Nucleus Accumbens Shell Subregions Research Articles

Chst9 marks a spatially and transcriptionally unique population of Oprm1-expressing neurons in the nucleus accumbens

Opioids produce addictive, analgesic, and euphoric effects via actions at mu opioid receptors (µORs). The µOR is encoded by the Oprm1 gene and is expressed in multiple brain regions that regulate reward and motivation, such as the nucleus accumbens (NAc). Oprm1 expression in NAc medium spiny neurons (MSNs) mediates opioid place preference, seeking, and consumption. However, recent single nucleus RNA sequencing (snRNA-seq) studies have revealed that multiple subpopulations of NAc neurons express Oprm1 mRNA, making it unclear which populations mediate diverse behaviors resulting from µOR activation. Using published snRNA-seq datasets from the rat NAc, we identified a novel population of MSNs that express the highest levels of Oprm1 of any NAc cell type. Here, we show that this population is selectively marked by expression of Chst9, a gene encoding a carbohydrate sulfotransferase. Notably, Chst9+ neurons exhibited more abundant expression of Oprm1 as compared to other cell types, and formed discrete cellular clusters along the medial and ventral borders of the NAc shell subregion. Moreover, CHST9 mRNA was also found to mark specific MSN populations in published human and primate snRNA-seq studies, indicating that this unique population may be conserved across species. Together, these results identify a spatially and transcriptionally distinct NAc neuron population characterized by the expression of Chst9. The abundant expression of Oprm1 in this population and the conservation of these cells across species suggests that they may play a key functional role in opioid response and identify this subpopulation as a target for further investigation.

Aberrant impulse control circuitry in obesity

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

The Impact of HIV Infection in Cocaine Seeking Behaviors

BackgroundSubstance use disorders (SUDs) are characterized by high propensity to relapse and are highly comorbid with HIV infection. The underlying neurobiology of this relationship is poorly understood. Preclinical research on the neurobiobehavioral outcomes of progressive HIV infections may yield crucial information to improve SUD prognosis and reduce risk of relapse in people living with HIV.MethodsTo model progressive HIV, adult male and female C57BL6J mice were inoculated with EcoHIV, a chimeric HIV‐1 which infects murine cells by replacing envelope glycoprotein gp120 with gp80. Five weeks after inoculation mice were trained in a cocaine conditioned place preference (CPP) paradigm (10mg/kg, i.p.) followed by extinction training. Stress‐induced reinstatement was assessed following administration of yohimbine, an α2 adrenergic antagonist, to determine EcoHIV effects. Neuronal activation in the prefrontal cortex (PFC) and nucleus accumbens (NAc) by cocaine exposure was assessed by quantitative analysis the expression of the immediate early gene, cFos.ResultsEcoHIV and sham‐inoculated mice exhibited similar cocaine CPP and extinction. However, EcoHIV mice showed significantly increased yohimbine‐induced reinstatement rate (p<0.05). cFos analysis revealed an elevated neural activation in PFC and NAc in response to cocaine. However, only neurons within infralimbic PFC (IL) and NAc shell subregions showed further increases in activity in cocaine exposed mice infected with EcoHIV vs shams.ConclusionEcoHIV infected mice escalated stress‐induced reinstatement of cocaine seeking compared to controls, suggesting that people living with HIV may be at elevated risk for stress‐induced relapse. Progressive EcoHIV infection may dysregulate IL and NAcShell activity to facilitate the cocaine seeking and reinstatement. Ongoing research will characterize how EcoHIV infection dysregulate IL‐NAcShell pathway specific activity during cocaine reward learning and stress‐induced relapse.

TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc.

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse. We focused on the shell subregion of nucleus accumbens (NAc), a key brain region of the brain reward system. We found that activation of TAAR1 by systemic and intra-NAc shell administration of the selective TAAR1 agonist RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation. Taken together, our findings indicate that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKIIα activity in the NAc. Our findings elucidate a novel mechanism of TAAR1 in regulating drug-induced reinstatement of cocaine-seeking and further suggests that TAAR1 is a promising target for the treatment of cocaine relapse.

