the cortex. Six healthy volunteers underwent two PET scans, first under control conditions and subsequently after DA depletion. The simplified reference tissue model as well as kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in seven cortical regions. We found no effect of DA depletion with α-MPT on [(11)C]FLB 457 binding in any of the regions examined. In contrast to the measurement of DA release, the combination of low D(2) receptor density and low basal DA levels in the cortex greatly reduce the power to detect alterations in [(11)C]FLB 457 binding secondary to DA depletion.

  12. Depletion potential in the infinite dilution limit

    NASA Astrophysics Data System (ADS)

    Yuste, Santos Bravo; Santos, Andrés; López de Haro, Mariano

    2008-04-01

    The depletion force and depletion potential between two in principle unequal "big" hard spheres embedded in a multicomponent mixture of "small" hard spheres are computed using the rational function approximation method for the structural properties of hard-sphere mixtures [S. B. Yuste, A. Santos, and M. López de Haro, J. Chem. Phys. 108, 3683 (1998)]. The cases of equal solute particles and of one big particle and a hard planar wall in a background monodisperse hard-sphere fluid are explicitly analyzed. An improvement over the performance of the Percus-Yevick theory and good agreement with available simulation results are found.

  13. The depletion of interstellar gaseous iron

    NASA Technical Reports Server (NTRS)

    Savage, B. D.; Bohlin, R. C.

    1979-01-01

    The Copernicus UV telescope was used to measure equivalent widths of interstellar Fe II resonance lines toward 55 early-type stars; the measurements permit the determination of Fe II column densities. The depletion of interstellar gaseous iron was obtained by combining these measurements with the results from a previous atomic and molecular hydrogen survey program; the derived depletions refer mostly to matter in H I regions. As an example, the nearly normal gaseous iron abundance in the distant high-latitude intermediate-velocity cloud toward HD 93521 is consistent with the idea that these clouds are produced by galactic supernova explosions.

  14. Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats.

    PubMed

    Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher

    2015-03-15

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 days, with each infusion of cocaine being paired with a cue light. After 21 days of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. PMID:25529183

  15. Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cue-Induced Reinstatement of Both Cocaine and Sucrose Seeking in Rats

    PubMed Central

    Guercio, Leonardo A.; Schmidt, Heath D.; Pierce, R. Christopher

    2015-01-01

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 d, with each infusion of cocaine being paired with a cue light. After 21 d of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. PMID:25529183

  16. The adenosine A2A receptor agonist, CGS-21680, blocks excessive rearing, acquisition of wheel running, and increases nucleus accumbens CREB phosphorylation in chronically food-restricted rats.

    PubMed

    Cabeza de Vaca, Soledad; Kannan, Pavitra; Pan, Yan; Jiang, Nancy; Sun, Yanjie; Carr, Kenneth D

    2007-04-20

    Adenosine A(2A) receptors are preferentially expressed in rat striatum, where they are concentrated in dendritic spines of striatopallidal medium spiny neurons and exist in a heteromeric complex with D(2) dopamine (DA) receptors. Behavioral and biochemical studies indicate an antagonistic relationship between A(2A) and D(2) receptors. Previous studies have demonstrated that food-restricted (FR) rats display behavioral and striatal cellular hypersensitivity to D(1) and D(2) DA receptor stimulation. These alterations may underlie adaptive, as well as maladaptive, behaviors characteristic of the FR rat. The present study examined whether FR rats are hypersensitive to the A(2A) receptor agonist, CGS-21680. In Experiment 1, spontaneous horizontal motor activity did not differ between FR and ad libitum fed (AL) rats, while vertical activity was greater in the former. Intracerebroventricular (i.c.v.) administration of CGS-21680 (0.25 and 1.0 nmol) decreased both types of motor activity in FR rats, and returned vertical activity levels to those observed in AL rats. In Experiment 2, FR rats given access to a running wheel for a brief period outside of the home cage rapidly acquired wheel running while AL rats did not. Pretreatment with CGS-21680 (1.0 nmol) blocked the acquisition of wheel running. When administered to FR subjects that had previously acquired wheel running, CGS-21680 suppressed the behavior. In Experiment 3, CGS-21680 (1.0 nmol) activated both ERK 1/2 and CREB in caudate-putamen with no difference between feeding groups. However, in nucleus accumbens (NAc), CGS-21680 failed to activate ERK 1/2 and selectively activated CREB in FR rats. These results indicate that FR subjects are hypersensitive to several effects of an adenosine A(2A) agonist, and suggest the involvement of an upregulated A(2A) receptor-linked signaling pathway in NAc. Medications targeting the A(2A) receptor may have utility in the treatment of maladaptive behaviors associated with FR

  17. Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain

    PubMed Central

    Bhide, Nirmal S.; Lipton, Jack; Cunningham, Jacobi; Yamamoto, Bryan K.; Gudelsky, Gary A.

    2009-01-01

    Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 hrs for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA preconditioned animals. Preconditioning with MDMA (10 mg/kg, i.p.) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not DA depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA induced hyperthermia in rats previously exposed to MDMA contributes towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute toward neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT

  18. 50 CFR 216.15 - Depleted species.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 false Depleted species. 216.15 Section 216.15 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS REGULATIONS GOVERNING THE TAKING AND IMPORTING OF MARINE...

  19. Neutral depletion versus repletion due to ionization

    SciTech Connect

    Fruchtman, A.; Makrinich, G.; Raimbault, J.-L.; Liard, L.; Rax, J.-M.; Chabert, P.

    2008-05-15

    Recent theoretical analyses which predicted unexpected effects of neutral depletion in both collisional and collisionless plasmas are reviewed. We focus on the depletion of collisionless neutrals induced by strong ionization of a collisionless plasma and contrast this depletion with the effect of strong ionization on thermalized neutrals. The collisionless plasma is analyzed employing a kinetic description. The collisionless neutrals and the plasma are coupled through volume ionization and wall recombination only. The profiles of density and pressure both of the plasma and of the neutral-gas and the profile of the ionization rate are calculated. It is shown that for collisionless neutrals the ionization results in neutral depletion, while when neutrals are thermalized the ionization induces a maximal neutral-density at the discharge center, which we call neutral repletion. The difference between the two cases stems from the relation between the neutral density and pressure. The pressure of the collisionless neutral-gas turns out to be maximal where its density is minimal, in contrast to the case of a thermalized neutral gas.

  20. 50 CFR 216.15 - Depleted species.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 10 2014-10-01 2014-10-01 false Depleted species. 216.15 Section 216.15 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION..., Prince William Sound, Yakutat Bay, Shelikof Strait, and off Kodiak Island and freshwater tributaries...

  1. 50 CFR 216.15 - Depleted species.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 10 2013-10-01 2013-10-01 false Depleted species. 216.15 Section 216.15 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION..., Prince William Sound, Yakutat Bay, Shelikof Strait, and off Kodiak Island and freshwater tributaries...

  2. Global Warming: Lessons from Ozone Depletion

    ERIC Educational Resources Information Center

    Hobson, Art

    2010-01-01

    My teaching and textbook have always covered many physics-related social issues, including stratospheric ozone depletion and global warming. The ozone saga is an inspiring good-news story that's instructive for solving the similar but bigger problem of global warming. Thus, as soon as students in my physics literacy course at the University of…

  3. Demonstration of jackhammer incorporating depleted uranium

    SciTech Connect

    Fischer, L E; Hoard, R W; Carter, D L; Saculla, M D; Wilson, G V

    2000-04-01

    The United States Government currently has an abundance of depleted uranium (DU). This surplus of about 1 billion pounds is the result of an enrichment process using gaseous diffusion to produce enriched and depleted uranium. The enriched uranium has been used primarily for either nuclear weapons for the military or nuclear fuel for the commercial power industry. Most of the depleted uranium remains at the enrichment process plants in the form of depleted uranium hexafluoride (DUF{sub 6}). The Department of Energy (DOE) recently began a study to identify possible commercial applications for the surplus material. One of these potential applications is to use the DU in high-density strikers/hammers in pneumatically driven tools, such as jack hammers and piledrivers to improve their impulse performance. The use of DU could potentially increase tunneling velocity and excavation into target materials with improved efficiency. This report describes the efforts undertaken to analyze the particulars of using DU in two specific striking applications: the jackhammer and chipper tool.

  4. Platelet depletion and severity of streptococcal endocarditis

    PubMed Central

    Dall, Lawrence; Miller, Todd; Herndon, Betty; Diez, Ireneo; Dew, Michelle

    1998-01-01

    OBJECTIVE: To evaluate the importance of thrombocytopenia in streptococcal endocarditis using an animal model. DESIGN: A model of human septic endocarditis was established in rats (polyethylene catheters across the aortic valve and administration of Streptococcus sanguis, 5×107 colony forming units [cfu] intravenous). Thrombocytopenia at four levels was produced by antiplatelet serum. Secondary methods of producing thrombocytopenia were also evaluated. At sacrifice (96 h after platelet depletion and 72 h after infection), vegetations were removed, weighed, diluted, plated and counted. Potential mechanisms of the dose-response relationship between vegetation density and platelet count were evaluated. SETTING: Controlled research laboratory experiments. POPULATION STUDIED: Animal models of streptococcal endocarditis. MAIN RESULTS: The bacterial density of the aortic valve vegetations significantly increased as the platelet count decreased (P=0.0007). In severely thrombocytopenic animals (two-dose antiplatelet serum), data suggest increased vegetation embolism. Platelet depletion, which was minimal with chemical methods, was produced most effectively by antithrombocyte serum. Platelet surfaces in endocarditis were found to express elevated CD62p proteins (72.7% endocarditis, 34.7% control). Platelet protein fractions were evaluated in vitro by both streptocidal (P=0.19) and phagocytosis-stimulating assays. Platelet presence in mature aortic valve vegetations averaged only about 2%. CONCLUSIONS: In platelet depletion experiments using a rat model, a dose-response relationship of peripheral circulating platelet depletion to aortic valve vegetation density was found. The mechanism relating thrombocytopenia to endocarditis severity remains unresolved. PMID:22346555

  5. Dissolution Treatment of Depleted Uranium Waste

    SciTech Connect

    Gates-Anderson, D D; Laue, C A; Fitch, T E

    2004-02-09

    Researchers at LLNL have developed a 3-stage process that converts pyrophoric depleted uranium metal turnings to a solidified final product that can be transported to and buried at a permitted land disposal site. The three process stages are: (1) pretreatment; (2) dissolution; and (3) solidification. Each stage was developed following extensive experimentation. This report presents the results of their experimental studies.

  6. Carbon depletion in turbulent molecular cloud cores

    NASA Astrophysics Data System (ADS)

    Boland, W.; de Jong, T.

    1982-10-01

    Observations of dense molecular cores indicate that about 10% of the carbon is still in the gas phase (depletion factor of about 0.1) in spite of the fact that the depletion time - the time needed for heavy elements to freeze out on dust grains - is several orders of magnitude smaller than the cloud lifetime. To resolve this problem, it is suggested that the material in molecular cloud cores is circulated by turbulence and that every time a parcel of gas and dust reaches the outer layers of the core, dust mantles that have formed by accretion in the center are evaporated and/or photodesorbed. The observed mild degree of depletion results because the circulation time and the depletion time are of the same order of magnitude. Since the time to reach molecular equilibrium in the outer layers of a cloud core is short compared with the circulation time the dust plays no role in the chemistry. In the center of a cloud core, the time to convert C to CO is of the order of the circulation time, so that an appreciable fraction of the gaseous carbon remains in atomic form. From a brief discussion of the energetics, it is concluded that the turbulence observed in molecular cloud cores can be maintained during the lifetime of the cloud if the envelope collapses onto the core at a rate of about 0.000001 solar mass per year.

  7. Contrasts between Antarctic and Arctic ozone depletion.

    PubMed

    Solomon, Susan; Portmann, Robert W; Thompson, David W J

    2007-01-01

    This work surveys the depth and character of ozone depletion in the Antarctic and Arctic using available long balloon-borne and ground-based records that cover multiple decades from ground-based sites. Such data reveal changes in the range of ozone values including the extremes observed as polar air passes over the stations. Antarctic ozone observations reveal widespread and massive local depletion in the heart of the ozone "hole" region near 18 km, frequently exceeding 90%. Although some ozone losses are apparent in the Arctic during particular years, the depth of the ozone losses in the Arctic are considerably smaller, and their occurrence is far less frequent. Many Antarctic total integrated column ozone observations in spring since approximately the 1980s show values considerably below those ever observed in earlier decades. For the Arctic, there is evidence of some spring season depletion of total ozone at particular stations, but the changes are much less pronounced compared with the range of past data. Thus, the observations demonstrate that the widespread and deep ozone depletion that characterizes the Antarctic ozone hole is a unique feature on the planet. PMID:17202269

  8. “When the going gets tough, who keeps going?” Depletion sensitivity moderates the ego-depletion effect

    PubMed Central

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T. D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS) was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion. PMID:25009523

  9. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

    ERIC Educational Resources Information Center

    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  10. Role of Mu and Delta Opioid Receptors in the Nucleus Accumbens in Cocaine-Seeking Behavior

    PubMed Central

    Simmons, Diana; Self, David W.

    2009-01-01

    Previous studies suggest that opioid receptors in the ventral tegmental area (VTA), but not the nucleus accumbens (NAc), play a role in relapse to drug-seeking behavior. However, environmental stimuli that elicit relapse also release the endogenous opioid β-endorphin in the NAc. Using a within–session extinction/reinstatement paradigm in rats that self-administer cocaine, we found that NAc infusions of the mu opioid receptor (MOR) agonist DAMGO moderately reinstated responding on the cocaine-paired lever at low doses (1.0–3.0 ng/side), whereas the delta opioid receptor (DOR) agonist DPDPE induced greater responding at higher doses (300–3000 ng/side) that also enhanced inactive lever responding. Using doses of either agonist that induced responding on only the cocaine-paired lever, we found that DAMGO-induced responding was blocked selectively by pretreatment with the MOR antagonist CTAP, while DPDPE-induced responding was selectively blocked by the DOR antagonist naltrindole. Cocaine-primed reinstatement was blocked by intra-NAc CTAP but not naltrindole, indicating a role for endogenous MOR-acting peptides in cocaine-induced reinstatement of cocaine-seeking behavior. In this regard, intra-NAc infusions of β-endorphin (100–1000 ng/side) induced marked cocaine-seeking behavior, an effect blocked by intra-NAc pretreatment with the MOR but not DOR antagonist. Conversely, cocaine seeking elicited by the enkephalinase inhibitor thiorphan (1–10 μg/side) was blocked by naltrindole but not CTAP. MOR stimulation in more dorsal caudate-putamen sites was ineffective, while DPDPE infusions induced cocaine seeking. Together, these findings establish distinct roles for MOR and DOR in cocaine relapse, and suggest that NAc MOR could be an important therapeutic target to neutralize the effects of endogenous β-endorphin release on cocaine relapse. PMID:19279569

  11. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior.

    PubMed

    Christoffel, Daniel J; Golden, Sam A; Heshmati, Mitra; Graham, Ami; Birnbaum, Shari; Neve, Rachael L; Hodes, Georgia E; Russo, Scott J

    2012-11-01

    Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

  12. Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making.

    PubMed

    Zalocusky, Kelly A; Ramakrishnan, Charu; Lerner, Talia N; Davidson, Thomas J; Knutson, Brian; Deisseroth, Karl

    2016-03-31

    A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making. PMID:27007845

  13. Targeting Dopamine D2 and Cannabinoid-1 (CB1) Receptors in Rat Nucleus Accumbens

    PubMed Central

    PICKEL, VIRGINA M.; CHAN, JANE; KEARN, CHRISTOPHER S.; MACKIE, KENNETH

    2006-01-01

    The nucleus accumbens (Acb) shell and core are essential components of neural circuitry mediating the reward and motor effects produced by activation of dopamine D2 or cannabinoid-1 (CB1) receptors. D2 receptors can form heterodimeric complexes with cannabinoid-1 (CB1) receptors and are also involved in control of the availability of both dopamine and endocannabinoids. Thus, the subcellular locations of D2 and CB1 receptors with respect to each other are implicit to their physiological actions in the Acb. We used electron microscopic immunocytochemistry to determine these locations in the Acb shell and core of rat brain. In each region, many neuronal profiles showed endomembrane and plasmalemmal distributions of one or both receptors. Approximately one-third of the labeled profiles were somata and dendrites, some of which showed overlapping subcellular distributions of D2 and CB1 immunoreactivities. The remaining labeled profiles were small axons and axon terminals containing CB1 and/or D2 receptors. Of the labeled terminals forming recognizable synapses, ~20% of those containing CB1 receptors contacted D2-labeled dendrites, while conversely, almost 15% of those containing D2 receptors contacted CB1-labeled dendrites. These results provide the first ultrastructural evidence that D2 and CB1 receptors in the Acb shell and core have subcellular distributions supporting both intracellular associations and local involvement of D2 receptors in making available endocannabinoids that are active on CB1 receptors in synaptic neurons. These distributions have direct relevance to the rewarding and euphoric as well as motor effects produced by marijuana and by addictive drugs enhancing dopamine levels in the Acb. PMID:16440297

  14. Neonatal Masculinization Blocks Increased Excitatory Synaptic Input in Female Rat Nucleus Accumbens Core.

    PubMed

    Cao, Jinyan; Dorris, David M; Meitzen, John

    2016-08-01

    Steroid sex hormones and genetic sex regulate the phenotypes of motivated behaviors and relevant disorders. Most studies seeking to elucidate the underlying neuroendocrine mechanisms have focused on how 17β-estradiol modulates the role of dopamine in striatal brain regions, which express membrane-associated estrogen receptors. Dopamine action is an important component of striatal function, but excitatory synaptic neurotransmission has also emerged as a key striatal substrate and target of estradiol action. Here, we focus on excitatory synaptic input onto medium spiny neurons (MSNs) in the striatal region nucleus accumbens core (AcbC). In adult AcbC, miniature excitatory postsynaptic current (mEPSC) frequency is increased in female compared with male MSNs. We tested whether increased mEPSC frequency in female MSNs exists before puberty, whether this increased excitability is due to the absence of estradiol or testosterone during the early developmental critical period, and whether it is accompanied by stable neuron intrinsic membrane properties. We found that mEPSC frequency is increased in female compared with male MSNs before puberty. Increased mEPSC frequency in female MSNs is abolished after neonatal estradiol or testosterone exposure. MSN intrinsic membrane properties did not differ by sex. These data indicate that neonatal masculinization via estradiol and/or testosterone action is sufficient for down-regulating excitatory synaptic input onto MSNs. We conclude that excitatory synaptic input onto AcbC MSNs is organized long before adulthood via steroid sex hormone action, providing new insight into a mechanism by which sex differences in motivated behavior and other AbcC functions may be generated or compromised.

  15. Nucleus Accumbens-Specific Interventions in RGS9-2 Activity Modulate Responses to Morphine

    PubMed Central

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-01-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc. PMID:24561386

  16. Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens

    PubMed Central

    Zhao, Changjiu; Eisinger, Brian Earl; Driessen, Terri M.; Gammie, Stephen C.

    2014-01-01

    Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. PMID:25414651

  17. Opposing Role for Egr3 in Nucleus Accumbens Cell Subtypes in Cocaine Action

    PubMed Central

    Chandra, Ramesh; Francis, T. Chase; Konkalmatt, Prasad; Amgalan, Ariunzaya; Gancarz, Amy M.; Dietz, David M.

    2015-01-01

    An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2α, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action. PMID:25995477

  18. Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction.

    PubMed

    del Castillo, Carmen; Morales, Lidia; Alguacil, Luis F; Salas, Elisabet; Garrido, Elisa; Alonso, Elba; Pérez-García, Carmen

    2009-07-01

    Vulnerability to the addictive effects of drugs of abuse varies among individuals, but the biological basis of these differences are poorly known. This work tries to increase this knowledge by comparing the brain proteome of animals with different rate of extinction of cocaine-seeking behaviour. To achieve this goal, we used a place-preference paradigm to separate Sprague Dawley rats in two groups: rats that extinguished (E) and rats that did not extinguish (NE) cocaine-seeking behaviour after a five-day period of drug abstinence. Once the phenotype was established, we compared the protein expression in the nucleus accumbens (NAC) of these animals after a single injection of either saline (SAL) or cocaine (COC, 15 mg/kg). The analysis of protein expression was performed by 2-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization time of flight mass spectrometry. When comparing E SAL and NE SAL animals we found significant differences in the expression level of 5 proteins: ATP synthase subunit alpha, fumarate hydratase, transketolase, NADH dehydrogenase [ubiquinone] flavoprotein 2 and glutathione transferase omega-1. A single injection of COC differently alters the NAC proteome of E and NE rats; thus in E COC animals there was an alteration in the expression of 6 proteins, including dihydropyrimidinase-related protein 2 and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10; whereas in NE COC rats 9 proteins were altered (including alpha-synuclein, peroxiredoxin-2 and peroxiredoxin-5). These proteins could be potential biomarkers of individual vulnerability to cocaine abuse and may be helpful in designing new treatments for cocaine addiction.