Acute morphine administration alters the power of local field potentials in mesolimbic pathway of freely moving rats: Involvement of dopamine receptors

Increasing number of evidence support the role of ventral tegmental area (VTA) and nucleus accumbens (NAc) in mediating the opiate effects as the two critical components of brain reward pathway. It is believed that VTA to NAC dopaminergic projections mediate the reinforcing effects induced by opioid drugs. Although numerous studies have investigated mechanisms of reward processing in these brain regions, alterations of local field potentials (LFPs), as an index of total synaptic currents, has not been previously addressed.In the present study, thin metal electrodes were implanted in both VTA and shell sub-region of NAc to simultaneously record the spontaneous LFPs in freely moving rats. After one week recovery period, a single dose of morphine was systemically administered and the LFP recording was performed 15, 30, 45 and 60 post-injection. Also, in order to assess the role of dopamine system, two groups of animals were pre-treated by selective antagonists of dopamine type-1 and type-2 receptors 15 min prior to morphine injection.The obtained results indicated that in VTA, acute morphine administration potentiates the power of all LFP frequency bands (i.e. delta, theta, alpha, beta and gamma). However, in NAc shell, theta wave was significantly attenuated by morphine and other components were not affected. In addition, pre-treatment with both antagonists prevented the observed effect of morphine on LFP power suggesting the involvement of dopamine receptors in this process. Future studies should address mechanisms of dopamine-morphine interactions. It is also valuable to focus on acute and chronic effects of morphine on LFP power and assessment of the observed effects following naloxone challenge.

Assessing contributions of nucleus accumbens shell subregions to reward-seeking behavior

BackgroundThe nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene ΔFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction. MethodsRats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of an intracranial microinfusion of either amphetamine or vehicle targeted to the NAcDMS or the NAcINT. ResultsSmall amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no significant difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case. ConclusionThese results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics.

Effects of high frequency stimulation of nucleus accumbens shell subregion on food intake in obesity rats and regulation of appetite-related hormones

Objective To explore the effects of chronic high frequency deep brain stimulation (DBS) of nucleus accumbens shell subregion on food intake and regulation of appetite-related hormones. Methods High-fat diet induced obesity rats were randomly divided into two groups, namely DBS group and sham-DBS group.Stimulating electrodes were implanted in the bilateral shell subregion of nucleus accumbens. The amount of food intake was measured before and during stimulation.Peripheral concentrations of ghrelin, NPY, and leptin were tested before and after DBS or sham-DBS. Results The amount of food intake began to significantly decrease once stimulation was on. After 7 days'continuous stimulation, peripheral concentrations of NPY and leptin decreased significantly (Leptin: pre-DBS: 32±10 vs.post-DBS: 20±10pg/ml, P<0.05; NPY: pre-DBS: 1 302±287 vs. post-DBS: 926±299 pg/ml, P<0.05), and ghrelin increased significantly (Pre-DBS: 1066±310 vs. Post-DBS: 1603±848 pg/ml, P<0.05). Conclusions NAc shell subregion is an effective DBS target to decrease food intake in obesity rats. NAc-shell DBS seems to temporarily inhibit the hypothalamic secretion of NPY. Increase of ghrelin levels maybe a second result of decreased food intake caused by NAc-shell stimulation. Key words: Deep brain stimulation; Nucleus accumbens; Obesity; Ghrelin; Leptin; Neuropeptide Y; Rats

3,4,5-Trimethoxycinnamin acid ameliorates restraint stress-induced anxiety and depression

The present study investigated whether 3,4,5-trimethoxycinnamic acid (TMCA) treatment ameliorated restraint stress-provoked anxiety- and depression-like behaviors in mice. Fourteen consecutive days of restraint stress produced anxiety- and depression-like behaviors, including reduced time and frequency in the open arms of the elevated plus maze (EPM), as well as enhanced immobility times in the forced swim test (FST). However, TMCA (50mg/kg) treatment ameliorated this effect; mice showed increased time and frequency of visits in the open arms of the EPM and showed reduced immobility in the FST. In parallel with the behavioral data, long-lasting stimulation of ΔFosB in the nucleus accumbens shell subregion was exhibited in response to TMCA. Furthermore, a reduction in expression of SC1, a target of ΔFosB, in the nucleus accumbens of mice subjected to restraint stress was significantly reversed by TMCA (50mg/kg) treatment. Collectively, these results suggest that TMCA treatment might provide a therapeutic strategy for treatment of anxiety and depression.

Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell

The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D1-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell-type- and brain-region-specific positive feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine.

Increases in αCaMKII phosphorylated on Thr286 in the nucleus accumbens shell but not the core during priming-induced reinstatement of morphine-seeking in rats

Addiction is a pathological usurpation of the neural processes that normally serve reward-related learning and memory. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an important molecule involved in the mechanisms of learning and memory, suggesting its roles in drug addiction. In this study, we detected the changes of CaMKII protein levels in the nucleus accumbens (NAc), a key nucleus involved in drug-reward, during the reinstatement of morphine-seeking behavior with animal model of morphine self-administration in rats. Moreover, considering that the NAc is also involved in the natural reward-related learning and memory, we detected the changes of CaMKII protein levels in the NAc during the reinstatement of natural reward-seeking with animal model of saccharin self-administration as a control. We found that the level of αCaMKII phosphorylated on Thr286 increased in the NAc shell subregion but not the NAc core during the reinstatement of morphine-seeking, compared with that after extinction. However, during the reinstatement of saccharin-seeking, the protein level of αCaMKII phosphorylated on Thr286 did not change in the NAc shell. Surprisingly, both αCaMKII phosphorylated on Thr286 and βCaMKII phosphorylated on Thr287 decreased in the NAc core during the reinstatement of saccharin-seeking. These results suggest that increased phosphorylation of CaMKII (Thr286) in the NAc shell is involved in the relapse to opioids-seeking and the mechanisms underlying the reinstatement of morphine-seeking are different from those involved in the reinstatement of natural reward-seeking.

Subregional, Dendritic Compartment, and Spine Subtype Specificity in Cocaine Regulation of Dendritic Spines in the Nucleus Accumbens

Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we used single-cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 h, 24 h, or 28 d) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites. Notably, all observed density changes were attributable to selective regulation of thin spines. At 4 h after injection, the proximal spine density is unchanged in the core but significantly increased in the shell. At 24 h, the density of proximal dendritic spines is reduced in the core but increased in the shell. Such downregulation of thin spines in the core persists through 28 d of withdrawal, whereas the spine density in the shell returns to baseline levels. Consistent with previous results, dendritic tips exhibited upregulation of dendritic spines after 24 h of withdrawal, an effect localized to the shell. The divergence in regulation of proximal spine density in NAc core versus shell by cocaine correlates with recently reported electrophysiological data from a similar drug administration regimen and might represent a key mediator of changes in the reward circuit that drive aspects of addiction.

Slow phasic changes in nucleus accumbens dopamine release during fixed ratio acquisition: a microdialysis study

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating behavioral output during reinforcement-seeking behavior. Several studies have investigated the characteristics of accumbens DA release during the performance of well-learned operant behaviors, but relatively few have focused on the initial acquisition of particular instrumental behaviors or operant schedules. The present experiments focused on the initial acquisition of operant performance on a reinforcement schedule by studying the transition from a fixed ratio 1 (FR1) schedule to another operant schedule with a higher ratio requirement (i.e. fixed ratio 5 [FR5]). Microdialysis sessions were conducted in different groups of rats that were tested on either the FR1 schedule; the first, second, or third day of FR5 training; or after weeks of FR5 training. Consistent with previous studies, well-trained rats performing on the FR5 schedule after weeks of training showed significant increases in extracellular DA in both core and shell subregions of nucleus accumbens during the behavioral session. On the first day of FR5 training, there was a substantial increase in DA release in nucleus accumbens shell (i.e. approximately 300% of baseline). In contrast, accumbens core DA release was greatest on the second day of FR5 training. In parallel experiments, DA release in core and shell subregions did not significantly increase during free consumption of the same high carbohydrate food pellets that were used in the operant experiments, despite the very high levels of food intake in experienced rats. However, in rats exposed to the high-carbohydrate food for the first time, there was a tendency for extracellular DA to show a small increase. These results demonstrate that transient increases in accumbens DA release occur during the initial acquisition of ratio performance, and suggest that core and shell subregions show different temporal patterns during acquisition of instrumental behavior.