  19. Changes in dopamine transporter binding in nucleus accumbens following chronic self-administration cocaine: heroin combinations.

    PubMed

    Pattison, Lindsey P; McIntosh, Scot; Sexton, Tammy; Childers, Steven R; Hemby, Scott E

    2014-10-01

    Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [(125) I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([(125) I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd ) and binding density (Bmax ) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. PMID:24916769

  20. Cue-Evoked Cocaine “Craving”: Role of Dopamine in the Accumbens Core

    PubMed Central

    Saunders, Benjamin T.; Yager, Lindsay M.

    2013-01-01

    Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state (“wanting” or “craving”) that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self-administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process. PMID:23986236

  1. Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Subjects with Major Depressive Disorder

    PubMed Central

    Pizzagalli, Diego A.; Holmes, Avram J.; Dillon, Daniel G.; Goetz, Elena L.; Birk, Jeffrey L.; Bogdan, Ryan; Dougherty, Darin D.; Iosifescu, Dan V.; Rauch, Scott L.; Fava, Maurizio

    2009-01-01

    Objective Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures. Method A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume. Conclusions These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume. PMID:19411368

  2. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    PubMed

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux. PMID:26706696

  3. Plasticity of GABAA receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats

    PubMed Central

    Liang, Jing; Lindemeyer, A. Kerstin; Suryanarayanan, Asha; Meyer, Edward M.; Marty, Vincent N.; Ahmad, S. Omar; Shao, Xuesi Max; Olsen, Richard W.

    2014-01-01

    Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABAARs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABAARs, which mediate the picrotoxin-sensitive tonic current (Itonic), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both Itonic and mIPSCs was decreased by CIE treatment. The average magnitude of Itonic was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABAAR subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission. PMID:24694935

  4. NPY mediates reward activity of morphine, via NPY Y1 receptors, in the nucleus accumbens shell.

    PubMed

    Desai, Sagar J; Upadhya, Manoj A; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2013-06-15

    Although the interaction between endogenous neuropeptide Y (NPY) and opioidergic systems in processing of reward has been speculated, experimental evidence is lacking. We investigated the role of NPY, and its Y1 receptors, in the nucleus accumbens shell (AcbSh) in morphine induced reward and reinforcement behavior. Rats were implanted with cannulae targeted at AcbSh for drug administration, and with stimulating electrode in the medial forebrain bundle (MFB). The rats were then conditioned in an operant conditioning chamber for electrical self-stimulation of the MFB. Increased rate of lever pressings was evaluated against the frequency of the stimulating current. Increase in rate of lever presses was considered as a measure of reward and reinforcement. About 30-70% increase in self-stimulation was observed following bilateral intra-AcbSh treatment with morphine, NPY or [Leu(31), Pro(34)]-NPY (NPY Y1/Y5 receptors agonist), however, BIBP3226 (selective NPY Y1 receptors antagonist) produced opposite effect. The reward effect of morphine was significantly potentiated by NPY or [Leu(31), Pro(34)]-NPY, but antagonized by BIBP3226. NPY-immunoreactivity in the AcbSh, arcuate nucleus (ARC) and lateral part of bed nucleus of stria terminalis (BNSTl) was significantly more in the operant conditioned rats than in naïve control. However, morphine administration to the conditioned rats resulted in significant decrease in the NPY-immunoreactivity in all these anatomical regions. Since the role of morphine in modulation of mesolimbic-dopaminergic pathway is well established, we suggest that NPY system in AcbSh, ARC and BNSTl, perhaps acting via Y1-receptor system, may be an important component of the mesolimbic-AcbSh reward circuitry triggered by endogenous opioids.

  5. Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

    PubMed

    Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

    2011-11-01

    Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

  6. κ-Opioid receptors within the nucleus accumbens shell mediate pair bond maintenance.

    PubMed

    Resendez, Shanna L; Kuhnmuench, Morgan; Krzywosinski, Tarin; Aragona, Brandon J

    2012-05-16

    The prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transition from general affiliation to aggressive rejection of novel conspecifics. This "selective aggression" is indicative of mate guarding that is necessary to maintain the initial pair bond. In the laboratory, the neurobiology of this behavior is studied using resident-intruder testing. Although it is well established that social behaviors in other species are mediated by endogenous opioid systems, opiate regulation of pair bond maintenance has never been studied. Here, we used resident-intruder testing to determine whether endogenous opioids within brain motivational circuitry mediate selective aggression in prairie voles. We first show that peripheral blockade of κ-opioid receptors with the antagonist norbinaltorphimine (nor-BNI; 100 mg/kg), but not with the preferential μ-opioid receptor antagonist naloxone (1, 10, or 30 mg/kg), decreased selective aggression in males. We then provide the first comprehensive characterization of κ- and μ-opioid receptors in the prairie vole brain. Finally, we demonstrate that blockade of κ-opioid receptors (500 ng nor-BNI) within the nucleus accumbens (NAc) shell abolishes selective aggression in both sexes, but blockade of these receptors within the NAc core enhances this behavior specifically in females. Blockade of κ-opioid receptors within the ventral pallidum or μ-opioid receptors with the specific μ-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (1 ng CTAP) within the NAc shell had no effect in either sex. Thus, κ-opioid receptors within the NAc shell mediate aversive social motivation that is critical for pair bond maintenance. PMID:22593047

  7. κ Opioid Receptors in the Nucleus Accumbens Shell Mediate Escalation of Methamphetamine Intake

    PubMed Central

    Schlosburg, Joel E.; Wee, Sunmee; Gould, Adam; George, Olivier; Grant, Yanabel; Zamora-Martinez, Eva R.; Edwards, Scott; Crawford, Elena; Vendruscolo, Leandro F.; Koob, George F.

    2015-01-01

    Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin–KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction. PMID:25762676

  8. Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.

    PubMed

    LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A

    2016-02-01

    Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux.

  9. Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making.

    PubMed

    Zalocusky, Kelly A; Ramakrishnan, Charu; Lerner, Talia N; Davidson, Thomas J; Knutson, Brian; Deisseroth, Karl

    2016-03-31

    A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making.

  10. Cocaine withdrawal-induced trafficking of delta-opioid receptors in rat nucleus accumbens.

    PubMed

    Ambrose-Lanci, Lisa M; Peiris, Niluk B; Unterwald, Ellen M; Van Bockstaele, Elisabeth J

    2008-05-19

    Interactions between the opioidergic and dopaminergic systems in the nucleus accumbens (NAcb) play a critical role in mediating cocaine withdrawal-induced effects on cell signaling and behavior. In support of this, increased activation of striatal dopamine-D1 receptors (D1R) results in desensitization of delta-opioid receptor (DOR) signaling through adenylyl cyclase during early cocaine withdrawal. A potential cellular substrate underlying receptor desensitization is receptor internalization. The present study examined the effect of cocaine withdrawal on subcellular localization of DOR in dendrites of the NAcb core (NAcbC) and shell (NAcbS) using immunoelectron microscopy. Female and male rats received binge-pattern cocaine or saline for 14 days and subsequently underwent 48 h withdrawal. Animals were transcardially perfused and tissue sections were processed for immunogold-silver localization of DOR. Semi-quantitative analysis revealed that cocaine withdrawal caused an increase in the percentage of DOR localized intracellularly in the NAcbS of male and female rats and the NAcbC of male rats compared to saline controls. In contrast, in the NAcbC of female rats, there was an increase in DOR associated with the plasma membrane following cocaine withdrawal. To determine whether modulation of D1R could directly impact DOR containing neurons, the hypothesis that DOR and D1R co-exist in common neurons of the NAcb was examined in naïve rats. Semi-quantitative analysis revealed a subset of profiles containing both DOR and D1R immunoreactivities. The present findings demonstrate a redistribution of DOR in the NAcb following cocaine withdrawal and provide anatomical evidence supporting D1R regulation of DOR function in a subset of NAcb neurons. PMID:18417105

  11. Exposure to Cocaine Dynamically Regulates the Intrinsic Membrane Excitability of Nucleus Accumbens Neurons

    PubMed Central

    Mu, Ping; Moyer, Jason T.; Ishikawa, Masago; Zhang, Yonghong; Panksepp, Jaak; Sorg, Barbara A.; Schlüter, Oliver M.; Dong, Yan

    2010-01-01

    Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that following short-term (2d) or long-term (21d) withdrawal from non-contingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or non-contingently. Specifically, the membrane excitability of NAcSh MSNs was decreased at 2d after withdrawal from either 5-day intraperitoneal (i.p.) injections (15 mg/kg) or cocaine self-administration (SA). At 21d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in i.p.-pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, upon a re-exposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in i.p.-pretreated rats. On the other hand, in SA-pretreated rats, the re-exposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and non-contingent cocaine administration. PMID:20220002

  12. Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access.

    PubMed

    Imperio, Caesar G; McFalls, Ashley J; Colechio, Elizabeth M; Masser, Dustin R; Vrana, Kent E; Grigson, Patricia S; Freeman, Willard M

    2016-05-01

    Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal responsibilities in favor of finding and using drugs. Only some recreational heroin users devolve into addiction but the basis of these individual differences is not known. We have shown in rats that avoidance of a heroin-paired taste cue reliably identifies individual animals with greater addiction-like behavior for heroin. Here rats received 5min access to a 0.15% saccharin solution followed by the opportunity to self-administer either saline or heroin for 6h. Large Suppressors of the heroin-paired taste cue displayed increased drug escalation, motivation for drug, and drug loading behavior compared with Small Suppressors. Little is known about the molecular mechanisms of these individual differences in addiction-like behavior. We examined the individual differences in mRNA expression in the nucleus accumbens (NAc) of rats that were behaviorally stratified by addiction-like behavior using next-generation sequencing. We hypothesized that based on the avoidance of the drug-paired cue there will be a unique mRNA profile in the NAc. Analysis of strand-specific whole genome RNA-Seq data revealed a number of genes differentially regulated in NAc based on the suppression of the natural saccharine reward. Large Suppressors exhibited a unique mRNA prolife compared to Saline controls and Small Suppressors. Genes related to immunity, neuronal activity, and behavior were differentially expressed among the 3 groups. In total, individual differences in avoidance of a heroin-paired taste cue are associated with addiction-like behavior along with differential NAc gene expression. PMID:26733446

  13. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

    PubMed

    Gaspari, Sevasti; Papachatzaki, Maria M; Koo, Ja Wook; Carr, Fiona B; Tsimpanouli, Maria-Efstratia; Stergiou, Eugenia; Bagot, Rosemary C; Ferguson, Deveroux; Mouzon, Ezekiell; Chakravarty, Sumana; Deisseroth, Karl; Lobo, Mary Kay; Zachariou, Venetia

    2014-07-01

    Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

  14. Oscillatory Activity in the Medial Prefrontal Cortex and Nucleus Accumbens Correlates with Impulsivity and Reward Outcome

    PubMed Central

    Rich, P. Dylan; Nevado-Holgado, Alejo J.; Fernando, Anushka B. P.; Van Dijck, Gert; Holzhammer, Tobias; Paul, Oliver; Ruther, Patrick; Paulsen, Ole; Robbins, Trevor W.; Dalley, Jeffrey W.

    2014-01-01

    Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour. PMID:25333512

  15. Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons.

    PubMed

    Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan

    2011-01-01

    Homeostatic response is an endowed self-correcting/maintaining property for living units, ranging from subcellular domains, single cells, and organs to the whole organism. Homeostatic responses maintain stable function through the ever-changing internal and external environments. In central neurons, several forms of homeostatic regulation have been identified, all of which tend to stabilize the functional output of neurons toward their prior "set-point." Medium spiny neurons (MSNs) within the forebrain region the nucleus accumbens (NAc) play a central role in gating/regulating emotional and motivational behaviors including craving and seeking drugs of abuse. Exposure to highly salient stimuli such as cocaine administration not only acutely activates a certain population of NAc MSNs, but also induces long-lasting changes in these neurons. It is these long-lasting cellular alterations that are speculated to mediate the increasingly strong cocaine-craving and cocaine-seeking behaviors. Why do the potentially powerful homeostatic mechanisms fail to correct or compensate for these drug-induced maladaptations in neurons? Based on recent experimental results, this review proposes a hypothesis of homeostatic dysregulation induced by exposure to cocaine. Specifically, we hypothesize that exposure to cocaine generates false molecular signals which misleads the homeostatic regulation process, resulting in maladaptive changes in NAc MSNs. Thus, many molecular and cellular alterations observed in the addicted brain may indeed result from homeostatic dysregulation. This review is among the first to introduce the concept of homeostatic neuroplasticity to understanding the molecular and cellular maladaptations following exposure to drugs of abuse. PMID:20708038

  16. Resting-State Functional Connectivity of the Nucleus Accumbens in Auditory and Visual Hallucinations in Schizophrenia

    PubMed Central

    Rolland, Benjamin; Amad, Ali; Poulet, Emmanuel; Bordet, Régis; Vignaud, Alexandre; Bation, Rémy; Delmaire, Christine; Thomas, Pierre; Cottencin, Olivier; Jardri, Renaud

    2015-01-01

    Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) < .05). Compared to the NoH group, the AH group exhibited significantly enhanced NAcc rs-FC with the left temporal superior gyrus, the cingulate gyri, and the VTA, whereas the VAH group, compared to the AH group, exhibited significantly enhanced NAcc rs-FC with the bilateral insula, putamen, parahippocampal gyri, and VTA. The strength in rs-FC between the NAcc and the VTA appeared to be positively associated with the presence of hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features. PMID:25053649

  17. Nucleus accumbens neuronal activity correlates to the animal's behavioral response to acute and chronic methylphenidate.

    PubMed

    Claussen, Catherine M; Chong, Samuel L; Dafny, Nachum

    2014-04-22

    Acute and chronic methylphenidate (MPD) exposure was recorded simultaneously for the rat's locomotor activity and the nucleus accumbens (NAc) neuronal activity. The evaluation of the neuronal events was based on the animal's behavior response to chronic MPD administration: 1) Animals exhibiting behavioral sensitization, 2) Animals exhibiting behavioral tolerance. The experiment lasted for 10days with four groups of animals; saline, 0.6, 2.5, and 10.0mg/kg MPD. For the main behavioral findings, about half of the animals exhibited behavioral sensitization or behavioral tolerance to 0.6, 2.5, and/or 10mg/kg MPD respectively. Three hundred and forty one NAc neuronal units were evaluated. Approximately 80% of NAc units responded to 0.6, 2.5, and 10.0mg/kg MPD. When the neuronal activity was analyzed based on the animals' behavioral response to chronic MPD exposure, significant differences were seen between the neuronal population responses recorded from animals that expressed behavioral sensitization when compared to the NAc neuronal responses recorded from animals exhibiting behavioral tolerance. Three types of neurophysiological sensitization and neurophysiological tolerance can be recognized following chronic MPD administration to the neuronal populations. Collectively, these findings show that the same dose of chronic MPD can elicit either behavioral tolerance or behavioral sensitization. Differential statistical analyses were used to verify our hypothesis that the neuronal activity recorded from animals exhibiting behavioral sensitization will respond differently to MPD compared to those animals exhibiting behavioral tolerance, thus, suggesting that it is essential to record the animal's behavior concomitantly with neuronal recordings.

  18. Resting-state functional connectivity of the nucleus accumbens in auditory and visual hallucinations in schizophrenia.

    PubMed

    Rolland, Benjamin; Amad, Ali; Poulet, Emmanuel; Bordet, Régis; Vignaud, Alexandre; Bation, Rémy; Delmaire, Christine; Thomas, Pierre; Cottencin, Olivier; Jardri, Renaud

    2015-01-01

    Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) < .05). Compared to the NoH group, the AH group exhibited significantly enhanced NAcc rs-FC with the left temporal superior gyrus, the cingulate gyri, and the VTA, whereas the VAH group, compared to the AH group, exhibited significantly enhanced NAcc rs-FC with the bilateral insula, putamen, parahippocampal gyri, and VTA. The strength in rs-FC between the NAcc and the VTA appeared to be positively associated with the presence of hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features.

  19. Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.

    PubMed

    Massart, Renaud; Barnea, Royi; Dikshtein, Yahav; Suderman, Matthew; Meir, Oren; Hallett, Michael; Kennedy, Pamela; Nestler, Eric J; Szyf, Moshe; Yadid, Gal

    2015-05-27

    One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 μm) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 μm) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nm) or the CDK5 inhibitor roscovitine (28 μm) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving.

  20. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli

    PubMed Central

    Cone, Jackson J.; Roitman, Jamie D.; Roitman, Mitchell F.

    2015-01-01

    Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e. hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS−). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS−, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. PMID:25708523

  1. Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour.

    PubMed

    Roberts, Michael D; Toedebusch, Ryan G; Wells, Kevin D; Company, Joseph M; Brown, Jacob D; Cruthirds, Clayton L; Heese, Alexander J; Zhu, Conan; Rottinghaus, George E; Childs, Thomas E; Booth, Frank W

    2014-05-15

    We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVR(non-run) and HVR(non-run)), as well as in rats after 6 days of voluntary wheel running (LVR(run) and HVR(run)). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that 'cell cycle'-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9-10 LVR(non-run) rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P < 0.001) and fewer immature (Dcx-positive) neurons (P < 0.001) than their G9-10 HVR counterparts. However, voluntary running wheel access in our G9-10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats.

  2. Imipramine Treatment and Resiliency Exhibit Similar Chromatin Regulation in the Mouse Nucleus Accumbens in Depression Models

    PubMed Central

    Wilkinson, Matthew B.; Xiao, Guanghua; Kumar, Arvind; LaPlant, Quincey; Renthal, William; Sikder, Devanjan; Kodadek, Thomas J.; Nestler, Eric J.

    2009-01-01

    Though it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use ChIP-chip assays—chromatin immunoprecipitation (ChIP) followed by genome wide promoter array analyses—to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that most of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice—those resistant to the deleterious effects of defeat stress—show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress. PMID:19535594

  3. Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

    PubMed Central

    Christoffel, Daniel J; Golden, Sam A; Heshmati, Mitra; Graham, Ami; Birnbaum, Shari; Neve, Rachael L; Hodes, Georgia E; Russo, Scott J

    2012-01-01

    Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses. PMID:22781845

  4. The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

    PubMed

    Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

    2012-12-11

    In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this 'paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT(4) receptors (5-HTR(4)) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR(1B) self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR(4) in the absence of 5-HTR(1B), associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR(4) overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR(4) knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR(4). Additionally, inactivating NAc-5-HTR(4) suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR(4)/CART pathway establishes a 'tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules.

  5. Effects of dietary tryptophan and phenylalanine–tyrosine depletion on phasic alertness in healthy adults – A pilot study

    PubMed Central

    Hildebrand, Patricia; Königschulte, Werner; Gaber, Tilman Jakob; Bubenzer-Busch, Sarah; Helmbold, Katrin; Biskup, Caroline Sarah; Langen, Karl-Josef; Fink, Gereon Rudolf; Zepf, Florian Daniel

    2015-01-01

    Background The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD) techniques were used. Methods The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake. Results Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same

  6. Nucleus accumbens GABAergic inhibition generates intense eating and fear that resists environmental retuning and needs no local dopamine.

    PubMed

    Richard, Jocelyn M; Plawecki, Andrea M; Berridge, Kent C

    2013-06-01

    Intense fearful behavior and/or intense appetitive eating behavior can be generated by localized amino acid inhibitions along a rostrocaudal anatomical gradient within medial shell of nucleus accumbens of the rat. This can be produced by microinjections in medial shell of either the γ-aminobutyric acid (GABA)A agonist muscimol (mimicking intrinsic GABAergic inputs) or the AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione), disrupting corticolimbic glutamate inputs). At rostral sites in medial shell, each drug robustly stimulates appetitive eating and food intake, whereas at more caudal sites the same drugs instead produce increasingly fearful behaviors such as escape, distress vocalizations and defensive treading (an antipredator behavior rodents emit to snakes and scorpions). Previously we showed that intense motivated behaviors generated by glutamate blockade require local endogenous dopamine and can be modulated in valence by environmental ambience. Here we investigated whether GABAergic generation of intense appetitive and fearful motivations similarly depends on local dopamine signals, and whether the valence of motivations generated by GABAergic inhibition can also be retuned by changes in environmental ambience. We report that the answer to both questions is 'no'. Eating and fear generated by GABAergic inhibition of accumbens shell does not need endogenous dopamine. Also, the appetitive/fearful valence generated by GABAergic muscimol microinjections resists environmental retuning and is determined almost purely by rostrocaudal anatomical placement. These results suggest that nucleus accumbens GABAergic release of fear and eating are relatively independent of modulatory dopamine signals, and more anatomically pre-determined in valence balance than release of the same intense behaviors by glutamate disruptions.

  7. Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues.

    PubMed

    Aitken, Tara J; Greenfield, Venuz Y; Wassum, Kate M

    2016-03-01

    Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc) core. This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one's current need state, such that cues only motivate actions when this is adaptive. But it remains unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here, we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the Pavlovian-to-instrumental transfer effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action. PMID:26715366

  8. Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues.

    PubMed

    Aitken, Tara J; Greenfield, Venuz Y; Wassum, Kate M

    2016-03-01

    Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc) core. This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one's current need state, such that cues only motivate actions when this is adaptive. But it remains unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here, we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the Pavlovian-to-instrumental transfer effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action.

  9. How Depleted is the MORB mantle?

    NASA Astrophysics Data System (ADS)

    Hofmann, A. W.; Hart, S. R.

    2015-12-01

    Knowledge of the degree of mantle depletion of highly incompatible elements is critically important for assessing Earth's internal heat production and Urey number. Current views of the degree of MORB source depletion are dominated by Salters and Stracke (2004), and Workman and Hart (2005). The first is based on an assessment of average MORB compositions, whereas the second considers trace element data of oceanic peridotites. Both require an independent determination of one absolute concentration, Lu (Salters & Stracke), or Nd (Workman & Hart). Both use parent-daughter ratios Lu/Hf, Sm/Nd, and Rb/Sr calculated from MORB isotopes combined with continental-crust extraction models, as well as "canonical" trace element ratios, to boot-strap the full range of trace element abundances. We show that the single most important factor in determining the ultimate degree of incompatible element depletion in the MORB source lies in the assumptions about the timing of continent extraction, exemplified by continuous extraction versus simple two-stage models. Continued crust extraction generates additional, recent mantle depletion, without affecting the isotopic composition of the residual mantle significantly. Previous emphasis on chemical compositions of MORB and/or peridotites has tended to obscure this. We will explore the effect of different continent extraction models on the degree of U, Th, and K depletion in the MORB source. Given the uncertainties of the two most popular models, the uncertainties of U and Th in DMM are at least ±50%, and this impacts the constraints on the terrestrial Urey ratio. Salters, F.J.M. and Stracke, A., 2004, Geochem. Geophys. Geosyst. 5, Q05004. Workman, R.K. and Hart, S.R., 2005, EPSL 231, 53-72.

  10. A worldwide view of groundwater depletion

    NASA Astrophysics Data System (ADS)

    van Beek, L. P.; Wada, Y.; van Kempen, C.; Reckman, J. W.; Vasak, S.; Bierkens, M. F.

    2010-12-01

    During the last decades, global water demand has increased two-fold due to increasing population, expanding irrigated area and economic development. Globally such demand can be met by surface water availability (i.e., water in rivers, lakes and reservoirs) but regional variations are large and the absence of sufficient rainfall and run-off increasingly encourages the use of groundwater resources, particularly in the (semi-)arid regions of the world. Excessive abstraction for irrigation frequently leads to overexploitation, i.e. if groundwater abstraction exceeds the natural groundwater recharge over extensive areas and prolonged times, persistent groundwater depletion may occur. Observations and various regional studies have revealed that groundwater depletion is a substantial issue in regions such as Northwest India, Northeast Pakistan, Central USA, Northeast China and Iran. Here we provide a global overview of groundwater depletion from the year 1960 to 2000 at a spatial resolution of 0.5 degree by assessing groundwater recharge with the global hydrological model PCR-GLOBWB and subtracting estimates of groundwater abstraction obtained from IGRAC-GGIS database. PCR-GLOBWB was forced by the CRU climate dataset downscaled to daily time steps using ERA40 re-analysis data. PCR-GLOBWB simulates daily global groundwater recharge (0.5 degree) while considering sub-grid variability of each grid cell (e.g., short and tall vegetation, different soil types, fraction of saturated soil). Country statistics of groundwater abstraction were downscaled to 0.5 degree by using water demand (i.e., agriculture, industry and domestic) as a proxy. To limit problems related to increased capture of discharge and increased recharge due to groundwater pumping, we restricted our analysis to sub-humid to arid areas. The uncertainty in the resulting estimates was assessed by a Monte Carlo analysis of 100 realizations of groundwater recharge and 100 realizations of groundwater abstraction

  11. Knockdown of Dopamine D2 Receptors in the Nucleus Accumbens Core Suppresses Methamphetamine-Induced Behaviors and Signal Transduction in Mice

    PubMed Central

    Miyamoto, Yoshiaki; Iida, Asako; Sato, Keiji; Muramatsu, Shin-ichi

    2015-01-01

    Background: Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D1 receptors and D2 receptors. Methods: In the present study, we investigated the role of D2 receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D2 receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D2 receptor-treated mice (miD2r mice) were assessed at a reduction in D2 receptor, but at no change in dopamine D1 receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice). Results: miD2r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD2r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD2r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD2r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD2r mice was also attenuated. Conclusions: These findings suggest that a D2 receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of

  12. Commonness, population depletion and conservation biology.

    PubMed

    Gaston, Kevin J; Fuller, Richard A

    2008-01-01

    Species conservation practice, as opposed to principle, generally emphasizes species at risk of imminent extinction. This results in priority lists principally of those with small populations and/or geographical ranges. However, recent work emphasizes the importance of common species to ecosystems. Even relatively small proportional declines in their abundance can result in large absolute losses of individuals and biomass, occurrences significantly disrupting ecosystem structure, function and services. Here, we argue that combined with evidence of dramatic declines in once common species, this suggests the need to pay more attention to such depletions. Complementing the focus on extinction risk, we highlight important implications for conservation, including the need to identify, monitor and alleviate significant depletion events.

  13. Copenhagen delegates advance phaseout of ozone depleters

    SciTech Connect

    Kirschner, E.

    1992-12-09

    As expected, delegates at the United Nations Ozone Layer Conference in Copenhagen sped up ozone depleter phaseouts from the 1987 Montreal Protocol and the 1990 London amendments. The changes bring the worldwide production phaseout of chlorofluorocarbons (CFCs) and other ozone depleters in developed countries in line with U.S. and European plans announced earlier this year. Adjustments to the protocol, which are binding on the signatories, change the phaseout for CFC, carbon tetrachloride, and methyl chloroform production and consumption to January 1, 1996 from 2000. The 75% reduction of 1986 levels from CFCs by January 1, 1994 is a compromise between European pressure for an 85% cut and the US goal of 70%. Halon production is to end January 1, 1994, as anticipated. Developing countries continue to have a 10-year grace period. Friends of the Earth ozone campaign director Liz Cook counters that the phaseout dates were scheduled with concern for the chemical industry, not for the ozone layer.

  14. Depleted uranium plasma reduction system study

    SciTech Connect

    Rekemeyer, P.; Feizollahi, F.; Quapp, W.J.; Brown, B.W.

    1994-12-01

    A system life-cycle cost study was conducted of a preliminary design concept for a plasma reduction process for converting depleted uranium to uranium metal and anhydrous HF. The plasma-based process is expected to offer significant economic and environmental advantages over present technology. Depleted Uranium is currently stored in the form of solid UF{sub 6}, of which approximately 575,000 metric tons is stored at three locations in the U.S. The proposed system is preconceptual in nature, but includes all necessary processing equipment and facilities to perform the process. The study has identified total processing cost of approximately $3.00/kg of UF{sub 6} processed. Based on the results of this study, the development of a laboratory-scale system (1 kg/h throughput of UF6) is warranted. Further scaling of the process to pilot scale will be determined after laboratory testing is complete.

  15. Endoplasmic-Reticulum Calcium Depletion and Disease

    PubMed Central

    Mekahli, Djalila; Bultynck, Geert; Parys, Jan B.; De Smedt, Humbert; Missiaen, Ludwig

    2011-01-01

    The endoplasmic reticulum (ER) as an intracellular Ca2+ store not only sets up cytosolic Ca2+ signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca2+ depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca2+ may no longer sustain essential cell functions. On the other hand, loss of luminal Ca2+ causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca2+ depletion. PMID:21441595

  16. Altitude latitude mapping of plasma depletions

    NASA Astrophysics Data System (ADS)

    Rajesh, P.; Liu, J.; Sinha, H.; Banerje, S.

    2007-12-01

    Plasma depletions, if generated at the geomagnetic equator, are expected to appear in the all sky images as dark bands extending pole ward. The all sky observations conducted from Kavalur (12.5¢ªN, 78.8¢ªE; 4.6¢ªN, geomagnetic), INDIA, but showed dark patches in 630.0 nm entering the imager field of view (FOV) from the northern edge in the post-sunset period. These patches gradually extended towards equator and became fully extended dark bands in the North-South direction by midnight. The series of such images appeared to be the airglow signatures of irregularities that are probably generated at off-equatorial latitudes and mapped to the lower or equatorial latitudes. Similar features were observed in several nights. This appearance of depletions as dark patches from the northern edge of the FOV is explained in this work

  17. Cyanate causes depletion of ascorbate in organisms.

    PubMed

    Koshiishi, I; Mamura, Y; Imanari, T

    1997-10-20

    Ascorbate-dehydroascorbate redox cycle plays a key role in protecting organisms from an excess of oxidants. Recently, we found a novel reaction of dehydroascorbate with cyanate under the conditions of neutral pH and ordinary temperature. In this report, we demonstrated that through this irreversible reaction, cyanate causes the depletion of ascorbate in the matrix, where the ascorbate-dehydroascorbate redox cycle revolves. When the leaves of weed (Erigeron canadensis) were soaked in sodium cyanate solution generally used as a herbicide, the depletion of ascorbate as well as dehydroascorbate in them was observed, followed by the change in color from green to brown. These results suggest that a possible way of cyanate toxicity is to inflict oxidative stress on organisms.

  18. Replacements For Ozone-Depleting Foaming Agents

    NASA Technical Reports Server (NTRS)

    Blevins, Elana; Sharpe, Jon B.

    1995-01-01

    Fluorinated ethers used in place of chlorofluorocarbons and hydrochlorofluorocarbons. Replacement necessary because CFC's and HCFC's found to contribute to depletion of ozone from upper atmosphere, and manufacture and use of them by law phased out in near future. Two fluorinated ethers do not have ozone-depletion potential and used in existing foam-producing equipment, designed to handle liquid blowing agents soluble in chemical ingredients that mixed to make foam. Any polyurethane-based foams and several cellular plastics blown with these fluorinated ethers used in processes as diverse as small batch pours, large sprays, or double-band lamination to make insulation for private homes, commercial buildings, shipping containers, and storage tanks. Fluorinated ethers proved useful as replacements for CFC refrigerants and solvents.

  19. The Behavioral Pharmacology of Effort-related Choice Behavior: Dopamine, Adenosine and Beyond

    PubMed Central

    Salamone, John D; Correa, Merce; Nunes, Eric J; Randall, Patrick A; Pardo, Marta

    2012-01-01

    For many years, it has been suggested that drugs that interfere with dopamine (DA) transmission alter the “rewarding” impact of primary reinforcers such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in effort-related choice behavior. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA-depleted rats show a heightened sensitivity to response costs, especially ratio requirements. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and show increased selection of low reinforcement/low cost options. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as symptoms such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders. PMID:22287808

  20. The behavioral pharmacology of effort-related choice behavior: dopamine, adenosine and beyond.

    PubMed

    Salamone, John D; Correa, Merce; Nunes, Eric J; Randall, Patrick A; Pardo, Marta

    2012-01-01

    For many years, it has been suggested that drugs that interfere with dopamine (DA) transmission alter the "rewarding" impact of primary reinforcers such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in effort-related choice behavior. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA-depleted rats show a heightened sensitivity to response costs, especially ratio requirements. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and show increased selection of low reinforcement/low cost options. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as symptoms such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders.

  1. The behavioral pharmacology of effort-related choice behavior: dopamine, adenosine and beyond.

    PubMed

    Salamone, John D; Correa, Merce; Nunes, Eric J; Randall, Patrick A; Pardo, Marta

    2012-01-01

    For many years, it has been suggested that drugs that interfere with dopamine (DA) transmission alter the "rewarding" impact of primary reinforcers such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in effort-related choice behavior. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA-depleted rats show a heightened sensitivity to response costs, especially ratio requirements. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and show increased selection of low reinforcement/low cost options. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as symptoms such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders. PMID:22287808

  2. Depletion modeling of liquid dominated geothermal reservoirs

    SciTech Connect

    Olsen, G.

    1984-06-01

    Depletion models for liquid-dominated geothermal reservoirs are derived and presented. The depletion models are divided into two categories: confined and unconfined. For both cases depletion models with no recharge (or influx), and depletion models including recharge, are used to match field data from the Svartsengi high temperature geothermal field in Iceland. The influx models included with the mass and energy balances are adopted from the petroleum engineering literature. The match to production data from Svartsengi is improved when influx was included. The Schilthuis steady-state influx gives a satisfactory match. The finite aquifer method of Fetkovitch, and the unsteady state method of Hurst gave reasonable answers, but not as good. The best match is obtained using Hurst simplified solution when lambda = 1.3 x 10{sup -4} m{sup -1}. From the match the cross-sectional area of the aquifer was calculated as 3.6 km{sup 2}. The drawdown was predicted using the Hurst simplified method, and compared with predicted drawdown from a boiling model and an empirical log-log model. A large difference between the models was obtained. The predicted drawdown using the Hurst simplified method falls between the other two. Injection has been considered by defining the net rate as being the production rate minus the injection rate. No thermal of transient effects were taken into account. Prediction using three different net rates shows that the pressure can be maintained using the Hurst simplified method if there is significant fluid reinjection. 32 refs., 44 figs., 2 tabs.

  3. Carbon sequestration in depleted oil shale deposits

    SciTech Connect

    Burnham, Alan K; Carroll, Susan A

    2014-12-02

    A method and apparatus are described for sequestering carbon dioxide underground by mineralizing the carbon dioxide with coinjected fluids and minerals remaining from the extraction shale oil. In one embodiment, the oil shale of an illite-rich oil shale is heated to pyrolyze the shale underground, and carbon dioxide is provided to the remaining depleted oil shale while at an elevated temperature. Conditions are sufficient to mineralize the carbon dioxide.

  4. The ultimate disposition of depleted uranium

    SciTech Connect

    Not Available

    1990-12-01

    Significant amounts of the depleted uranium (DU) created by past uranium enrichment activities have been sold, disposed of commercially, or utilized by defense programs. In recent years, however, the demand for DU has become quite small compared to quantities available, and within the US Department of Energy (DOE) there is concern for any risks and/or cost liabilities that might be associated with the ever-growing inventory of this material. As a result, Martin Marietta Energy Systems, Inc. (Energy Systems), was asked to review options and to develop a comprehensive plan for inventory management and the ultimate disposition of DU accumulated at the gaseous diffusion plants (GDPs). An Energy Systems task team, under the chairmanship of T. R. Lemons, was formed in late 1989 to provide advice and guidance for this task. This report reviews options and recommends actions and objectives in the management of working inventories of partially depleted feed (PDF) materials and for the ultimate disposition of fully depleted uranium (FDU). Actions that should be considered are as follows. (1) Inspect UF{sub 6} cylinders on a semiannual basis. (2) Upgrade cylinder maintenance and storage yards. (3) Convert FDU to U{sub 3}O{sub 8} for long-term storage or disposal. This will include provisions for partial recovery of costs to offset those associated with DU inventory management and the ultimate disposal of FDU. Another recommendation is to drop the term tails'' in favor of depleted uranium'' or DU'' because the tails'' label implies that it is waste.'' 13 refs.

  5. Clara epithelial cell depletion in the lung.

    PubMed

    Sonar, Sanchaita S; Dudda, Jan C

    2013-01-01

    The bronchial epithelium has been increasingly recognized as an important immunomodulatory compartment in asthma and other lung diseases. Clara cells, which comprise the nonciliated secretory epithelial cells, are an important epithelial cell type with functions in the regulation of lung homeostasis and inflammation. Using naphthalene, Clara cells can be depleted within 24 h and regenerate by 1 month, hence, providing an easy method to study the impact of Clara cells on lung inflammation.

  6. The ultimate disposition of depleted uranium

    SciTech Connect

    Lemons, T.R.

    1991-12-31

    Depleted uranium (DU) is produced as a by-product of the uranium enrichment process. Over 340,000 MTU of DU in the form of UF{sub 6} have been accumulated at the US government gaseous diffusion plants and the stockpile continues to grow. An overview of issues and objectives associated with the inventory management and the ultimate disposition of this material is presented.

  7. Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

    PubMed Central

    Hearing, Matthew C.; Jedynak, Jakub; Ebner, Stephanie R.; Ingebretson, Anna; Asp, Anders J.; Fischer, Rachel A.; Schmidt, Clare; Larson, Erin B.; Thomas, Mark John

    2016-01-01

    Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type–specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10–14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies. PMID:26739562

  8. Investigating the dynamics of the brain response to music: A central role of the ventral striatum/nucleus accumbens.

    PubMed

    Mueller, Karsten; Fritz, Thomas; Mildner, Toralf; Richter, Maxi; Schulze, Katrin; Lepsien, Jöran; Schroeter, Matthias L; Möller, Harald E

    2015-08-01

    Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines.

  9. RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles

    PubMed Central

    Keebaugh, Alaine C.; Barrett, Catherine E.; LaPrairie, Jamie L.; Jenkins, Jasmine J.; Young, Larry J.

    2015-01-01

    Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the nucleus accumbens (NAcc) inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior. PMID:25874849

  10. BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli

    PubMed Central

    Sun, HaoSheng; Martin, Jennifer A.; Werner, Craig T.; Wang, Zi-Jun; Damez-Werno, Diane M.; Scobie, Kimberly N.; Shao, Ning-Yi; Dias, Caroline; Rabkin, Jacqui; Koo, Ja Wook; Gancarz, Amy M.; Mouzon, Ezekiell A.; Neve, Rachael L.; Shen, Li; Dietz, David M.

    2016-01-01

    ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. SIGNIFICANCE STATEMENT We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes. PMID:27053203

  11. Reward-guided learning beyond dopamine in the nucleus accumbens: The integrative functions of cortico-basal ganglia networks

    PubMed Central

    Yin, Henry H.; Ostlund, Sean B.; Balleine, Bernard W.

    2009-01-01

    Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise. It now appears that, in reward-guided learning, the functions of ventral and dorsal striata, and the cortico-basal ganglia circuitry associated with them, can be dissociated. Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance, the dorsal striatum is necessary for the acquisition and expression of instrumental actions. Such findings suggest the existence of multiple independent yet interacting functional systems that are implemented in iterating and hierarchically organized cortico-basal ganglia networks engaged in appetitive behaviors ranging from Pavlovian approach responses to goal-directed instrumental actions controlled by action-outcome contingencies. PMID:18793321

  12. Cage-induced stereotypic behaviour in laboratory mice covaries with nucleus accumbens FosB/ΔFosB expression.

    PubMed

    Phillips, Danielle; Choleris, Elena; Ervin, Kelsy S J; Fureix, Carole; Harper, Laura; Reynolds, Kathryn; Niel, Lee; Mason, Georgia J

    2016-03-15

    Stereotypic behaviour (SB) occurs in certain human disorders (e.g. autism), and animals treated with stimulants or raised in impoverished conditions, including laboratory mice in standard cages. Dysfunctional cortico-basal ganglia pathways have been implicated in these examples, but for cage-induced forms of SB, the relative roles of ventral versus dorsal striatum had not been fully ascertained. Here, we used immunohistochemical staining of FosB and ΔFosB to assess long-term activation within the nucleus accumbens and caudate-putamen of C57BL/6 mice. Housed in typical laboratory cages, these mice spontaneously developed different degrees of route-tracing, bar-mouthing and other forms of SB (spending 0% to over 50% of their active time budgets in this behaviour). The most highly stereotypic mice showed the most elevated FosB/ΔFosB activity in the nucleus accumbens. No such patterns occurred in the caudate-putamen. The cage-induced SB common in standard-housed mice thus involves elevated activity within the ventral striatum, suggesting an aetiology closer to compulsive gambling, eating and drug-seeking than to classic amphetamine stereotypies and other behaviours induced by motor loop over-activation.