Sensitizing regimens of (±)3, 4-methylenedioxymethamphetamine (ecstasy) elicit enduring and differential structural alterations in the brain motive circuit of the rat

Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received two daily injections of either 5.0 mg/kg (±)-MDMA or saline vehicle, ∼6 h apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia

Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed. Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

Differential activation of cAMP response element binding protein in discrete nucleus accumbens subregions during early and late cocaine sensitization.

The present study examined the differential cocaine-induced activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) throughout discrete zones of analysis of the nucleus accumbens (NAc) in rats. CREB-dependent gene transcription, which may underlie long-lasting drug-induced changes in behavior and the subjective effects of cocaine, varies depending on the stage of drug exposure or withdrawal and the cell population involved. Using immunohistochemistry, the authors analyzed changes in CREB phosphorylation in the NAc after 5 days of cocaine, a short or long drug-free period, and a subsequent challenge injection. The NAc shell was separated into 5 zones of analysis previously defined by neurochemistry and connectivity. Repeated cocaine resulted in CREB phosphorylation in all analyzed subregions of the NAc excluding the most ventrolateral region of the shell 2 weeks after cessation of repeated cocaine, but rats challenged after 2 drug-free days yielded a more localized activation of CREB in the 3 most dorsomedial zones of the shell. The temporal and anatomical determinants of cocaine-induced CREB activity may indicate functional differences among NAc shell subregions and suggest the involvement of CREB in early and late cocaine effects.

NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D2/3 dopamine receptor stimulation in rats

Recent experiments from this laboratory demonstrated synergistic effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation on brain stimulation reward and locomotor activity. Using place conditioning, this study explored further the interaction between DA and glutamate (Glu) using the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the AMPA/kainate receptor antagonist NBQX, and the D(2/3) DA receptor agonist 7-OH-DPAT. Effects of these compounds, alone and combined, were measured in male Sprague--Dawley rats using an unbiased two-compartment place conditioning procedure. 7-OH-DPAT (0.03--5.0 mg kg(-1), s.c.) administered immediately prior to conditioning was ineffective; when administered 15 min prior to conditioning, only the highest dose (5.0 mg kg(-1), s.c.) induced conditioned place preference (CPP). Acquisition of 7-OH-DPAT-induced CPP was blocked by MK-801 (0.06 or 0.13 mg kg(-1), i.p.) or NBQX (0.5 microg) microinjected into the nucleus accumbens (NAS) shell subregion. Intra-NAS shell administration of 7-OH-DPAT (5.0 microg) or NBQX (0.5 microg), alone or combined, failed to induce place conditioning, and this lack of effect was not due to state dependency. Administration of MK-801 or 7-OH-DPAT (5.0 mg kg(-1)) during the conditioning phase acutely increased horizontal activity, but neither compound, alone or combined, induced conditioned locomotor effects. Acquisition of place conditioning induced by systemic administration of 7-OH-DPAT is blocked by systemic NMDA receptor antagonism by MK-801 or by the AMPA/kainate receptor antagonist NBQX microinjected into the NAS shell subregion.