  13. Investigating the dynamics of the brain response to music: A central role of the ventral striatum/nucleus accumbens.

    PubMed

    Mueller, Karsten; Fritz, Thomas; Mildner, Toralf; Richter, Maxi; Schulze, Katrin; Lepsien, Jöran; Schroeter, Matthias L; Möller, Harald E

    2015-08-01

    Ventral striatal activity has been previously shown to correspond well to reward value mediated by music. Here, we investigate the dynamic brain response to music and manipulated counterparts using functional magnetic resonance imaging (fMRI). Counterparts of musical excerpts were produced by either manipulating the consonance/dissonance of the musical fragments or playing them backwards (or both). Results show a greater involvement of the ventral striatum/nucleus accumbens both when contrasting listening to music that is perceived as pleasant and listening to a manipulated version perceived as unpleasant (backward dissonant), as well as in a parametric analysis for increasing pleasantness. Notably, both analyses yielded a ventral striatal response that was strongest during an early phase of stimulus presentation. A hippocampal response to the musical stimuli was also observed, and was largely mediated by processing differences between listening to forward and backward music. This hippocampal involvement was again strongest during the early response to the music. Auditory cortex activity was more strongly evoked by the original (pleasant) music compared to its manipulated counterparts, but did not display a similar decline of activation over time as subcortical activity. These findings rather suggest that the ventral striatal/nucleus accumbens response during music listening is strongest in the first seconds and then declines. PMID:25976924

  14. Pumping test evaluation of stream depletion parameters.

    PubMed

    Lough, Hilary K; Hunt, Bruce

    2006-01-01

    Descriptions are given of a pumping test and a corresponding analysis that permit calculation of all five hydrogeological parameters appearing in the Hunt (2003) solution for stream depletion caused by ground water abstraction from a well beside a stream. This solution assumes that flow in the pumped aquifer is horizontal, flow in the overlying aquitard or system of aquitards is vertical, and the free surface in the top aquitard is allowed to draw down. The definition of an aquitard in this paper is any layer with a vertical hydraulic conductivity much lower than the horizontal hydraulic conductivity of the pumped aquifer. These "aquitards" may be reasonably permeable layers but are distinguished from the pumped aquifer by their hydraulic conductivity contrast. The pumping test requires a complete set of drawdown measurements from at least one observation well. This well must be deep enough to penetrate the pumped aquifer, and pumping must continue for a sufficient time to ensure that depleted streamflow becomes a significant portion of the well abstraction rate. Furthermore, two of the five parameters characterize an aquitard that overlies the pumped aquifer, and values for these parameters are seen to be dependent upon the initial water table elevation in the aquitard. The field test analyzed herein used a total of eight observation wells screened in the pumped aquifer, and measurements from these wells gave eight sets of parameters that are used in a sensitivity analysis to determine the relative importance of each parameter in the stream depletion calculations. PMID:16857031

  15. Barium depletion in hollow cathode emitters

    NASA Astrophysics Data System (ADS)

    Polk, James E.; Mikellides, Ioannis G.; Capece, Angela M.; Katz, Ira

    2016-01-01

    Dispenser hollow cathodes rely on a consumable supply of Ba released by BaO-CaO-Al2O3 source material in the pores of a tungsten matrix to maintain a low work function surface. The examination of cathode emitters from long duration tests shows deposits of tungsten at the downstream end that appear to block the flow of Ba from the interior. In addition, a numerical model of Ba transport in the cathode plasma indicates that the Ba partial pressure in the insert may exceed the equilibrium vapor pressure of the dominant Ba-producing reaction, and it was postulated previously that this would suppress Ba loss in the upstream part of the emitter. New measurements of the Ba depletion depth from a cathode insert operated for 8200 h reveal that Ba loss is confined to a narrow region near the downstream end, confirming this hypothesis. The Ba transport model was modified to predict the depletion depth with time. A comparison of the calculated and measured depletion depths gives excellent qualitative agreement, and quantitative agreement was obtained assuming an insert temperature 70 °C lower than measured beginning-of-life values.

  16. Antarctic springtime depletion of atmospheric mercury.

    PubMed

    Ebinghaus, Ralf; Kock, Hans H; Temme, Christian; Einax, Jürgen W; Lowe, Astrid G; Richter, Andreas; Burrows, John P; Schroeder, William H

    2002-03-15

    Unlike other heavy metals that are inherently associated with atmospheric aerosols, mercury in ambient air exists predominantly in the gaseous elemental form. Because of its prolonged atmospheric residence time, elemental mercury vapor is distributed on a global scale. Recently, Canadian researchers have discovered that total gaseous mercury levels in the lower tropospheric boundary layer in the Canadian Arctic are often significantly depleted during the months after polar sunrise. A possible explanation may involve oxidation of elemental mercury, followed by adsorption and deposition of the oxidized form, leading to an increased input of atmospheric mercury into the Arctic ecosystem. Here we present the first continuous high-time-resolution measurements of total gaseous mercury in the Antarctic covering a 12-month period between January 2000 and January 2001 at the German Antarctic research station Neumayer (70 degrees 39' S, 8 degrees 15' W). We report that mercury depletion events also occur in the Antarctic after polar sunrise and compare our measurements with a data setfrom Alert, Nunavut, Canada. We also present indications that BrO radicals and ozone play a key role in the boundary-layer chemistry during springtime mercury depletion events in the Antarctic troposphere.

  17. A Comprehensive Study of Interstellar Depletions

    NASA Astrophysics Data System (ADS)

    Jenkins, Edward

    2004-07-01

    We propose to analyze interstellar gas-phase abundances of Ga, Sn, Pb, B, S by measuring their absorption features in the spectra of stars observed in SNAP survey programs 8241, 8662 and 9434 {plus other programs that have had archive data released to the public}. The lines of Pb II and B II are extremely weak, so stars will be grouped into cases having different levels of general depletion and then within each category the spectra will be coadded to enhance the detectability of the lines. These data will be combined with results derived by S. Cartledge and coworkers on O and Kr, plus data soon to be published for Ge, Cu, Mg, Mn, Ni and P, in order to understand the general behavior of depletions of atoms onto dust grains under different conditions, using a new analysis technique developed by Jenkins {2003}. A better knowledge of the systematics of depletions will be beneficial to studies of the compositions of dust grains and will also aid investigations of total element abundances in distant damped L-alpha {DLA} systems seen in the spectra of quasars recorded by ground-based telescopes.

  18. Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress

    PubMed Central

    Hodes, Georgia E.; Pfau, Madeline L.; Purushothaman, Immanuel; Ahn, H. Francisca; Golden, Sam A.; Christoffel, Daniel J.; Magida, Jane; Brancato, Anna; Takahashi, Aki; Flanigan, Meghan E.; Ménard, Caroline; Aleyasin, Hossein; Koo, Ja Wook; Lorsch, Zachary S.; Feng, Jian; Heshmati, Mitra; Wang, Minghui; Turecki, Gustavo; Neve, Rachel; Zhang, Bin; Shen, Li; Nestler, Eric J.

    2015-01-01

    Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. SIGNIFICANCE STATEMENT Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic

  19. Integrative proteomic analysis of the nucleus accumbens in rhesus monkeys following cocaine self-administration.

    PubMed

    Tannu, N S; Howell, L L; Hemby, S E

    2010-02-01

    The reinforcing effects and long-term consequences of cocaine self-administration have been associated with brain regions of the mesolimbic dopamine pathway, namely the nucleus accumbens (NAc). Studies of cocaine-induced biochemical adaptations in rodent models have advanced our knowledge; however, unbiased detailed assessments of intracellular alterations in the primate brain are scarce, yet essential, to develop a comprehensive understanding of cocaine addiction. To this end, two-dimensional difference in gel electrophoresis (2D-DIGE) was used to compare changes in cytosolic protein abundance in the NAc between rhesus monkeys self-administering cocaine and controls. Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser-desorption ionization time-of-flight time-of-flight (MALDI-TOF-TOF). In total, 1098 spots were subjected to statistical analysis with 22 spots found to be differentially abundant of which 18 proteins were positively identified by mass spectrometry. In addition, approximately 1000 protein spots were constitutively expressed of which 21 proteins were positively identified by mass spectrometry. Increased levels of proteins in the cocaine-exposed monkeys include glial fibrillary acidic protein, syntaxin-binding protein 3, protein kinase C isoform, adenylate kinase isoenzyme 5 and mitochondrial-related proteins, whereas decreased levels of proteins included beta-soluble N-ethylmaleimide-sensitive factor attachment protein and neural and non-neural enolase. Using a complimentary proteomics approach, the differential expression of phosphorylated proteins in the cytosolic fraction of these subjects was examined. Two-dimensional gel electrophoresis (2DGE) was followed by gel staining with Pro-Q Diamond phosphoprotein gel stain, enabling differentiation of approximately 150 phosphoprotein spots between the groups. Following excision and

  20. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression

    PubMed Central

    Barr, Jeffrey L.; Forster, Gina L.; Unterwald, Ellen M.

    2014-01-01

    Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In the present study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-D-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A:NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. PMID:24832868

  1. Lesions of the dopaminergic innervation of the nucleus accumbens medial shell delay the generation of preference for sucrose, but not of sexual pheromones.

    PubMed

    Martínez-Hernández, José; Lanuza, Enrique; Martínez-García, Fernando

    2012-01-15

    Male sexual pheromones are rewarding stimuli for female mice, able to induce conditioned place preference. To test whether processing these natural reinforcing stimuli depends on the dopaminergic innervation of the nucleus accumbens, as for other natural rewards, we compare the effects of specific lesions of the dopaminergic innervation of the medial shell of the nucleus accumbens on two different appetitive behaviours, 'pheromone seeking' and sucrose preferential intake. Female mice, with no previous experience with either adult male chemical stimuli or with sucrose, received injections of 6-hydroxydopamine (or vehicle) in the medial shell of the accumbens. Then, we analyzed their preference for male soiled-bedding and their preferential intake of a sucrose solution, with particular emphasis on the dynamics of acquisition of both natural rewards. The results indicate that both lesioned and sham animals showed similar preference for male sexual pheromones, which was constant along the test (linear dynamics). In contrast, lesioned animals differed from sham operated mice in the dynamics of sucrose consumption in their first test of sucrose preference. Sham animals showed an initial sucrose preference followed by preference for water, which can be interpreted as sucrose neophobia. Lesioned animals showed no preference at the beginning of the test, and a delayed sucrose preference appeared followed by a delayed neophobia. The next day, during a second sucrose-preference test, both groups displayed comparable and sustained preferential sucrose intake. Therefore, dopamine in the medial shell of the nucleus accumbens has a different role on the reward of sexual pheromones and sucrose.

  2. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    ERIC Educational Resources Information Center

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  3. AMPA/Kainate, NMDA, and Dopamine D1 Receptor Function in the Nucleus Accumbens Core: A Context-Limited Role in the Encoding and Consolidation of Instrumental Memory

    ERIC Educational Resources Information Center

    Hernandez, Pepe J.; Andrzejewski, Matthew E.; Sadeghian, Kenneth; Panksepp, Jules B.; Kelley, Ann E.

    2005-01-01

    Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of…

  4. No Evidence for Sex Differences in the Electrophysiological Properties and Excitatory Synaptic Input onto Nucleus Accumbens Shell Medium Spiny Neurons123

    PubMed Central

    Will, Tyler; Hauser, Caitlin A.; Cao, Jinyan

    2016-01-01

    Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. These investigations yield accumulating evidence of sexually different electrophysiological properties, excitatory synaptic input, and sensitivity to neuromodulator/hormone action in select striatal regions both before and after puberty. It is unknown whether the electrical properties of neurons in the nucleus accumbens shell differ by sex, and whether sex differences in excitatory synaptic input are present before puberty. To test the hypothesis that these properties differ by sex, we performed whole-cell patch-clamp recordings on male and female medium spiny neurons (MSNs) in acute brain slices obtained from prepubertal rat nucleus accumbens shell. We analyzed passive and active electrophysiological properties, and miniature EPSCs (mEPSCs). No sex differences were detected; this includes those properties, such as intrinsic excitability, action potential afterhyperpolarization, threshold, and mEPSC frequency, that have been found to differ by sex in other striatal regions and/or developmental periods. These findings indicate that, unlike other striatal brain regions, the electrophysiological properties of nucleus accumbens shell MSNs do not differ by sex. Overall, it appears that sex differences in striatal function, including motivated behavior and reward, are likely mediated by other factors and striatal regions. PMID:27022621

  5. DeltaFosB is increased in the nucleus accumbens by amphetamine but not social housing or isolation in the prairie vole.

    PubMed

    Hostetler, C M; Bales, K L

    2012-05-17

    The nucleus accumbens is a key region that mediates aspects of immediate and long-term adaptations to various stimuli. For example, both repeated amphetamine and pair-bonding increase dopamine D1 receptor binding in the nucleus accumbens of the monogamous prairie vole (Microtus ochrogaster). This upregulation has significant and stimulus-dependent behavioral consequences. A promising candidate for these and other adaptations is the transcription factor ΔfosB. ΔfosB is a highly stable protein that persists in the brain over long periods of time, leading to increasing and accumulating levels with repeated or continuous exposure to specific stimuli. Within the nucleus accumbens, ΔfosB is specifically increased in medium spiny neurons containing D1 receptors. To explore whether ΔfosB is altered by drug and social experience in prairie voles, we performed three separate experiments. In the first experiment, animals were treated with repeated injections of amphetamine and then brain tissue was analyzed for ΔfosB expression. As expected, 4 days of amphetamine treatment increased ΔfosB in the nucleus accumbens, consistent with previous findings in other laboratory species. In the second experiment, animals were housed for 10 days with one of three social partners: a familiar same-sex sibling, an unfamiliar same-sex partner, or an unfamiliar opposite-sex partner. Here, we predicted that 10 days of housing with an opposite-sex partner would act as a "social reward," leading to upregulation of ΔfosB expression in the nucleus accumbens. In a third experiment, we also investigated whether 10 days of social isolation would result in altered ΔfosB activity. We hypothesized that isolation would lead to decreased levels of nucleus accumbens ΔfosB, as seen in other studies. However, neither opposite-sex cohabitation nor social isolation affected ΔfosB expression in the nucleus accumbens. These findings suggest that social stimuli, in contrast to drugs of abuse, are not

  6. 26 CFR 52.4682-1 - Ozone-depleting chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 17 2014-04-01 2014-04-01 false Ozone-depleting chemicals. 52.4682-1 Section 52... EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4682-1 Ozone-depleting chemicals. (a) Overview. This section provides rules relating to the tax imposed on ozone-depleting chemicals (ODCs) under section...

  7. 26 CFR 52.4682-1 - Ozone-depleting chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Ozone-depleting chemicals. 52.4682-1 Section 52... EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4682-1 Ozone-depleting chemicals. (a) Overview. This section provides rules relating to the tax imposed on ozone-depleting chemicals (ODCs) under section...

  8. 26 CFR 52.4682-1 - Ozone-depleting chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 17 2011-04-01 2011-04-01 false Ozone-depleting chemicals. 52.4682-1 Section 52... EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4682-1 Ozone-depleting chemicals. (a) Overview. This section provides rules relating to the tax imposed on ozone-depleting chemicals (ODCs) under section...

  9. 26 CFR 52.4682-1 - Ozone-depleting chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 17 2013-04-01 2013-04-01 false Ozone-depleting chemicals. 52.4682-1 Section 52... EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4682-1 Ozone-depleting chemicals. (a) Overview. This section provides rules relating to the tax imposed on ozone-depleting chemicals (ODCs) under section...

  10. 26 CFR 52.4682-1 - Ozone-depleting chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 17 2012-04-01 2012-04-01 false Ozone-depleting chemicals. 52.4682-1 Section 52... EXCISE TAXES (CONTINUED) ENVIRONMENTAL TAXES § 52.4682-1 Ozone-depleting chemicals. (a) Overview. This section provides rules relating to the tax imposed on ozone-depleting chemicals (ODCs) under section...

  11. Children's Models of the Ozone Layer and Ozone Depletion.

    ERIC Educational Resources Information Center

    Christidou, Vasilia; Koulaidis, Vasilis

    1996-01-01

    The views of 40 primary students on ozone and its depletion were recorded through individual, semi-structured interviews. The data analysis resulted in the formation of a limited number of models concerning the distribution and role of ozone in the atmosphere, the depletion process, and the consequences of ozone depletion. Identifies five target…

  12. 26 CFR 1.642(e)-1 - Depreciation and depletion.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Depreciation and depletion. 1.642(e)-1 Section 1... (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.642(e)-1 Depreciation and depletion. An estate or trust is allowed the deductions for depreciation and depletion, but only to the extent...

  13. A modern depleted uranium manufacturing facility

    SciTech Connect

    Zagula, T.A.

    1995-07-01

    The Specific Manufacturing Capabilities (SMC) Project located at the Idaho National Engineering Laboratory (INEL) and operated by Lockheed Martin Idaho Technologies Co. (LMIT) for the Department of Energy (DOE) manufactures depleted uranium for use in the U.S. Army MIA2 Abrams Heavy Tank Armor Program. Since 1986, SMC has fabricated more than 12 million pounds of depleted uranium (DU) products in a multitude of shapes and sizes with varying metallurgical properties while maintaining security, environmental, health and safety requirements. During initial facility design in the early 1980`s, emphasis on employee safety, radiation control and environmental consciousness was gaining momentum throughout the DOE complex. This fact coupled with security and production requirements forced design efforts to focus on incorporating automation, local containment and computerized material accountability at all work stations. The result was a fully automated production facility engineered to manufacture DU armor packages with virtually no human contact while maintaining security, traceability and quality requirements. This hands off approach to handling depleted uranium resulted in minimal radiation exposures and employee injuries. Construction of the manufacturing facility was complete in early 1986 with the first armor package certified in October 1986. Rolling facility construction was completed in 1987 with the first certified plate produced in the fall of 1988. Since 1988 the rolling and manufacturing facilities have delivered more than 2600 armor packages on schedule with 100% final product quality acceptance. During this period there was an annual average of only 2.2 lost time incidents and a single individual maximum radiation exposure of 150 mrem. SMC is an example of designing and operating a facility that meets regulatory requirements with respect to national security, radiation control and personnel safety while achieving production schedules and product quality.

  14. Rhenium Disulfide Depletion-Load Inverter

    NASA Astrophysics Data System (ADS)

    McClellan, Connor; Corbet, Chris; Rai, Amritesh; Movva, Hema C. P.; Tutuc, Emanuel; Banerjee, Sanjay K.

    2015-03-01

    Many semiconducting Transition Metal Dichalcogenide (TMD) materials have been effectively used to create Field-Effect Transistor (FET) devices but have yet to be used in logic designs. We constructed a depletion-load voltage inverter using ultrathin layers of Rhenium Disulfide (ReS2) as the semiconducting channel. This ReS2 inverter was fabricated on a single micromechanically-exfoliated flake of ReS2. Electron beam lithography and physical vapor deposition were used to construct Cr/Au electrical contacts, an Alumina top-gate dielectric, and metal top-gate electrodes. By using both low (Aluminum) and high (Palladium) work-function metals as two separate top-gates on a single ReS2 flake, we create a dual-gated depletion mode (D-mode) and enhancement mode (E-mode) FETs in series. Both FETs displayed current saturation in the output characteristics as a result of the FET ``pinch-off'' mechanism and On/Off current ratios of 105. Field-effect mobilities of 23 and 17 cm2V-1s-1 and subthreshold swings of 97 and 551 mV/decade were calculated for the E-mode and D-mode FETs, respectively. With a supply voltage of 1V, at low/negative input voltages the inverter output was at a high logic state of 900 mV. Conversely with high/positive input voltages, the inverter output was at a low logic state of 500 mV. The inversion of the input signal demonstrates the potential for using ReS2 in future integrated circuit designs and the versatility of depletion-load logic devices for TMD research. NRI SWAN Center and ARL STTR Program.

  15. Depletion of the Outer Asteroid Belt

    NASA Technical Reports Server (NTRS)

    Liou, Jer-Chyi; Malhotra, Renu

    1997-01-01

    During the early history of the solar system, it is likely that the outer planets changed their distance from the sun, and hence, their influence on the asteroid belt evolved with time. The gravitational influence of Jupiter and Saturn on the orbital evolution of asteroids in the outer asteroid belt was calculated. The results show that the sweeping of mean motion resonances associated with planetary migration efficiently destabilizes orbits in the outer asteroid belt on a time scale of 10 million years. This mechanism provides an explanation for the observed depletion of asteroids in that region.

  16. Cognitive inflexibility after prefrontal serotonin depletion.

    PubMed

    Clarke, H F; Dalley, J W; Crofts, H S; Robbins, T W; Roberts, A C

    2004-05-01

    Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.

  17. Scientific assessment of ozone depletion: 1991

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Over the past few years, there have been highly significant advances in the understanding of the impact of human activities on the Earth's stratospheric ozone layer and the influence of changes in chemical composition of the radiative balance of the climate system. Specifically, since the last international scientific review (1989), there have been five major advances: (1) global ozone decreases; (2) polar ozone; (3) ozone and industrial halocarbons; (4) ozone and climate relations; and (5) ozone depletion potentials (ODP's) and global warming potentials (GWP's). These topics and others are discussed.

  18. Correlation between cosmic rays and ozone depletion.

    PubMed

    Lu, Q-B

    2009-03-20

    This Letter reports reliable satellite data in the period of 1980-2007 covering two full 11-yr cosmic ray (CR) cycles, clearly showing the correlation between CRs and ozone depletion, especially the polar ozone loss (hole) over Antarctica. The results provide strong evidence of the physical mechanism that the CR-driven electron-induced reaction of halogenated molecules plays the dominant role in causing the ozone hole. Moreover, this mechanism predicts one of the severest ozone losses in 2008-2009 and probably another large hole around 2019-2020, according to the 11-yr CR cycle. PMID:19392251

  19. Ozone depletion: implications for the veterinarian.

    PubMed

    Kopecky, K E

    1978-09-15

    Man has inadvertently modified the stratosphere. There is a good possibility that the ozone layer is being depleted by the use of jet aircraft (SST), chlorofluoromethane propellants, and nitrogen fertilizers. Under unpolluted conditions, the production of ozone equals its destruction. By man's intervention, however, the destruction may exceed the production. The potential outcome is increased intensity of solar ultraviolet (280-400 nm) radiation and penetration to the earth's surface of previously absorbed wavelengths below about 280 nm. The increased ultraviolet radiation would increase the likelihood of skin cancer in man and ocular squamous cell carcinoma in cattle. The climate also might be modified, possibly in an undesirable way.

  20. Capstone Depleted Uranium Aerosols: Generation and Characterization

    SciTech Connect

    Parkhurst, MaryAnn; Szrom, Fran; Guilmette, Ray; Holmes, Tom; Cheng, Yung-Sung; Kenoyer, Judson L.; Collins, John W.; Sanderson, T. Ellory; Fliszar, Richard W.; Gold, Kenneth; Beckman, John C.; Long, Julie

    2004-10-19

    In a study designed to provide an improved scientific basis for assessing possible health effects from inhaling depleted uranium (DU) aerosols, a series of DU penetrators was fired at an Abrams tank and a Bradley fighting vehicle. A robust sampling system was designed to collect aerosols in this difficult environment and continuously monitor the sampler flow rates. Aerosols collected were analyzed for uranium concentration and particle size distribution as a function of time. They were also analyzed for uranium oxide phases, particle morphology, and dissolution in vitro. The resulting data provide input useful in human health risk assessments.

  1. Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

    PubMed Central

    Abrahao, Karina Possa; Oliveira Goeldner, Francine; Souza-Formigoni, Maria Lucia Oliveira

    2014-01-01

    In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor

  2. Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis.

    PubMed

    Bhatt, Apoorva; Kremer, Laurent; Dai, Annie Z; Sacchettini, James C; Jacobs, William R

    2005-11-01

    Inhibition or inactivation of InhA, a fatty acid synthase II (FASII) enzyme, leads to mycobacterial cell lysis. To determine whether inactivation of other enzymes of the mycolic acid-synthesizing FASII complex also leads to lysis, we characterized the essentiality of two beta-ketoacyl-acyl carrier protein synthases, KasA and KasB, in Mycobacterium smegmatis. Using specialized transduction for allelic exchange, null kasB mutants, but not kasA mutants, could be generated in Mycobacterium smegmatis, suggesting that unlike kasB, kasA is essential. To confirm the essentiality of kasA, and to detail the molecular events that occur following depletion of KasA, we developed CESTET (conditional expression specialized transduction essentiality test), a genetic tool that combines conditional gene expression and specialized transduction. Using CESTET, we were able to generate conditional null inhA and kasA mutants. We studied the effects of depletion of KasA in M. smegmatis using the former strain as a reference. Depletion of either InhA or KasA led to cell lysis, but with different biochemical and morphological events prior to lysis. While InhA depletion led to the induction of an 80-kDa complex containing both KasA and AcpM, the mycobacterial acyl carrier protein, KasA depletion did not induce the same complex. Depletion of either InhA or KasA led to inhibition of alpha and epoxy mycolate biosynthesis and to accumulation of alpha'-mycolates. Furthermore, scanning electron micrographs revealed that KasA depletion resulted in the cell surface having a "crumpled" appearance, in contrast to the blebs observed on InhA depletion. Thus, our studies support the further exploration of KasA as a target for mycobacterial-drug development. PMID:16267284

  3. Changes in benzodiazepine-GABA receptor coupling in an accumbens-habenula circuit after chronic diazepam treatment.

    PubMed Central

    Brett, R. R.; Pratt, J. A.

    1995-01-01

    1. The effects of subacute and of chronic diazepam treatment upon binding to the GABAA receptor have been examined by use of receptor autoradiography for determining flunitrazepam (FNZP) binding, GABA enhancement of FNZP binding. SR 95531 2-(3'-carboxy-2',propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding and GABA binding in parallel sections from rat brain. Prior to the autoradiographic procedures, a behavioural assessment of the rats was made in the elevated plus-maze test of anxiety. 2. Rats receiving diazepam either subacutely (3 days) or chronically (28 days) by both continuous release, from previously implanted subcutaneous silastic capsules, or by daily injection (5 mg kg-1) did not display changes in FNZP or GABA binding in any of the 47 brain structures analysed. Similarly, there were no significant effects of treatment upon mean total entries or on the open:total ratio for entries in the elevated plus-maze. 3. There were reductions in the GABA enhancement of FNZP binding in the nucleus accumbens and central grey after subacute diazepam treatment. This effect persisted in the nucleus accumbens after chronic treatment. Less marked effects occurred in the lateral habenula, dorsal raphe and substantia nigra pars compacta. In the dorsal tegmental nucleus, GABA enhancement of FNZP binding was enhanced after chronic treatment and this was accompanied by reductions in SR 95531 binding. Treatment did not otherwise affect SR 95531 binding, with the exception of the dorsal raphe where binding was decreased after subacute treatment. 4. In general, the patterns of binding produced by the two different treatment routes were very similar. However, SR 95531 binding was lower in certain hippocampal fields in the i.p. treated animals compared to the rats implanted with silastic capsules. 5. It is concluded that repeated administration of diazepam evokes changes in benzodiazepine and GABA receptor coupling, and to a lesser extent changes in low affinity GABA

  4. Mesospheric ionization and O2 1Delta(g) depletion

    NASA Technical Reports Server (NTRS)

    Spear, K. A.; Solomon, S.

    1987-01-01

    Observations of O2 1Delta(g) emission during solar proton events reveal large depletions below 80 and near 90 km. The lower-altitude depletions are believed to be due to odd hydrogen production and associated depletion of ozone, but the mechanism producing the depletion near 90 km has not yet been established. In this paper, it is proposed that an exothermic charge exchange reaction between O2(+) and O2 1Delta(g) is likely to be responsible for these high-altitude depletions. In particular, it is shown that the vertical structure of the observed change in airglow emission is consistent with this mechanism.

  5. Imaging neurotransmitter uptake and depletion in astrocytes

    SciTech Connect

    Tan, W. |; Haydon, P.G.; Yeung, E.S.

    1997-08-01

    An ultraviolet (UV) laser-based optical microscope and charge-coupled device (CCD) detection system was used to obtain chemical images of biological cells. Subcellular structures can be easily seen in both optical and fluorescence images. Laser-induced native fluorescence detection provides high sensitivity and low limits of detection, and it does not require coupling to fluorescent dyes. We were able to quantitatively monitor serotonin that has been taken up into and released from individual astrocytes on the basis of its native fluorescence. Different regions of the cells took up different amounts of serotonin with a variety of uptake kinetics. Similarly, we observed different serotonin depletion dynamics in different astrocyte regions. There were also some astrocyte areas where no serotonin uptake or depletion was observed. Potential applications include the mapping of other biogenic species in cells as well as the ability to image their release from specific regions of cells in response to external stimuli. {copyright} {ital 1997} {ital Society for Applied Spectroscopy}

  6. Halocarbon ozone depletion and global warming potentials

    NASA Technical Reports Server (NTRS)

    Cox, Richard A.; Wuebbles, D.; Atkinson, R.; Connell, Peter S.; Dorn, H. P.; Derudder, A.; Derwent, Richard G.; Fehsenfeld, F. C.; Fisher, D.; Isaksen, Ivar S. A.

    1990-01-01

    Concern over the global environmental consequences of fully halogenated chlorofluorocarbons (CFCs) has created a need to determine the potential impacts of other halogenated organic compounds on stratospheric ozone and climate. The CFCs, which do not contain an H atom, are not oxidized or photolyzed in the troposphere. These compounds are transported into the stratosphere where they decompose and can lead to chlorine catalyzed ozone depletion. The hydrochlorofluorocarbons (HCFCs or HFCs), in particular those proposed as substitutes for CFCs, contain at least one hydrogen atom in the molecule, which confers on these compounds a much greater sensitivity toward oxidation by hydroxyl radicals in the troposphere, resulting in much shorter atmospheric lifetimes than CFCs, and consequently lower potential for depleting ozone. The available information is reviewed which relates to the lifetime of these compounds (HCFCs and HFCs) in the troposphere, and up-to-date assessments are reported of the potential relative effects of CFCs, HCFCs, HFCs, and halons on stratospheric ozone and global climate (through 'greenhouse' global warming).

  7. The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

    PubMed

    Bradfield, Laura A; McNally, Gavan P

    2010-07-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

  8. A Single Intra-PFC Infusion of BDNF Prevents Cocaine-Induced Alterations in Extracellular Glutamate within the Nucleus Accumbens

    PubMed Central

    Berglind, William J.; Whitfield, Timothy W.; LaLumiere, Ryan T.; Kalivas, Peter W.; McGinty, Jacqueline F.

    2009-01-01

    The glutamatergic pathway arising in the dorsomedial prefrontal cortex (dmPFC) and projecting to the nucleus accumbens (NAc) core is a critical component of the reward circuitry that underlies reinstatement to cocaine-seeking behavior. Brain derived neurotrophic factor (BDNF) is expressed by and modulates PFC-NAc neurons. BDNF infusion into the dmPFC attenuates reinstatement to cocaine-seeking behavior as well as some cocaine-induced molecular adaptations within the NAc. In the present study, it is demonstrated that a single intra-dmPFC infusion of BDNF prevents cocaine self administration-induced reduction in basal extracelluar glutamate, as well as cocaine prime-induced increases in extracellular glutamate levels within the NAc. These data suggest that intra-PFC BDNF attenuates reinstatement to cocaine-seeking behavior by normalizing cocaine-induced neuroadaptations that alter glutamate neurotransmission within the NAc. PMID:19321768

  9. Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence.

    PubMed

    Zan, Gui-Ying; Wang, Qian; Wang, Yu-Jun; Liu, Yao; Hang, Ai; Shu, Xiao-Hong; Liu, Jing-Gen

    2015-09-15

    The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/κ opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of κ opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/κ opioid receptor system, and shed light on the κ opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal.

  10. Comparative analysis of oxytocin receptor density in the nucleus accumbens: an adaptation for female and male alloparental care?

    PubMed

    Olazábal, Daniel E

    2014-01-01

    Parental behavior is commonly displayed by progenitors. However, other individuals, genetically related (e.g. siblings, aunts, uncles) or not with the newborns, also display parental behavior (commonly called alloparental, or adoptive behavior). I hypothesize that species that live in family or social groups where other non-reproductive members (males and females) take care of infants, have brain adaptations to promote or facilitate that behavioral response. The present work revises the evidence supporting the hypothesis that high density of oxytocin receptors (OXTR) in the nucleus accumbens (NA) is one of those adaptations. All species known to have high NA OXTR show not only female, but also male alloparental care. Therefore, I predict that high NA OXTR could be present in all species in which juvenile and adult male alloparental behavior have been observed. Strategies to test this and other alternative working hypothesis and its predictions are presented. PMID:25446893

  11. White-Matter Tract Connecting Anterior Insula to Nucleus Accumbens Correlates with Reduced Preference for Positively Skewed Gambles

    PubMed Central

    Leong, Josiah K.; Pestilli, Franco; Wu, Charlene C.; Samanez-Larkin, Gregory R.; Knutson, Brian

    2016-01-01

    SUMMARY Individuals sometimes show inconsistent risk preferences, including excessive attraction to gambles featuring small chances of winning large amounts (called “positively skewed” gambles). While functional neuroimaging research indicates that nucleus accumbens (NAcc) and anterior insula (AIns) activity inversely predict risky choice, structural connections between these regions have not been described in humans. By combining diffusion-weighted MRI with tractography, we identified the anatomical trajectory of white-matter tracts projecting from the AIns to the NAcc and statistically validated these tracts using Linear Fascicle Evaluation (LiFE) and virtual lesions. Coherence of the right AIns-NAcc tract correlated with reduced preferences for positively skewed gambles. Further, diminished NAcc activity during gamble presentation mediated the association between tract structure and choice. These results identify an unreported tract connecting the AIns to the NAcc in humans and support the notion that structural connections can alter behavior by influencing brain activity as individuals weigh uncertain gains against uncertain losses. PMID:26748088

  12. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

    PubMed

    Ma, Delin; Shuler, Jeffrey M; Raider, Kayla D; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Stanford, John A

    2015-07-10

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

  13. Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity.

    PubMed

    Ary, Alexis W; Cozzoli, Debra K; Finn, Deborah A; Crabbe, John C; Dehoff, Marlin H; Worley, Paul F; Szumlinski, Karen K

    2012-06-01

    Neuronal activity dependent pentraxin (Narp) interacts with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors to facilitate excitatory synapse formation by aggregating them at established synapses. Alcohol is well-characterized to influence central glutamatergic transmission, including AMPA receptor function. Herein, we examined the influence of injected and ingested alcohol upon Narp protein expression, as well as basal Narp expression in mouse lines selectively bred for high blood alcohol concentrations under limited access conditions. Alcohol up-regulated accumbens Narp levels, concomitant with increases in levels of the GluR1 AMPA receptor subunit. However, accumbens Narp or GluR1 levels did not vary as a function of selectively bred genotype. We next employed a Narp knock-out (KO) strategy to begin to understand the behavioral relevance of alcohol-induced changes in protein expression in several assays of alcohol reward. Compared to wild-type mice, Narp KO animals: fail to escalate daily intake of high alcohol concentrations under free-access conditions; shift their preference away from high alcohol concentrations with repeated alcohol experience; exhibit a conditioned place-aversion in response to the repeated pairing of 3 g/kg alcohol with a distinct environment and fail to exhibit alcohol-induced locomotor hyperactivity following repeated alcohol treatment. Narp deletion did not influence the daily intake of either food or water, nor did it alter any aspect of spontaneous or alcohol-induced motor activity, including the development of tolerance to its motor-impairing effects with repeated treatment. Taken together, these data indicate that Narp induction, and presumably subsequent aggregation of AMPA receptors, may be important for neuroplasticity within limbic subcircuits mediating or maintaining the rewarding properties of alcohol.

  14. Differential effects of acute and repeated stress on hippocampus and amygdala inputs to the nucleus accumbens shell

    PubMed Central

    Gill, Kathryn M.; Grace, Anthony A.

    2013-01-01

    The basolateral amygdala (BLA) and ventral subiculum (vSub) of the hippocampus convey emotion and context information, respectively, to the nucleus accumbens (NAc). Using in vivo extracellular recordings from NAc neurons, we examined how acute and repeated restraint stress alters the plasticity of the vSub and BLA afferent pathways. High frequency (HFS) and low frequency (LFS) stimulation was applied to the vSub to assess the impact on NAc responses to vSub and BLA inputs. In addition, iontophoretic application of the D2-antagonist sulpiride was used to explore the role of dopamine in the NAc in mediating the effects of stress on plasticity. Acute and repeated restraint caused disparate effects on BLA- and vSub-evoked responses in the NAc. Following repeated restraint, but not after acute restraint, HFS of the vSub failed to potentiate the vSub-NAc pathway while instead promoting a long lasting reduction of the BLA-NAc pathway, and these effects were independent of D2-receptor activity. In contrast, LFS to the vSub pathway after acute restraint resulted in potentiation in the vSub-NAc pathway while BLA-evoked responses were unchanged. When sulpiride was applied prior to LFS of the vSub after acute stress, there was a pronounced decrease in vSub-evoked responses similar to control animals. This work provides new insight into the impact of acute and repeated stress on the integration of context and emotion inputs in the nucleus accumbens. These data support a model of stress whereby the hippocampus is inappropriately activated and dominates the information processing within this circuit via a dopaminergic mechanism after acute bouts of stress. PMID:23745764

  15. Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.

    PubMed

    De Luca, Maria Antonietta; Castelli, M Paola; Loi, Barbara; Porcu, Alessandra; Martorelli, Mariella; Miliano, Cristina; Kellett, Kathryn; Davidson, Colin; Stair, Jacqueline L; Schifano, Fabrizio; Di Chiara, Gaetano

    2016-06-01

    In order to investigate the in vivo dopamine (DA) stimulant properties of selected 3rd generation Spice/K2 cannabinoids, BB-22, 5F-PB-22, 5F-AKB-48 and STS-135, their in vitro affinity and agonist potency at native rat and mice CB1 receptors was studied. The compounds bind with high affinity to CB1 receptors in rat cerebral cortex homogenates and stimulate CB1-induced [(35)S]GTPγS binding with high potency and efficacy. BB-22 and 5F-PB-22 showed the lowest Ki of binding to CB1 receptors (0.11 and 0.13 nM), i.e., 30 and 26 times lower respectively than that of JWH-018 (3.38 nM), and a potency (EC50, 2.9 and 3.7 nM, respectively) and efficacy (Emax, 217% and 203%, respectively) as CB1 agonists higher than JWH-018 (EC50, 20.2 nM; Emax, 163%). 5F-AKB-48 and STS-135 had higher Ki for CB1 binding, higher EC50 and lower Emax as CB1 agonists than BB-22 and 5F-PB-22 but still comparatively more favourable than JWH-018. The agonist properties of all the compounds were abolished or drastically reduced by the CB1 antagonist/inverse agonist AM251 (0.1 μM). No activation of G-protein was observed in CB1-KO mice. BB-22 (0.003-0.01 mg/kg i.v.) increased dialysate DA in the accumbens shell but not in the core or in the medial prefrontal cortex, with a bell shaped dose-response curve and an effect at 0.01 mg/kg and a biphasic time-course. Systemic AM251 (1.0 mg/kg i.p.) completely prevented the stimulant effect of BB-22 on dialysate DA in the NAc shell. All the other compounds increased dialysate DA in the NAc shell at doses consistent with their in vitro affinity for CB1 receptors (5F-PB-22, 0.01 mg/kg; 5F-AKB-48, 0.1 mg/kg; STS-135, 0.15 mg/kg i.v.). 3rd generation cannabinoids can be even more potent and super-high CB1 receptor agonists compared to JWH-018. Future research will try to establish if these properties can explain the high toxicity and lethality associated with these compounds.

  16. Microfabrics in depleted mantle plaeotransform (New Caledonia)

    NASA Astrophysics Data System (ADS)

    Teyssier, Christian; Chatzaras, Vasileios; Von Der Handt, Anette

    2016-04-01

    The New Caledonia ophiolite contains several wrench zones that have been interpreted as paleotransforms. These transform-ridge systems developed at the transition between ridge development and intra-oceanic subduction that resulted in depleted mantle (about 18 % melt according to olivine Mg# - spinel Cr#). The most prominent is the Bogota Peninsula paleotransform, a 10 km wide shear zone in which strain localizes in the 2 km wide Ouassé mylonite zone. This strain gradient is associated with microstructure and microfabric evolution that informs the relationship between hydration and strain in mantle mylonite. Olivine recrystallized grain size varies from about 1 mm to about 0.2 mm toward the mylonite zone. The strain gradient is also demonstrated by increasing deformation of orthopyroxene (opx) grains that become elongate porphyroclasts in the mylonite zone. Orthopyroxene geothermometry reveals T ~ 1050-1000 C (Ca-opx) and 950-850 C (Cr-Al-opx) in the least deformed rocks. In the mylonite zone a wider range of T is recorded, with minima reaching 850 C (Ca-opx) and 750 C (Cr-Al-opx). Electron microprobe analysis also detects the presence of 20-200 micron interstitial, high-temperature amphibole (pargasite), with modal abundance increasing in the mylonite zone; this suggests that high-temperature pervasive fluid flow may have played a role in strain localization and mylonitization. Olivine crystallographic fabrics include A-type and E-type, the latter possibly reflecting hydration of shear zone tectonites. E-type fabrics are present in both mylonite and less deformed rocks, and appear to be more common in rocks with olivine grain size < 400 microns. A correlation between E-type fabrics and amphibole mode is being investigated. The shear zone protolith was depleted mantle in which the ridge-transform system was permeated by fluids. These fluids initially originated at the subduction interface, but during the transform evolution, ocean water likely permeated the shear

  17. Depleted uranium waste assay at AWE

    SciTech Connect

    Miller, T.J.

    2007-07-01

    The Atomic Weapons Establishment (AWE) at Aldermaston has recently conducted a Best Practical Means (BPM) study, for solid Depleted Uranium (DU) waste assay, in order to satisfy key stakeholders that AWE is applying best practice. This study has identified portable passive High Resolution Gamma Spectrometry (HRGS), combined with an analytical software package called Spectral Nondestructive Assay Platform (SNAP), as the preferred option with the best balance between performance and costs. HRGS/SNAP performance has been assessed by monitoring 200 l DU waste drum standards and also heterogeneous, high density drums from DU firing trials. Accuracy was usually within 30 % with Detection Limits (DL) in the region of 10 g DU for short count times. Monte Carlo N-Particle (MCNP) calculations have been used to confirm the shape of the calibration curve generated by the SNAP software procured from Eberline Services Inc. (authors)

  18. Health effects of embedded depleted uranium.

    PubMed

    McClain, David E; Benson, Kimberly A; Dalton, Tom K; Ejnik, John; Emond, Christy A; Hodge, Shelly J; Kalinich, John F; Landauer, Michael R; Livengood, David R; Miller, Alexandra C; Pellmar, Terry C; Stewart, Michael D; Villa, Vilmar; Xu, Jiaquan

    2002-02-01

    The health effects of embedded fragments of depleted uranium (DU) are being investigated to determine whether current surgical fragment-removal policies are appropriate for this metal. The authors studied rodents implanted with DU pellets as well as cultured human cells exposed to DU compounds. Results indicate that uranium from implanted DU fragments distributes to tissues distant from implantation sites, including bone, kidney, muscle, and liver. Despite levels of uranium in kidney that would be nephrotoxic after acute exposure, no histological or functional kidney toxicity was observed with embedded DU, indicating that the kidney adapts when exposed chronically. Nonetheless, further studies of the long-term health impact are needed. DU is mutagenic and transforms human osteoblastic cells into a tumorigenic phenotype. It alters neurophysiological parameters in rat hippocampus, crosses the placental barrier, and enters fetal tissue. Preliminary data also indicate decreased rodent litter size when animals are bred 6 months or longer after DU implantation. PMID:11873491

  19. Arctic Ozone Depletion from UARS MLS Measurements

    NASA Technical Reports Server (NTRS)

    Manney, G. L.