Glutamate and Dopamine in Nucleus Accumbens Core and Shell: Sequence Learning Versus Performance

This study sought to determine whether neurochemical changes associated with chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the learning impairments also associated with this Pb regimen, and whether core or shell subregions of nucleus accumbens would be more important to such effects. If so, then mimicking these neurochemical changes in normal (control) rats should reproduce these Pb-induced learning impairments. For this purpose, the effects of DA (20–80 μg), the non-competitive NMDA antagonist MK-801 (1.0–2.5 μg) or DA+ MK-801 (40+1.0, 80+2.5 μg) were infused in core or shell of nucleus accumbens in normal rats and effects on a multiple schedule of repeated learning (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb exposure, selectively reducing RL accuracy with no corresponding changes in P accuracy, an effect derived from an increased frequency of perseverative errors. DA produced non-specific changes, reducing accuracy levels in RL and P components. Accuracy and rate effects of DA could be reversed by concurrent administration of the higher MK-801 dose. In shell, MK-801, primarily the lower dose, reduced accuracy in both the RL and P components, while DA did not produce any systematic effects. Collectively, these results point to a greater importance of core as compared to shell in the mediation of learning of spatial sequences, and suggest that inhibition of glutamatergic NMDA function may play a critical role in the selective learning impairments associated with chronic low level Pb exposure.

D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

Although interference with dopamine (DA) systems can suppress lever pressing for food reinforcement, it is not clear whether this effect occurs because of a general disruption of food motivation. One way of assessing this has been a choice procedure in which a rat responds on an fixed ratio 5 (FR5) schedule for preferred Bioserve pellets while a less preferred lab chow is concurrently available in the operant chamber. Untreated rats consume little of the chow, preferring to respond for the Bioserve pellets. Previous studies have shown that depleting DA in the accumbens substantially decreased lever pressing while increasing chow consumption. In the present study, low doses (0.0625–1.0 μg) of the D1 antagonist SCH 23390 or the D2 antagonist raclopride were injected into the either the core or shell subregions of nucleus accumbens, and rats were tested on the concurrent lever pressing/feeding task. Analysis of the dose response curves showed that injections of SCH 23390 into the core were more potent than injections into the shell for suppressing lever pressing (i.e., the ED 50 was lower in the core). Nevertheless, injections of either drug into either site suppressed lever pressing and increased intake of the concurrently available chow. Across both drugs and at both sites, the amount of chow consumed was negatively correlated with the total number of responses. Neither drug significantly increased response duration, suggesting that accumbens DA antagonism did not produce the type of motor impairment that leads to severe alterations in the form of lever pressing. In summary, the blockade of D1 or D2 receptors in nucleus accumbens core or shell decreased lever pressing for food reinforcers, but rats remained directed toward the acquisition and consumption of food. These results indicate that accumbens D1 antagonism does not decrease lever pressing because of a general reduction in food motivation. Nevertheless, interference with accumbens DA does appear to set constraints upon which responses are selected for obtaining food, and may impair the ability of animals to overcome work-related response costs in order to obtain food.

Motor activation by amphetamine infusion into nucleus accumbens core and shell subregions of rats differentially sensitive to dopaminergic drugs

Selective breeding based on activity in a swim test has been used to produce lines of rats that show a high level of activity in the swim test (Swim High-active (SwHi) rats) and a low level of activity in the swim test (Swim Low-active (SwLo) rats). Previous studies have indicated that dopamine (DA) function is enhanced in SwHi rats and reduced in SwLo rats; a principal finding was that SwLo rats showed much smaller increases in ambulatory activity after systemic administration of amphetamine than did SwHi or non-selected rats. In light of the importance of the nucleus accumbens (NAC) in amphetamine-induced activity, the present study investigated whether DA function in NAC differs in SwHi and SwLo rats. Amphetamine was infused bilaterally into either the core or shell subregion of NAC, and ambulation or swim test activity was then measured. In SwLo rats, infusion of amphetamine (0.2–2.0 μg) into either NAC core or shell produced moderate increases in ambulation. In SwHi rats, infusion of amphetamine into NAC shell produced similar moderate increases in ambulation, but infusion into the core produced markedly larger dose-related increases in ambulation. In the swim test, infusion of amphetamine (1.0 μg) increased activity by affecting the dominant behavior of each line; i.e. struggling increased in SwHi rats and floating decreased in SwLo rats, with large effects seen in both lines with infusion into either NAC core or shell. These results support the idea that the distinct behavioral characteristics of SwHi and SwLo rats are mediated in part by differences in NAC-DA function.

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or ‘prepulse’. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions — the core and shell — that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D 2 antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPH or CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.