    1995-01-01

    Microwave Limb Sounder (MLS) measurements of ozone during four Arctic winters are compared. The evolution of ozone in the lower stratosphere is related to temperature, chlorine monoxide (also measured by MLS), and the evolution of the polar vortex. Lagrangian transport calculations using winds from the United Kingdom Meteorological Office's Stratosphere-Troposphere Data Assimilation system are used to estimate to what extent the evolution of lower stratospheric ozone is controlled by dynamics. Observations, along with calculations of the expected dynamical behavior, show evidence for chemical ozone depletion throughout most of the Arctic lower stratospheric vortex during the 1992-93 middle and late winter, and during all of the 1994-95 winter that was observed by MLS. Both of these winters were unusually cold and had unusually cold and had unusually strong Arctic polar vortices compared to meteorological data over the past 17 years.

  20. Anxiety, ego depletion, and sports performance.

    PubMed

    Englert, Chris; Bertrams, Alex

    2012-10-01

    In the present article, we analyzed the role of self-control strength and state anxiety in sports performance. We tested the hypothesis that self-control strength and state anxiety interact in predicting sports performance on the basis of two studies, each using a different sports task (Study 1: performance in a basketball free throw task, N = 64; Study 2: performance in a dart task, N = 79). The patterns of results were as expected in both studies: Participants with depleted self-control strength performed worse in the specific tasks as their anxiety increased, whereas there was no significant relation for participants with fully available self-control strength. Furthermore, different degrees of available self-control strength did not predict performance in participants who were low in state anxiety, but did in participants who were high in state anxiety. Thus increasing self-control strength could reduce the negative anxiety effects in sports and improve athletes' performance under pressure.

  1. Modelling chemical depletion profiles in regolith

    USGS Publications Warehouse

    Brantley, S.L.; Bandstra, J.; Moore, J.; White, A.F.

    2008-01-01

    Chemical or mineralogical profiles in regolith display reaction fronts that document depletion of leachable elements or minerals. A generalized equation employing lumped parameters was derived to model such ubiquitously observed patterns:C = frac(C0, frac(C0 - Cx = 0, Cx = 0) exp (??ini ?? over(k, ??) ?? x) + 1)Here C, Cx = 0, and Co are the concentrations of an element at a given depth x, at the top of the reaction front, or in parent respectively. ??ini is the roughness of the dissolving mineral in the parent and k???? is a lumped kinetic parameter. This kinetic parameter is an inverse function of the porefluid advective velocity and a direct function of the dissolution rate constant times mineral surface area per unit volume regolith. This model equation fits profiles of concentration versus depth for albite in seven weathering systems and is consistent with the interpretation that the surface area (m2 mineral m- 3 bulk regolith) varies linearly with the concentration of the dissolving mineral across the front. Dissolution rate constants can be calculated from the lumped fit parameters for these profiles using observed values of weathering advance rate, the proton driving force, the geometric surface area per unit volume regolith and parent concentration of albite. These calculated values of the dissolution rate constant compare favorably to literature values. The model equation, useful for reaction fronts in both steady-state erosional and quasi-stationary non-erosional systems, incorporates the variation of reaction affinity using pH as a master variable. Use of this model equation to fit depletion fronts for soils highlights the importance of buffering of pH in the soil system. Furthermore, the equation should allow better understanding of the effects of important environmental variables on weathering rates. ?? 2008.

  2. Depleted uranium mobility across a weapons testing site: isotopic investigation of porewater, earthworms, and soils.

    PubMed

    Oliver, Ian W; Graham, Margaret C; MacKenzie, Angus B; Ellam, Robert M; Farmer, John G

    2008-12-15

    The mobility and bioavailability of depleted uranium (DU) in soils at a UK Ministry of Defence (UK MoD) weapons testing range were investigated. Soil and vegetation were collected near a test-firing position and at eight points along a transect line extending approximately 200 m down-slope, perpendicular to the firing line, toward a small stream. Earthworms and porewaters were subsequently separated from the soils and both total filtered porewater (<0.2 microm) and discrete size fractions (0.2 microm-100 kDa, 100-30 kDa, 30-3 kDa, and <3 kDa)obtainedvia centrifugal ultrafiltration were examined. Uranium concentrations were determined by inductively coupled plasma optical emission spectrometry (ICP-OES) for soils and ICP-mass spectrometry (MS) for earthworms and porewaters, while 235U:238U atom ratios were determined by multicollector (MC)-ICP-MS. Comparison of the porewater and earthworm isotopic values with those of the soil solids indicated that DU released into the environment during weapons test-firing operations was more labile and more bioavailable than naturally occurring U in the soils at the testing range. Importantly, DU was shown to be present in soil porewater even at a distance of approximately 185 m from the test-firing position and, along the extent of the transect was apparently associated with organic colloids.

  3. Depleted uranium mobility across a weapons testing site: isotopic investigation of porewater, earthworms, and soils.

    PubMed

    Oliver, Ian W; Graham, Margaret C; MacKenzie, Angus B; Ellam, Robert M; Farmer, John G

    2008-12-15

    The mobility and bioavailability of depleted uranium (DU) in soils at a UK Ministry of Defence (UK MoD) weapons testing range were investigated. Soil and vegetation were collected near a test-firing position and at eight points along a transect line extending approximately 200 m down-slope, perpendicular to the firing line, toward a small stream. Earthworms and porewaters were subsequently separated from the soils and both total filtered porewater (<0.2 microm) and discrete size fractions (0.2 microm-100 kDa, 100-30 kDa, 30-3 kDa, and <3 kDa)obtainedvia centrifugal ultrafiltration were examined. Uranium concentrations were determined by inductively coupled plasma optical emission spectrometry (ICP-OES) for soils and ICP-mass spectrometry (MS) for earthworms and porewaters, while 235U:238U atom ratios were determined by multicollector (MC)-ICP-MS. Comparison of the porewater and earthworm isotopic values with those of the soil solids indicated that DU released into the environment during weapons test-firing operations was more labile and more bioavailable than naturally occurring U in the soils at the testing range. Importantly, DU was shown to be present in soil porewater even at a distance of approximately 185 m from the test-firing position and, along the extent of the transect was apparently associated with organic colloids. PMID:19174886

  4. Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins.

    PubMed

    Dailly, Eric; Chenu, Franck; Petit-Demoulière, Benoit; Bourin, Michel

    2006-01-15

    The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels (p<0.01 in comparison with control group) in hypothalamus (-44%), hippocampus (-91%), striatum (-40%) and cortex (-68%) was 50mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.

  5. Brief mindfulness induction could reduce aggression after depletion.

    PubMed

    Yusainy, Cleoputri; Lawrence, Claire

    2015-05-01

    Many experiments have shown that one's ability to refrain from acting on aggressive impulses is likely to decrease following a prior act of self-control. This temporary state of self-control failure is known as ego-depletion. Although mindfulness is increasingly used to treat and manage aggressive behaviour, the extent to which mindfulness may counteract the depletion effect on aggression is yet to be determined. This study (N=110) investigated the effect of a laboratory induced one-time mindfulness meditation session on aggression following depletion. Aggression was assessed by the intensity of aversive noise blast participants delivered to an opponent on a computerised task. Depleted participants who received mindfulness induction behaved less aggressively than depleted participants with no mindfulness induction. Mindfulness also improved performance on a second measure of self-control (i.e., handgrip perseverance); however, this effect was independent of depletion condition. Motivational factors may help explain the dynamics of mindfulness, self-control, and aggression.

  6. Failure to Replicate Depletion of Self-Control

    PubMed Central

    Xu, Xiaomeng; Demos, Kathryn E.; Leahey, Tricia M.; Hart, Chantelle N.; Trautvetter, Jennifer; Coward, Pamela; Middleton, Kathryn R.; Wing, Rena R.

    2014-01-01

    The limited resource or strength model of self-control posits that the use of self-regulatory resources leads to depletion and poorer performance on subsequent self-control tasks. We conducted four studies (two with community samples, two with young adult samples) utilizing a frequently used depletion procedure (crossing out letters protocol) and the two most frequently used dependent measures of self-control (handgrip perseverance and modified Stroop). In each study, participants completed a baseline self-control measure, a depletion or control task (randomized), and then the same measure of self-control a second time. There was no evidence for significant depletion effects in any of these four studies. The null results obtained in four attempts to replicate using strong methodological approaches may indicate that depletion has more limited effects than implied by prior publications. We encourage further efforts to replicate depletion (particularly among community samples) with full disclosure of positive and negative results. PMID:25333564

  7. Groundwater depletion in the United States (1900−2008)

    USGS Publications Warehouse

    Konikow, Leonard F.

    2013-01-01

    A natural consequence of groundwater withdrawals is the removal of water from subsurface storage, but the overall rates and magnitude of groundwater depletion in the United States are not well characterized. This study evaluates long-term cumulative depletion volumes in 40 separate aquifers or areas and one land use category in the United States, bringing together information from the literature and from new analyses. Depletion is directly calculated using calibrated groundwater models, analytical approaches, or volumetric budget analyses for multiple aquifer systems. Estimated groundwater depletion in the United States during 1900–2008 totals approximately 1,000 cubic kilometers (km3). Furthermore, the rate of groundwater depletion has increased markedly since about 1950, with maximum rates occurring during the most recent period (2000–2008) when the depletion rate averaged almost 25 km3 per year (compared to 9.2 km3 per year averaged over the 1900–2008 timeframe).

  8. Using depletion to control colloidal crystal assemblies of hard cuboctahedra.

    PubMed

    Karas, Andrew S; Glaser, Jens; Glotzer, Sharon C

    2016-06-21

    Depletion interactions arise from entropic forces, and their ability to induce aggregation and even ordering of colloidal particles through self-assembly is well established, especially for spherical colloids. We vary the size and concentration of penetrable hard sphere depletants in a system of cuboctahedra, and we show how depletion changes the preferential facet alignment of the colloids and thereby selects different crystal structures. Moreover, we explain the cuboctahedra phase behavior using perturbative free energy calculations. We find that cuboctahedra can form a stable simple cubic phase, and, remarkably, that the stability of this phase can be rationalized only by considering the effects of both the colloid and depletant entropy. We corroborate our results by analyzing how the depletant concentration and size affect the emergent directional entropic forces and hence the effective particle shape. We propose the use of depletants as a means of easily changing the effective shape of self-assembling anisotropic colloids. PMID:27194463

  9. Cocaine treatment increases expression of a 40 kDa catecholamine-regulated protein in discrete brain regions.

    PubMed

    Sharan, Niki; Chong, Victor Z; Nair, Venugopalan D; Mishra, Ram K; Hayes, Robert J; Gardner, Eliot L

    2003-01-01

    Previous reports from our laboratory have described brain-specific catecholamine-regulated proteins, which bind dopamine and related catecholamines. Evidence from the molecular cloning of a 40 kDa catecholamine-regulated protein (CRP40) revealed that CRP40 is dopamine-inducible and has properties similar to those of the 70 kDa heat shock protein (HSP70) family. The present study investigates the effects of acute and chronic cocaine treatment on CRP40 expression in the striatum, nucleus accumbens, prefrontal cortex, and medulla. Acute treatment with cocaine increased CRP40 expression in the nucleus accumbens and striatum, whereas chronic treatment with cocaine increased CRP40 expression in the nucleus accumbens only. Neither of these treatments affected CRP40 levels in the prefrontal cortex or medulla. In addition, pretreatment with the spin-trapping agent alpha-phenyl-tert-butylnitrone did not attenuate cocaine-induced expression of CRP40, suggesting that the observed increases in CRP40 levels were not caused by free radicals. On the other hand, pretreatment with anisomycin, a protein synthesis inhibitor, blocked the cocaine-induced expression of CRP40. Thus, protein synthesis may be involved in the observed CRP40 level increases. Furthermore, neither acute nor chronic cocaine treatment affected levels of inducible or constitutively expressed HSP70, which indicates a specificity of cocaine's effects on CRP40. Since cocaine has been shown to increase extracellular dopamine levels, these findings suggest that increased expression of CRP40 is associated with high extracellular levels of dopamine (or its metabolites). Elevated levels of CRP40 could play a protective role for dopamine neurons in response to increased oxidative stress that has been shown to be induced by cocaine and that can lead to apoptosis and neurodegeneration. PMID:12422371

  10. Depletion theory and the precipitation of protein by polymer.

    PubMed

    Odijk, Theo

    2009-03-26

    The depletion theory of nanoparticles immersed in a semidilute polymer solution is reinterpreted in terms of depleted chains of polymer segments. Limitations and extensions of mean-field and scaling theories are discussed. An explicit expression for the interaction between two small spheres is also reviewed. The depletion free energy for a particle of general shape is given in terms of the capacitance or effective Stokes radius. This affords a reasonable explanation for the effect of polymer on protein precipitation.

  11. ELEMENTAL DEPLETIONS IN THE MAGELLANIC CLOUDS AND THE EVOLUTION OF DEPLETIONS WITH METALLICITY

    SciTech Connect

    Tchernyshyov, Kirill; Meixner, Margaret; Seale, Jonathan; Fox, Andrew; Friedman, Scott D.; Dwek, Eli; Galliano, Frédéric

    2015-10-01

    We present a study of the composition of gas and dust in the Large and Small Magellanic Clouds (LMC and SMC) using UV absorption spectroscopy. We measure P ii and Fe ii along 84 spatially distributed sightlines toward the MCs using archival Far Ultraviolet Spectroscopic Explorer observations. For 16 of those sightlines, we also measure Si ii, Cr ii, and Zn ii from new Hubble Space Telescope Cosmic Origins Spectrograph observations. We analyze these spectra using a new spectral line analysis technique based on a semi-parametric Voigt profile model. We have combined these measurements with H i and H{sub 2} column densities and reference stellar abundances from the literature to derive gas-phase abundances, depletions, and gas-to-dust ratios (GDRs). Of our 84 P and 16 Zn measurements, 80 and 13, respectively, are depleted by more than 0.1 dex, suggesting that P and Zn abundances are not accurate metallicity indicators at and above the metallicity of the SMC. Si, Cr, and Fe are systematically less depleted in the SMC than in the Milky Way (MW) or LMC. The minimum Si depletion in the SMC is consistent with zero. We find GDR ranges of 190–565 in the LMC and 480–2100 in the SMC, which is broadly consistent with GDRs from the literature. These ranges represent actual location to location variation and are evidence of dust destruction and/or growth in the diffuse neutral phase of the interstellar medium. Where they overlap in metallicity, the gas-phase abundances of the MW, LMC, and SMC and damped Lyα systems evolve similarly with metallicity.

  12. Elemental Depletions in the Magellanic Clouds and the Evolution of Depletions with Metallicity

    NASA Astrophysics Data System (ADS)

    Tchernyshyov, Kirill; Meixner, Margaret; Seale, Jonathan; Fox, Andrew; Friedman, Scott D.; Dwek, Eli; Galliano, Frédéric

    2015-10-01

    We present a study of the composition of gas and dust in the Large and Small Magellanic Clouds (LMC and SMC) using UV absorption spectroscopy. We measure P ii and Fe ii along 84 spatially distributed sightlines toward the MCs using archival Far Ultraviolet Spectroscopic Explorer observations. For 16 of those sightlines, we also measure Si ii, Cr ii, and Zn ii from new Hubble Space Telescope Cosmic Origins Spectrograph observations. We analyze these spectra using a new spectral line analysis technique based on a semi-parametric Voigt profile model. We have combined these measurements with H i and H2 column densities and reference stellar abundances from the literature to derive gas-phase abundances, depletions, and gas-to-dust ratios (GDRs). Of our 84 P and 16 Zn measurements, 80 and 13, respectively, are depleted by more than 0.1 dex, suggesting that P and Zn abundances are not accurate metallicity indicators at and above the metallicity of the SMC. Si, Cr, and Fe are systematically less depleted in the SMC than in the Milky Way (MW) or LMC. The minimum Si depletion in the SMC is consistent with zero. We find GDR ranges of 190-565 in the LMC and 480-2100 in the SMC, which is broadly consistent with GDRs from the literature. These ranges represent actual location to location variation and are evidence of dust destruction and/or growth in the diffuse neutral phase of the interstellar medium. Where they overlap in metallicity, the gas-phase abundances of the MW, LMC, and SMC and damped Lyα systems evolve similarly with metallicity.

  13. C18O Depletion in Starless Cores in Taurus

    NASA Astrophysics Data System (ADS)

    Ford, Amanda Brady; Shirley, Yancy L.

    2011-02-01

    We present here findings for C18O depletion in eight starless cores in Taurus: TMC-2, L1498, L1512, L1489, L1517B, L1521E, L1495A-S, and L1544. We compare observations of the C18O J = 2-1 transition taken with the ALMA prototype receiver on the Heinrich Hertz Submillimeter Telescope to results of radiative transfer modeling using RATRAN. We use temperature and density profiles calculated from dust continuum radiative transfer models to model the C18O emission. We present modeling of three cores, TMC-2, L1489, and L1495A-S, which have not been modeled before, and compare our results for the five cores with published models. We find that all of the cores but one, L1521E, are substantially depleted. We also find that varying the temperature profiles of these model cores has a discernable effect, and varying the central density has an even larger effect. We find no trends with depletion radius or depletion fraction with the density or temperature of these cores, suggesting that the physical structure alone is insufficient to fully constrain evolutionary state. We are able to place tighter constraints on the radius at which C18O is depleted than the absolute fraction of depletion. As the timeline of chemical depletion depends sensitively on the fraction of depletion, this difficulty in constraining depletion fraction makes comparison with other timescales, such as the free-fall timescale, very difficult.

  14. Regret causes ego-depletion and finding benefits in the regrettable events alleviates ego-depletion.

    PubMed

    Gao, Hongmei; Zhang, Yan; Wang, Fang; Xu, Yan; Hong, Ying-Yi; Jiang, Jiang

    2014-01-01

    This study tested the hypotheses that experiencing regret would result in ego-depletion, while finding benefits (i.e., "silver linings") in the regret-eliciting events counteracted the ego-depletion effect. Using a modified gambling paradigm (Experiments 1, 2, and 4) and a retrospective method (Experiments 3 and 5), five experiments were conducted to induce regret. Results revealed that experiencing regret undermined performance on subsequent tasks, including a paper-and-pencil calculation task (Experiment 1), a Stroop task (Experiment 2), and a mental arithmetic task (Experiment 3). Furthermore, finding benefits in the regret-eliciting events improved subsequent performance (Experiments 4 and 5), and this improvement was mediated by participants' perceived vitality (Experiment 4). This study extended the depletion model of self-regulation by considering emotions with self-conscious components (in our case, regret). Moreover, it provided a comprehensive understanding of how people felt and performed after experiencing regret and after finding benefits in the events that caused the regret. PMID:24940811

  15. [REACTIVE CHANGES IN THE ASTROCYTES OF FOREBRAIN NUCLEUS ACCUMBENS AFTER RESTRICTION OF BLOOD FLOW IN THE BASIN OF BOTH COMMON CAROTID ARTERIES IN RATS].

    PubMed

    Naumov, N G

    2016-01-01

    Reactive changes of astrocytes were studied in forebrain nucleus accumbens in rats (n = 12) after global cerebral ischemia induced by bilateral occlusion of both common carotid arteries, which is a frequently used model to assess the effectiveness of pharmacological agents that have anti-ischemic and neuroprotective properties. Under these conditions, the nucleus accumbens was in the area of partial ischemia. Morphometric study of nucleus accumbens was performed in three groups of rats (4 animals in each group) after ligation of both common carotid arteries, after a sham operation and in healthy animals. Astrocytes were demonstrated in serial sections using the reaction to glial fibrillary acidic protein counterstained with hematoxylin. 7 days after the surgery, in each animal the number of astrocytes was counted in the sections in 7 successiive squares of 0.01 mm2 each, the distance between their bodies and the capillary wall was measured within the circle of 20 μm radius, the cell body area and the length of their main processes were determined. It is found that astrocytes in the nucleus accumbens in the model of bilateral occlusion of the common carotid arteries for 7 days experienced a partial state of ischemia. Their reactive changes were manifested by the signs of the cytotoxic edema, damaging intermediate filament proteins in their bodies, processes and in the perivascular glial membranes. The concentration of the astrocyte cell bodies near blood capillaries is the adaptation mechanism and is a condition for the survival of cells under the restriction of blood flow in the brain. PMID:27487658

  16. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

    PubMed Central

    Graves, Steven M.; Clark, Mary J.; Traynor, John R.; Hu, Xiu-Ti; Napier, T. Celeste

    2014-01-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq–mediated signaling pathways. PMID:25229719

  17. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism.

    PubMed

    Graves, Steven M; Clark, Mary J; Traynor, John R; Hu, Xiu-Ti; Napier, T Celeste

    2015-02-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq-mediated signaling pathways.

  18. Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal.

    PubMed

    Anderson, Ethan M; Reeves, Turi; Kapernaros, Katherine; Neubert, John K; Caudle, Robert M

    2015-12-01

    Opioid withdrawal causes a dysphoric state that can lead to complications in pain patients and can propagate use in drug abusers and addicts. Opioid withdrawal changes the activity of neurons in the nucleus accumbens, an area rich in both opioid-binding mu opioid receptors and glutamate-binding NMDA receptors. Because the accumbens is an area important for reward and aversion, plastic changes in this area during withdrawal could alter future behaviors in animals. We discovered an increase in phosphorylation of serine 897 in the NR1 subunit of the NMDA receptor (pNR1) during acute morphine withdrawal. This serine can be phosphorylated by protein kinase A (PKA) and dephosphorylated by calcineurin. We next demonstrated that this increased pNR1 change is associated with an increase in NR1 surface expression. NR1 surface expression and pNR1 levels during acute withdrawal were both reduced by the NMDA receptor antagonist MK-801 (dizocilpine hydrogen maleate) and the PKA inhibitor H-89(N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride hydrate). We also found that pNR1 levels remained high after an extended morphine withdrawal period of 2 months, correlated with reward-seeking behavior for palatable food, and were associated with a decrease in accumbal calcineurin levels. These data suggest that NR1 phosphorylation changes during the acute withdrawal phase can be long lasting and may reflect a permanent change in NMDA receptors in the accumbens. These altered NMDA receptors in the accumbens could play a role in long-lasting behaviors associated with reward and opioid use.

  19. Reacquisition of cocaine conditioned place preference and its inhibition by previous social interaction preferentially affect D1-medium spiny neurons in the accumbens corridor

    PubMed Central

    Prast, Janine M.; Schardl, Aurelia; Schwarzer, Christoph; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2014-01-01

    We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders. PMID:25309368

  20. Diallyl disulphide depletes glutathione in Candida albicans

    PubMed Central

    Lemar, Katey M.; Aon, Miguel A.; Cortassa, Sonia; O’Rourke, Brian; T. Müller, Carsten; Lloyd, David

    2008-01-01

    Using two-photon scanning laser microscopy, we investigated the effect of an Allium sativum (garlic) constituent, diallyl disulphide (DADS), on key physiological functions of the opportunistic pathogen Candida albicans. A short 30 min exposure to 0.5 mm DADS followed by removal induced 70% cell death (50% necrotic, 20% apoptotic) within 2 h, increasing to 75% after 4 h. The early intracellular events associated with DADS-induced cell death were monitored with two-photon fluorescence microscopy to track mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) and NADH or reduced glutathione (GSH) under aerobic conditions. DADS treatment decreased intracellular GSH and elevated intracellular ROS levels. Additionally, DADS induced a marked decrease of ΔΨm and lowered respiration in cell suspensions and isolated mitochondria. In vitro kinetic experiments in cell-free extracts suggest that glutathione-S-transferase (GST) is one of the intracellular targets of DADS. Additional targets were also identified, including inhibition of a site or sites between complexes II-IV in the electron transport chain, as well as the mitochondrial ATP-synthase. The results indicate that DADS is an effective antifungal agent able to trigger cell death in Candida, most probably by eliciting oxidative stress as a consequence of thiol depletion and impaired mitochondrial function. PMID:17534841

  1. Recirculating cooling water solute depletion models

    SciTech Connect

    Price, W.T.

    1990-03-16

    Chromates have been used for years to inhibit copper corrosion in the plant Recirculating Cooling Water (RCW) system. However, chromates have become an environmental problem in recent years both in the chromate removal plant (X-616) operation and from cooling tower drift. In response to this concern, PORTS is replacing chromates with Betz Dianodic II, a combination of phosphates, BZT, and a dispersant. This changeover started with the X-326 system in 1989. In order to control chemical concentrations in X-326 and in systems linked to it, we needed to be able to predict solute concentrations in advance of the changeover. Failure to predict and control these concentrations can result in wasted chemicals, equipment fouling, or increased corrosion. Consequently, Systems Analysis developed two solute concentration models. The first simulation represents the X-326 RCW system by itself; and models the depletion of a solute once the feed has stopped. The second simulation represents the X-326, X-330, and the X-333 systems linked together by blowdown. This second simulation represents the concentration of a solute in all three systems simultaneously. 4 figs.

  2. Thermal stress depletes energy reserves in Drosophila

    PubMed Central

    Klepsatel, Peter; Gáliková, Martina; Xu, Yanjun; Kühnlein, Ronald P.

    2016-01-01

    Understanding how environmental temperature affects metabolic and physiological functions is of crucial importance to assess the impacts of climate change on organisms. Here, we used different laboratory strains and a wild-caught population of the fruit fly Drosophila melanogaster to examine the effect of temperature on the body energy reserves of an ectothermic organism. We found that permanent ambient temperature elevation or transient thermal stress causes significant depletion of body fat stores. Surprisingly, transient thermal stress induces a lasting “memory effect” on body fat storage, which also reduces survivorship of the flies upon food deprivation later after stress exposure. Functional analyses revealed that an intact heat-shock response is essential to protect flies from temperature-dependent body fat decline. Moreover, we found that the temperature-dependent body fat reduction is caused at least in part by apoptosis of fat body cells, which might irreversibly compromise the fat storage capacity of the flies. Altogether, our results provide evidence that thermal stress has a significant negative impact on organismal energy reserves, which in turn might affect individual fitness. PMID:27641694

  3. Supercontinuum Stimulated Emission Depletion Fluorescence Lifetime Imaging

    SciTech Connect

    Lesoine, Michael; Bose, Sayantan; Petrich, Jacob; Smith, Emily

    2012-06-13

    Supercontinuum (SC) stimulated emission depletion (STED) fluorescence lifetime imaging is demonstrated by using time-correlated single-photon counting (TCSPC) detection. The spatial resolution of the developed STED instrument was measured by imaging monodispersed 40-nm fluorescent beads and then determining their fwhm, and was 36 ± 9 and 40 ± 10 nm in the X and Y coordinates, respectively. The same beads measured by confocal microscopy were 450 ± 50 and 430 ± 30 nm, which is larger than the diffraction limit of light due to underfilling the microscope objective. Underfilling the objective and time gating the signal were necessary to achieve the stated STED spatial resolution. The same fluorescence lifetime (2.0 ± 0.1 ns) was measured for the fluorescent beads by using confocal or STED lifetime imaging. The instrument has been applied to study Alexa Fluor 594-phalloidin labeled F-actin-rich projections with dimensions smaller than the diffraction limit of light in cultured cells. Fluorescence lifetimes of the actin-rich projections range from 2.2 to 2.9 ns as measured by STED lifetime imaging.

  4. Ozone depletion: 20 Years after the alarm

    SciTech Connect

    Not Available

    1994-08-15

    Scientific curiosity in 1973 led to the challenge of determining the ultimate atmospheric fate of the chlorofluoromethanes, CFC-11 (CCl[sub 3]F) and CFC-12 (CCl[sub 2]F[sub 2]), whose presence at measurable levels in surface air had been detected only two years earlier. In retrospect, the decision to pursue the chemistry of CFC molecules to their final destruction and beyond foreordained an unusual outcome because CFCs are chemically inert and easily survive under almost all natural conditions. By midsummer 1994, the world is well on its way in transition to a CFC-free economy, although not yet to a CFC-free atmosphere. The rates of increase in atmospheric concentration for the three major CFCs (CFC-11, -12, and -113) have all slowed markedly in response to the restrictions of the revised Montreal protocol. Because of their long lifetimes, however, significant but gradually diminishing quantities of CFCs will remain in the atmosphere throughout the 21st century. Atomic chlorine will continue to be released into the stratosphere as long as CFCs persist, and ozone depletion will follow. The existence of the Montreal protocol and the agreement among industrial, governmental, and university scientists on its wisdom offers considerable promise for the handling of future global environmental problems.

  5. Thermal stress depletes energy reserves in Drosophila.

    PubMed

    Klepsatel, Peter; Gáliková, Martina; Xu, Yanjun; Kühnlein, Ronald P

    2016-09-19

    Understanding how environmental temperature affects metabolic and physiological functions is of crucial importance to assess the impacts of climate change on organisms. Here, we used different laboratory strains and a wild-caught population of the fruit fly Drosophila melanogaster to examine the effect of temperature on the body energy reserves of an ectothermic organism. We found that permanent ambient temperature elevation or transient thermal stress causes significant depletion of body fat stores. Surprisingly, transient thermal stress induces a lasting "memory effect" on body fat storage, which also reduces survivorship of the flies upon food deprivation later after stress exposure. Functional analyses revealed that an intact heat-shock response is essential to protect flies from temperature-dependent body fat decline. Moreover, we found that the temperature-dependent body fat reduction is caused at least in part by apoptosis of fat body cells, which might irreversibly compromise the fat storage capacity of the flies. Altogether, our results provide evidence that thermal stress has a significant negative impact on organismal energy reserves, which in turn might affect individual fitness.

  6. Levels of depleted uranium in Kosovo soils.

    PubMed

    Sansone, U; Stellato, L; Jia, G; Rosamilia, S; Gaudino, S; Barbizzi, S; Belli, M

    2001-01-01

    The United Nations Environment Programme (UNEP) has performed a field survey at 11 sites located in Kosovo, where depleted uranium (DU) ammunitions were used by the North Atlantic Treaty Organization (NATO) during the last Balkans conflict (1999). Soil sampling was performed to assess the spread of DU ground contamination around and within the NATO target sites and the migration of DU along the soil profile. The 234U/238U and 235U/238U activity concentration ratios have been used as an indicator of natural against anthropogenic sources of uranium. The results show that levels of 238U activity concentrations in soils above 100 Bq x kg(-1) can be considered a 'tracer' of the presence of DU in soils. The results also indicate that detectable ground surface contamination by DU is limited to areas within a few metres from localised points of concentrated contamination caused by penetrator impacts. Vertical distribution of DU along the soil profile is measurable up to a depth of 10-20 cm. This latter aspect is of particular relevance for the potential risk of future contamination of groundwater.

  7. Residue depletion of tilmicosin in chicken tissues.

    PubMed

    Zhang, Yue; Jiang, Haiyang; Jin, Xingjun; Shen, Zhangqi; Shen, Jianzhong; Fu, Caixia; Guo, Junlin

    2004-05-01

    A high-performance liquid chromatography (HPLC) method with detection at 290 nm was modified and validated for the determination of tilmicosin residues in broiler chicken tissues. The limits of detection (LOD) of the method were 0.01 microg/g for muscle and 0.025 microg/g for liver and kidney. Average recoveries ranged from 80.4 to 88.3%. Relative standard deviation values ranged from 5.2 to 12.1%. Residue depletion of tilmicosin in broiler chickens was examined after dosing over a 5-day period by incorporation of the drug into drinking water at 37.5 and 75.0 mg/L. Tilmicosin concentrations in liver and kidney were highest on day 3 of medication and on day 5 in muscle, in both low- and high-dose groups. The residue levels in both groups were significantly higher in liver than in kidney or muscle. A minimum withdrawal time of 9 days was indicated for residue levels in muscle, liver, and kidney tissues below the maximum residue level (MRL).

  8. Thermal stress depletes energy reserves in Drosophila.

    PubMed

    Klepsatel, Peter; Gáliková, Martina; Xu, Yanjun; Kühnlein, Ronald P

    2016-01-01

    Understanding how environmental temperature affects metabolic and physiological functions is of crucial importance to assess the impacts of climate change on organisms. Here, we used different laboratory strains and a wild-caught population of the fruit fly Drosophila melanogaster to examine the effect of temperature on the body energy reserves of an ectothermic organism. We found that permanent ambient temperature elevation or transient thermal stress causes significant depletion of body fat stores. Surprisingly, transient thermal stress induces a lasting "memory effect" on body fat storage, which also reduces survivorship of the flies upon food deprivation later after stress exposure. Functional analyses revealed that an intact heat-shock response is essential to protect flies from temperature-dependent body fat decline. Moreover, we found that the temperature-dependent body fat reduction is caused at least in part by apoptosis of fat body cells, which might irreversibly compromise the fat storage capacity of the flies. Altogether, our results provide evidence that thermal stress has a significant negative impact on organismal energy reserves, which in turn might affect individual fitness. PMID:27641694

  9. Nucleus accumbens response to food cues predicts subsequent snack consumption in women and increased body mass index in those with reduced self-control.

    PubMed

    Lawrence, Natalia S; Hinton, Elanor C; Parkinson, John A; Lawrence, Andrew D

    2012-10-15

    Individuals have difficulty controlling their food consumption, which is due in part to the ubiquity of tempting food cues in the environment. Individual differences in the propensity to attribute incentive (motivational) salience to and act on these cues may explain why some individuals eat more than others. Using fMRI in healthy women, we found that food cue related activity in the nucleus accumbens, a key brain region for food motivation and reward, was related to subsequent snack food consumption. However, both nucleus accumbens activation and snack food consumption were unrelated to self-reported hunger, or explicit wanting and liking for the snack. In contrast, food cue reactivity in the ventromedial prefrontal cortex was associated with subjective hunger/appetite, but not with consumption. Whilst the food cue reactivity in the nucleus accumbens that predicted snack consumption was not directly related to body mass index (BMI), it was associated with increased BMI in individuals reporting low self-control. Our findings reveal a neural substrate underpinning automatic environmental influences on consumption in humans and demonstrate how self-control interacts with this response to predict BMI. Our data provide support for theoretical models that advocate a 'dual hit' of increased incentive salience attribution to food cues and poor self-control in determining vulnerability to overeating and overweight. PMID:22776461

  10. Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats.

    PubMed

    Kitamura, Yoshihisa; Yagi, Takahiko; Kitagawa, Kouhei; Shinomiya, Kazuaki; Kawasaki, Hiromu; Asanuma, Masato; Gomita, Yutaka

    2010-08-01

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

  11. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

    PubMed Central

    Peciña, Susana; Schulkin, Jay; Berridge, Kent C

    2006-01-01

    Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent

  12. Influence of Roller Burnishing Parameters on Depletion of Plasticity Reserve

    NASA Astrophysics Data System (ADS)

    Blumenstein, V. Yu; Petrenko, K. P.

    2016-04-01

    Roller burnishing process considerably increases surface quality and service life of machine parts. Efficiency of roller burnishing rises greatly when technological inheritance (TI) is taken into account. Research results of degree of plasticity reserve depletion (DPRD) while roller burnishing are presented. Results obtained made it possible to establish mechanisms of strain accumulation and plasticity reserve depletion according to roller burnishing parameters.

  13. Analysis of Hydrogen Depletion Using a Scaled Passive Autocatalytic Recombiner

    SciTech Connect

    Blanchat, T.K.; Malliakos, A.

    1998-10-28

    Hydrogen depletion tests of a scaled passive autocatalytic recombine (pAR) were performed in the Surtsey test vessel at Sandia National Laboratories (SNL). The experiments were used to determine the hydrogen depletion rate of a PAR in the presence of steam and also to evaluate the effect of scale (number of cartridges) on the PAR performance at both low and high hydrogen concentrations.

  14. Optimal Allocation of Sampling Effort in Depletion Surveys

    EPA Science Inventory

    We consider the problem of designing a depletion or removal survey as part of estimating animal abundance for populations with imperfect capture or detection rates. In a depletion survey, animals are captured from a given area, counted, and withheld from the population. This proc...

  15. 26 CFR 1.613-1 - Percentage depletion; general rule.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Percentage depletion; general rule. 1.613-1 Section 1.613-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613-1 Percentage depletion;...

  16. 26 CFR 1.613-1 - Percentage depletion; general rule.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Percentage depletion; general rule. 1.613-1 Section 1.613-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613-1 Percentage depletion; general rule. (a) In general. In the case of a...

  17. Depletion of Appalachian coal reserves - how soon?

    USGS Publications Warehouse

    Milici, R.C.

    2000-01-01

    Much of the coal consumed in the US since the end of the last century has been produced from the Pennsylvanian strata of the Appalachian basin. Even though quantities mined in the past are less than they are today, this basin yielded from 70% to 80% of the nation's annual coal production from the end of the last century until the early 1970s. During the last 25 years, the proportion of the nation's coal that was produced annually from the Appalachian basin has declined markedly, and today it is only about 40% of the total. The amount of coal produced annually in the Appalachian basin, however, has been rising slowly over the last several decades, and has ranged generally from 400 to 500 million tons (Mt) per year. A large proportion of Appalachian historical production has come from relatively few counties in southwestern Pennsylvania, northern and southern West Virginia, eastern Kentucky, Virginia and Alabama. Many of these counties are decades past their years of peak production and several are almost depleted of economic deposits of coal. Because the current major consumer of Appalachian coal is the electric power industry, coal quality, especially sulfur content, has a great impact on its marketability. High-sulfur coal deposits in western Pennsylvania and Ohio are in low demand when compared with the lower sulfur coals of Virginia and southern West Virginia. Only five counties in the basin that have produced 500 Mt or more exhibit increasing rates of production at relatively high levels. Of these, six are in the central part of the basin and only one, Greene County, Pennsylvania, is in the northern part of the basin. Decline rate models, based on production decline rates and the decline rate of the estimated, 'potential' reserve, indicate that Appalachian basin annual coal production will be 200 Mt or less by the middle of the next century. Published by Elsevier Science B.V.Much of the coal consumed in the US since the end of the last century has been produced

  18. Charged micelle depletion attraction and interfacial colloidal phase behavior.

    PubMed

    Iracki, Tara D; Beltran-Villegas, Daniel J; Eichmann, Shannon L; Bevan, Michael A

    2010-12-21

    Ensemble total internal reflection microscopy (TIRM) is used to directly measure the evolution of colloid-surface depletion attraction with increasing sodium dodecyl sulfate (SDS) concentration near the critical micelle concentration (CMC). Measured potentials are well described by a modified Asakura-Oosawa (AO) depletion potential in addition to electrostatic and van der Waals contributions. The modified AO potential includes effects of electrostatic interactions between micelles and surfaces via effective depletant dimensions in an excluded volume term and partitioning in an osmotic pressure term. Directly measured colloid-surface depletion potentials are used in Monte Carlo (MC) simulations to capture video microscopy (VM) measurements of micelle-mediated quasi-two-dimensional phase behavior including fluid, crystal, and gel microstructures. Our findings provide information to develop more rigorous and analytically simple models of depletion attraction in charged micellar systems. PMID:21077612

  19. Ozone depletion during solar proton events in solar cycle 21

    NASA Technical Reports Server (NTRS)

    Mcpeters, R. D.; Jackman, C. H.

    1985-01-01

    Ozone profile data from the Solar Backscattered Ultraviolet Instrument on Nimbus 7 from 1979 to the present and clear cases of ozone destruction associated with five sudden proton events (SPEs) on June 7, 1979, August 21, 1979, October 13-14, 1981, July 13, 1982, and December 8, 1982 are found. During the SPE on July 13, 1982, the largest of this solar cycle, no depletion at all at 45 km is observed, but there is a 15 percent ozone depletion at 50 km increasing to 27 percent at 55 km, all at a solar zenith angle of 85 deg. A strong variation of the observed depletion with solar zenith angle is found, with maximum depletion occurring at the largest zenith angles (near 85 deg) decreasing to near zero for angles below about 70 deg. The observed depletion is short lived, disappearing within hours of the end of the SPE.

  20. The timing and mechanism of depletion in Lewisian granulites

    NASA Technical Reports Server (NTRS)

    Cohen, A. S.; Onions, R. K.; Ohara, M. J.

    1988-01-01

    Large Ion Lithophile (LIL) depletion in Lewisian granulites is discussed. Severe depletions in U, Th, and other LIL have been well documented in Lewisan mafic and felsic gneisses, but new Pb isotopic analyses show little or no depletion in lithologies with high solidus temperatures, such as peridotite. This suggests that LIL transport in this terrane took place by removal of partial melts rather than by pervasive flooding with externally derived CO2. The Pb and Nd isotopic data gathered on these rocks show that the depletion and granulite metamorphism are distinct events about 250 Ma apart. Both fluid inclusions and cation exchange geothermometers date from the later metamorphic event and therefore have little bearing on the depletion event, suggesting a note of caution for interpretations of other granulite terranes.

  1. Ionogram range/time plots, satellite traces and optical depletions

    NASA Astrophysics Data System (ADS)

    Lynn, Kenneth; Shiokawa, Kazuo; Otsuka, Yuichi; Wilkinson, Phil

    2012-07-01

    Range/time plots derived from 5 minute ionograms have a variety of uses including finding TIDs, following major height variations in the F2 ionosphere and tracking the movement of low latitude electron depletions as verified by co-incident observations by optical methods. This paper investigates these applications with particular emphasis on following optical depletions via ionosonde as observed at Darwin, Australia. Similar additional range/time plots are also discussed from Vanimo and Port Moresby in New Guinea and Tennant Creek and Townsville in Australia. While much theoretical work has been expended on explaining the development of equatorial bubble/depletions, current work highlights the apparently strong development of depletions at times of year when the pre-sunset height rise and following fall is minimal in contrast to current conventional thinking. In contrast, depletions are not observed at Australian equatorial longitudes when the pre- and post- sunset height variations are greatest in magnitude and consistency.

  2. Barium Depletion in Hollow Cathode Emitters

    NASA Technical Reports Server (NTRS)

    Polk, James E.; Capece, Angela M.; Mikellides, Ioannis G.; Katz, Ira

    2009-01-01

    The effect of tungsten erosion, transport and redeposition on the operation of dispenser hollow cathodes was investigated in detailed examinations of the discharge cathode inserts from an 8200 hour and a 30,352 hour ion engine wear test. Erosion and subsequent re-deposition of tungsten in the electron emission zone at the downstream end of the insert reduces the porosity of the tungsten matrix, preventing the ow of barium from the interior. This inhibits the interfacial reactions of the barium-calcium-aluminate impregnant with the tungsten in the pores. A numerical model of barium transport in the internal xenon discharge plasma shows that the barium required to reduce the work function in the emission zone can be supplied from upstream through the gas phase. Barium that flows out of the pores of the tungsten insert is rapidly ionized in the xenon discharge and pushed back to the emitter surface by the electric field and drag from the xenon ion flow. This barium ion flux is sufficient to maintain a barium surface coverage at the downstream end greater than 0.6, even if local barium production at that point is inhibited by tungsten deposits. The model also shows that the neutral barium pressure exceeds the equilibrium vapor pressure of the impregnant decomposition reaction over much of the insert length, so the reactions are suppressed. Only a small region upstream of the zone blocked by tungsten deposits is active and supplies the required barium. These results indicate that hollow cathode failure models based on barium depletion rates in vacuum dispenser cathodes are very conservative.

  3. Ozone Depletion Potential of CH3Br

    NASA Technical Reports Server (NTRS)

    Sander, Stanley P.; Ko, Malcolm K. W.; Sze, Nien Dak; Scott, Courtney; Rodriquez, Jose M.; Weisenstein, Debra K.

    1998-01-01

    The ozone depletion potential (ODP) of methyl bromide (CH3Br) can be determined by combining the model-calculated bromine efficiency factor (BEF) for CH3Br and its atmospheric lifetime. This paper examines how changes in several key kinetic data affect BEF. The key reactions highlighted in this study include the reaction of BrO + H02, the absorption cross section of HOBr, the absorption cross section and the photolysis products of BrON02, and the heterogeneous conversion of BrON02 to HOBR and HN03 on aerosol particles. By combining the calculated BEF with the latest estimate of 0.7 year for the atmospheric lifetime of CH3Br, the likely value of ODP for CH3Br is 0.39. The model-calculated concentration of HBr (approximately 0.3 pptv) in the lower stratosphere is substantially smaller than the reported measured value of about I pptv. Recent publications suggested models can reproduce the measured value if one assumes a yield for HBr from the reaction of BrO + OH or from the reaction of BrO + H02. Although the DeAlore et al. evaluation concluded any substantial yield of HBr from BrO + HO2 is unlikely, for completeness, we calculate the effects of these assumed yields on BEF for CH3Br. Our calculations show that the effects are minimal: practically no impact for an assumed 1.3% yield of HBr from BrO + OH and 10% smaller for an assumed 0.6% yield from BrO + H02.

  4. Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

    PubMed

    Zou, Feng; Wu, Xinhuai; Zhai, Tianye; Lei, Yu; Shao, Yongcong; Jin, Xiao; Tan, Shuwen; Wu, Bing; Wang, Lubin; Yang, Zheng

    2015-11-01

    Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals. PMID:26280556

  5. Violence as a source of pleasure or displeasure is associated with specific functional connectivity with the nucleus accumbens

    PubMed Central

    Porges, Eric C.; Decety, Jean

    2013-01-01

    The appraisal of violent stimuli is dependent on the social context and the perceiver's individual characteristics. To identify the specific neural circuits involved in the perception of violent videos, forty-nine male participants were scanned with functional MRI while watching video-clips depicting Mixed Martial Arts (MMA) and Capoeira as a baseline. Prior to scanning, a self-report measure of pleasure or displeasure when watching MMA was collected. Watching MMA was associated with activation of the anterior insula (AI), brainstem, ventral tegmental area (VTA), striatum, medial, and lateral prefrontal cortex, orbitofrontal cortex, somatosensory cortex, and supramarginal gyrus. While this pattern of brain activation was not related to participants' reported experience of pleasure or displeasure, pleasurable ratings of MMA predicted increased functional connectivity (FC) seeded in the nucleus accumbens (NAcc) (a structure known to be responsive to anticipating both positive and negative outcomes) with the subgenual anterior cingulate cortex (ACC) and anterior insular cortex (AIC) (regions involved in positive feelings and visceral somatic representations). Displeasure ratings of MMA were related to increased FC with regions of the prefrontal cortex and superior parietal lobule, structures implicated in cognitive control and executive attention. These data suggest that functional connectivity is an effective approach to investigate the relationship between subjective feelings of pleasure and pain of neural structures known to respond to both the anticipation of positive and negative outcomes. PMID:23964226

  6. Violence as a source of pleasure or displeasure is associated with specific functional connectivity with the nucleus accumbens.

    PubMed

    Porges, Eric C; Decety, Jean

    2013-01-01

    The appraisal of violent stimuli is dependent on the social context and the perceiver's individual characteristics. To identify the specific neural circuits involved in the perception of violent videos, forty-nine male participants were scanned with functional MRI while watching video-clips depicting Mixed Martial Arts (MMA) and Capoeira as a baseline. Prior to scanning, a self-report measure of pleasure or displeasure when watching MMA was collected. Watching MMA was associated with activation of the anterior insula (AI), brainstem, ventral tegmental area (VTA), striatum, medial, and lateral prefrontal cortex, orbitofrontal cortex, somatosensory cortex, and supramarginal gyrus. While this pattern of brain activation was not related to participants' reported experience of pleasure or displeasure, pleasurable ratings of MMA predicted increased functional connectivity (FC) seeded in the nucleus accumbens (NAcc) (a structure known to be responsive to anticipating both positive and negative outcomes) with the subgenual anterior cingulate cortex (ACC) and anterior insular cortex (AIC) (regions involved in positive feelings and visceral somatic representations). Displeasure ratings of MMA were related to increased FC with regions of the prefrontal cortex and superior parietal lobule, structures implicated in cognitive control and executive attention. These data suggest that functional connectivity is an effective approach to investigate the relationship between subjective feelings of pleasure and pain of neural structures known to respond to both the anticipation of positive and negative outcomes. PMID:23964226

  7. Long-lasting deficits in hedonic and nucleus accumbens reactivity to sweet rewards by sugar overconsumption during adolescence.

    PubMed

    Naneix, Fabien; Darlot, Florence; Coutureau, Etienne; Cador, Martine

    2016-03-01

    Adolescence is a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system might constitute an important factor in vulnerability to pathological development. In spite of the dramatic increase in the consumption of sweet palatable foods during adolescence in our modern societies, the long-term consequences of such exposure on brain reward processing remain poorly understood. Here, we investigated in rats the long-lasting effects of sugar overconsumption during their adolescence on their adult reactivity to the hedonic properties of sweet rewards. Adolescent rats with continuous access to 5% sucrose solution (from postnatal day 30-46) showed escalating intake. At adulthood (post-natal day 70), using two-bottle free choice tests, sucrose-exposed rats showed lower intake than non-exposed rats suggesting decreased sensitivity to the rewarding properties of sucrose. In Experiment 1, we tested their hedonic-related orofacial reactions to intraoral infusion of tasty solutions. We showed that sucrose-exposed rats presented less hedonic reactions in response to sweet tastes leaving the reactivity to water or quinine unaltered. Hence, in Experiment 2, we observed that this hedonic deficit is associated with lower c-Fos expression levels in the nucleus accumbens, a brain region known to play a central role in hedonic processing. These findings demonstrate that a history of high sucrose intake during the critical period of adolescence induces long-lasting deficits in hedonic treatment that may contribute to reward-related disorders.

  8. Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness "liking" and "wanting".

    PubMed

    Castro, Daniel C; Berridge, Kent C

    2014-03-19

    A specialized cubic-millimeter hotspot in the rostrodorsal quadrant of medial shell in nucleus accumbens (NAc) of rats may mediate opioid enhancement of gustatory hedonic impact or "liking". Here, we selectively stimulated the three major subtypes of opioid receptors via agonist microinjections [mu (DAMGO), delta (DPDPE), or kappa (U50488H)] and constructed anatomical maps for functional localizations of consequent changes in hedonic "liking" (assessed by affective orofacial reactions to sucrose taste) versus "wanting" (assessed by changes in food intake). Results indicated that the NAc rostrodorsal quadrant contains a shared opioid hedonic hotspot that similarly mediates enhancements of sucrose "liking" for mu, delta, and kappa stimulations. Within the rostrodorsal hotspot boundaries each type of stimulation generated at least a doubling or higher enhancement of hedonic reactions, with comparable intensities for all three types of opioid stimulation. By contrast, a negative hedonic coldspot was mapped in the caudal half of medial shell, where all three types of opioid stimulation suppressed "liking" reactions to approximately one-half normal levels. Different anatomical patterns were produced for stimulation of food "wanting", reflected in food intake. Altogether, these results indicate that the rostrodorsal hotspot in medial shell is unique for generating opioid-induced hedonic enhancement, and add delta and kappa signals to mu as hedonic generators within the hotspot. Also, the identification of a separable NAc caudal coldspot for hedonic suppression, and separate NAc opioid mechanisms for controlling food "liking" versus "wanting" further highlights NAc anatomical heterogeneity and localizations of function within subregions of medial shell.

  9. Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens.

    PubMed

    Ng, Enoch; Varaschin, Rafael K; Su, Ping; Browne, Caleb J; Hermainski, Joanna; Le Foll, Bernard; Pongs, Olaf; Liu, Fang; Trudeau, Louis-Eric; Roder, John C; Wong, Albert H C

    2016-03-15

    Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior.

  10. Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study.

    PubMed

    Papoiu, Alexandru D P; Kraft, Robert A; Coghill, Robert C; Yosipovitch, Gil

    2015-02-01

    Opioid receptors in the central nervous system are important modulators of itch transmission. In this study, we examined the effect of mixed-action opioid butorphanol on histamine itch, cowhage itch, and heat pain in healthy volunteers. Using functional MRI, we investigated significant changes in cerebral perfusion to identify the critical brain centers mediating the antipruritic effect of butorphanol. Butorphanol suppressed the itch induced experimentally with histamine, reduced the intensity of cowhage itch by approximately 35%, and did not affect heat pain sensitivity. In comparison with the placebo, butorphanol produced a bilateral deactivation of claustrum, insula, and putamen, areas activated during itch processing. Analysis of cerebral perfusion patterns of brain processing of itch versus itch inhibition under the effect of the drug revealed that the reduction in cowhage itch by butorphanol was correlated with changes in cerebral perfusion in the midbrain, thalamus, S1, insula, and cerebellum. The suppression of histamine itch by butorphanol was paralleled by the activation of nucleus accumbens and septal nuclei, structures expressing high levels of kappa opioid receptors. In conclusion, important relays of the mesolimbic circuit were involved in the inhibition of itch by butorphanol and could represent potential targets for the development of antipruritic therapy. PMID:25211175

  11. TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice.

    PubMed

    De Vry, Jochen; Vanmierlo, Tim; Martínez-Martínez, Pilar; Losen, Mario; Temel, Yasin; Boere, Janneke; Kenis, Gunter; Steckler, Thomas; Steinbusch, Harry W M; De Baets, Marc; Prickaerts, Jos

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) exerts antidepressant-like effects in the hippocampus and pro-depressant effects in the nucleus accumbens (NAc). It is thought that downstream signaling of the BDNF receptor TrkB mediates the effects of BDNF in these brain structures. Here, we evaluate how TrkB regulates affective behavior in the hippocampus and NAc. We overexpressed TrkB by electroporating a non-viral plasmid in the NAc or hippocampus in mice. Depression- and anxiety-like behaviors were evaluated in the sucrose test (anhedonia), the forced swim test (despair) and the elevated zero maze (anxiety). Targeted brain tissue was biochemically analyzed to identify molecular mechanisms responsible for the observed behavior. Overexpressing TrkB in the NAc increased the number of young neuronal cells and decreased despair and basal corticosterone levels. TrkB overexpression in the hippocampus increased astrocyte production and activation of the transcription factor CREB, yet without altering affective behavior. Our data suggest antidepressant effects of BDNF-TrkB in the NAc, which could not be explained by activation of the transcription factors CREB or β-catenin. The effects TrkB has on depression-related behavior in different brain regions appear to critically depend on the targeted cell type.

  12. Gene expression analysis of heat shock proteins in the nucleus accumbens of rats with different morphine seeking behaviours.

    PubMed

    Salas, Elisabet; Bocos, Carlos; Del Castillo, Carmen; Pérez-García, Carmen; Morales, Lidia; Alguacil, Luis F

    2011-11-20

    Heat-shock proteins play functional roles on brain regulatory processes which are deeply involved in drug addiction, such as synaptic plasticity. However, few studies have been focused on gene expression of heat-shock proteins (Hsp) as potential diagnostic tools for addiction risk. This work tries to provide new knowledge on this field by using two rat models of differential vulnerability to morphine addiction in order to study differential gene expression of a selected group of Hsp genes in the nucleus accumbens (NAc). Hsp70-1A, 84, 86 and 105 genes were similarly regulated by an acute injection of morphine in two subpopulations of Sprague Dawley (SD) rats showing different rates of extinction of morphine conditioned preference. However, Lewis and Fischer rats, two strains that differ in many aspects of drug seeking behaviours, exhibited marked differences in their expression patterns of Hsp84, 86 and 105. These results suggest that differential Hsp gene expression could be related to addiction vulnerability and recommend further work to validate these proteins as potential markers for drug addiction risk.

  13. Cocaine-Induced Plasticity in the Nucleus Accumbens is Cell-Specific and Develops Without Prolonged Withdrawal

    PubMed Central

    Dobi, Alice; Seabold, Gail K.; Christensen, Christine H.; Bock, Roland; Alvarez, Veronica A.

    2011-01-01

    Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different non-contingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) was observed in D1-expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPAR to NMDAR ratios, higher spine density and enlarged spine heads were observed in the absence of withdrawal following a long cocaine treatment. These synaptic adaptations expressed in D1-containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D1-expressing MSNs, which although they take time to develop, do not require prolonged cocaine withdrawal. PMID:21289199

  14. Cocaine-Induced Behavioral Sensitization in Mice: Effects of Microinjection of Dopamine D2 Receptor Antagonist into the Nucleus Accumbens

    PubMed Central

    Jung, Eun-Sol; Lee, Hyo Jin; Sim, Hye-Ri

    2013-01-01

    To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R-/- mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R-/-) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R-/- mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization. PMID:24167417

  15. Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization.

    PubMed

    Xu, Chun-Mei; Wang, Jun; Wu, Ping; Xue, Yan-Xue; Zhu, Wei-Li; Li, Qian-Qian; Zhai, Hai-Feng; Shi, Jie; Lu, Lin

    2011-07-01

    As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3β (GSK-3β) has been considered to be important in the synaptic plasticity that underlies dopamine-related behaviors and diseases. We recently found that GSK-3β activity in the nucleus accumbens (NAc) core is critically involved in cocaine-induced behavioral sensitization. The present study further explored the association between the changes in GSK-3β activity in the NAc and the chronic administration of methamphetamine. We also examined whether blocking GSK-3β activity in the NAc could alter the initiation and expression of methamphetamine (1 mg/kg, i.p.)-induced locomotor sensitization in rats using systemic administration of lithium chloride (LiCl, 100 mg/kg, i.p) and brain region-specific administration of the GSK-3β inhibitor SB216763 (1 ng/side). We found that GSK-3β activity increased in the NAc core, but not NAc shell, after chronic methamphetamine administration. The initiation and expression of methamphetamine-induced locomotor sensitization was attenuated by systemic administration of LiCl and direct infusion of SB216763 into the NAc core, but not NAc shell. These results indicate that GSK-3β activity in the NAc core mediates the initiation and expression of methamphetamine-induced locomotor sensitization, suggesting that GSK-3β may be a potential target for the treatment of psychostimulant addiction.

  16. Sex differences in interactions between nucleus accumbens and visual cortex by explicit visual erotic stimuli: an fMRI study.

    PubMed

    Lee, S W; Jeong, B S; Choi, J; Kim, J-W

    2015-01-01

    Men tend to have greater positive responses than women to explicit visual erotic stimuli (EVES). However, it remains unclear, which brain network makes men more sensitive to EVES and which factors contribute to the brain network activity. In this study, we aimed to assess the effect of sex difference on brain connectivity patterns by EVES. We also investigated the association of testosterone with brain connection that showed the effects of sex difference. During functional magnetic resonance imaging scans, 14 males and 14 females were asked to see alternating blocks of pictures that were either erotic or non-erotic. Psychophysiological interaction analysis was performed to investigate the functional connectivity of the nucleus accumbens (NA) as it related to EVES. Men showed significantly greater EVES-specific functional connection between the right NA and the right lateral occipital cortex (LOC). In addition, the right NA and the right LOC network activity was positively correlated with the plasma testosterone level in men. Our results suggest that the reason men are sensitive to EVES is the increased interaction in the visual reward networks, which is modulated by their plasma testosterone level. PMID:25971857

  17. The nucleus accumbens is involved in both the pursuit of social reward and the avoidance of social punishment

    PubMed Central

    Kohls, Gregor; Perino, Michael T.; Taylor, James M.; Madva, Elizabeth N.; Cayless, Sarah J.; Troiani, Vanessa; Price, Elinora; Faja, Susan; Herrington, John D.; Schultz, Robert T.

    2013-01-01

    Human social motivation is characterized by the pursuit of social reward and the avoidance of social punishment. The ventral striatum/nucleus accumbens (VS/Nacc), in particular, has been implicated in the reward component of social motivation, i.e., the ‘wanting’ of social incentives like approval. However, it is unclear to what extent the VS/Nacc is involved in avoiding social punishment like disapproval, an intrinsically pleasant outcome. Thus, we conducted an event-related functional magnetic resonance imaging (fMRI) study using a social incentive delay task with dynamic video stimuli instead of static pictures as social incentives in order to examine participants' motivation for social reward gain and social punishment avoidance. As predicted, the anticipation of avoidable social punishment (i.e., disapproval) recruited the VS/Nacc in a manner that was similar to VS/Nacc activation observed during the anticipation of social reward gain (i.e., approval). Stronger VS/Nacc activity was accompanied by faster reaction times of the participants to obtain those desired outcomes. This data support the assumption that dynamic social incentives elicit robust VS/Nacc activity, which likely reflects motivation to obtain social reward and to avoid social punishment. Clinical implications regarding the involvement of the VS/Nacc in social motivation dysfunction in autism and social phobia are discussed. PMID:23911778

  18. Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine.

    PubMed

    Sun, Li-Li; Zhang, Yan; Liu, Jian-feng; Wang, Jun; Zhu, Wei-li; Zhao, Li-yan; Xue, Yan-xue; Lu, Lin; Shi, Jie

    2013-09-01

    Melanin-concentrating hormone (MCH) is a neuropeptide and its receptor is extensively expressed throughout the brain. MCH has been suggested to regulate the rewarding and reinforcing effects of psychostimulants by potentiating the dopaminergic system within the midbrain. Moreover, MCH and its receptor can regulate ERK activity. The present study investigated the role of MCH in the nucleus accumbens (NAc) in rats behaviourally sensitized to methamphetamine (Meth). We found that the development of Meth-induced locomotor sensitization was attenuated by MCH infused into the NAc shell but not core. Moreover, the elevation of ERK phosphorylation in the NAc shell induced by Meth was inhibited by locally infused MCH. Infusion of the MCH receptor 1 (MCHR1) antagonist SNAP 94847 into the NAc shell but not core augmented the initiation of locomotor sensitization and amplitude of elevated phosphorylated ERK levels induced by Meth. The expression of Meth-induced locomotor sensitization and ERK alterations after 1 wk withdrawal were not affected by either MCH or SNAP 94847 infused into the NAc shell or core. These results indicate that MCH in the NAc shell plays a critical role in the development but not expression of Meth-induced locomotor sensitization in rats, which might be mediated by the ERK signalling pathway. Our study suggests that MCH might be a potential target for the treatment of Meth addiction.

  19. Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

    PubMed Central

    Castro, Daniel C.; Cole, Shannon L.; Berridge, Kent C.

    2015-01-01

    The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (“liking”) and motivational incentive salience (“wanting”) of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including “liking” and “wanting” for food rewards. PMID:26124708

  20. Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake.

    PubMed

    Zhu, Xianglong; Ottenheimer, David; DiLeone, Ralph J

    2016-01-01

    While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have disti