Cholinergic depletion in the nucleus accumbens: effects on amphetamine response and sensorimotor gating

A delicate balance between dopaminergic and cholinergic activity in the ventral striatum or nucleus accumbens (N.Acc) appears to be important for optimal performance of a wide range of behaviours. While functional interactions between these systems are complex, some data suggest that acetylcholine in the N.Acc. may dampen the effects of excessive dopamine (DA) release. We proposed that a reduction in the density of cholinergic interneurons in the N.Acc would result in behavioural alterations suggestive of a hyper-responsiveness of the N.Acc DA system. The present study aimed to produce a sustainable depletion of cholinergic neurons in the N.Acc in the rat and study the effects of such lesions on DA-dependent behaviour. A novel saporin immunotoxin targeting choline acetyltransferase was microinjected bilaterally into the N.Acc of adult rats. We confirmed histologically that two weeks post-injection, animals show a local, selective depletion of cholinergic interneurons (mean cell loss of 44%). Cholinergic-depleted rats showed a marked increase in the locomotor activating effects of amphetamine. In addition, such lesions induced a disruption of sensorimotor gating processes, reflected in a reduction in the prepulse inhibition of the acoustic startle response, which was reversed by haloperidol.These data are suggestive of pronounced hyper-responsiveness of the meso-accumbens DA system which may be of relevance to the pathophysiology of schizophrenia, a condition where selective reduction in the number of ventral striatal cholinergic neurons has been demonstrated.     

Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine

Administration of amphetamine to mice evokes hyperlocomotion. Dopamine deficient (DD) mice, in which tyrosine hydroxylase (TH) has been specifically inactivated in dopaminergic neurons, have a blunted response to amphetamine, indicating that the hyperlocomotive response requires dopamine. Dopamine production can be restored to specific brain regions by using adeno-associated viruses expressing TH and GTP cyclohydrolase 1 (GTPCH1). Restoration of dopamine specifically to the nucleus accumbens (NAc) of DD mice completely restores the ability of these mice to respond to amphetamine. This response is specific to the dopamine production in the NAc, as restoration of dopamine production to the caudate putamen (CPu) does not fully restore the hyperlocomotive response to amphetamine. These data support previous studies in which accumbal dopamine is required for producing a normal locomotor response to amphetamine and further show that release of dopamine restricted to the NAc is sufficient for this response     

Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood

Neonatal quinpirole treatment to rats produces long‐term increases in D₂ receptor sensitivity that persists throughout the animal's lifetime, a phenomenon referred to as D₂ priming. Male and female Sprague‐dawley rats were administered quinpirole (1 mg kg^?1) or saline from postnatal days (P)1–11. At P60, all animals were given an injection of quinpirole (100 μg kg^?1), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D₂ receptor priming because yawning is a D₂ receptor mediated event. Beginning 1–3 days later, locomotor sensitization was tested through administration of d‐amphetamine (1 mg kg^?1) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed. Findings indicated that D₂‐priming enhanced horizontal activity in response to amphetamine in females compared to males at Days 1 and 4 of locomotor sensitization testing, and D₂‐priming enhanced turning in response to amphetamine. Seven to ten days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1–3.0 mg kg^?1). D₂‐primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine. Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D₂ priming. These results indicate that D₂ receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D₂ receptor sensitivity is a hallmark. Synapse 64:289–300, 2010. © 2009 Wiley‐Liss, Inc.     

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper‐responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic‐lesioned and control rats showed reliable stress‐induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion‐induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Ventral pallidal neuronal responses to dopamine receptor stimulation in the nucleus accumbens

The possible role of ventral pallidum (VP) in expressing dopaminergic actions in the nucleus accumbens was studied electrophysiologically using extracellular single unit recording and iontophoretic techniques in urethane-anaesthetized rats. Microinjections of dopamine (130 mM, 5-10 micrograms/0.2-0.4 microliters) into the nucleus accumbens resulted in a gradual, but prolonged, increase in the firing rate of VP neurones. Injections of the D1 agonist SKF38393 (34 mM, 2 micrograms/0.2 microliters), followed by the D2 agonist quinpirole (40 mM, 2 micrograms/0.2 microliters) into the accumbens, but not in the reverse order, resulted in a similar increase in the activity of VP neurones, mimicking the dopaminergic effect. Injections of either the D1 or the D2 agonist alone into the accumbens, however, produced no significant changes. Furthermore, iontophoretic application of picrotoxin, a gamma-aminobutyric acid (GABA) antagonist, or naloxone, an opiate (including enkephalin) antagonist on the same VP neurone which responded to accumbens dopamine injection also increase its spontaneous firing rate. Thus, pre-activation of D1 receptors in the accumbens was essential for the subsequent physiological expression of D2 receptors in inducing an increase in the firing rate of VP neurones. Dopamine in the accumbens may suppress the tonic inhibitory GABAergic and enkephalinergic outputs to the VP, resulting in an increase in firing rate of VP neurones. Since previous behavioural studies have shown that dopaminergic stimulation in the accumbens increases locomotor activity, the increased firing rate of ventral pallidal neurones may be expressing the postsynaptic actions of dopamine receptor stimulations in the accumbens as initiation of locomotor activity.     

Rostral-caudal differences in effects of nucleus accumbens amphetamine on VTA ICSS

That dopamine (DA) plays a role in reward-related learning is well documented but the mechanisms through which it acts are not well understood. The present set of experiments investigated the role of DA receptor subtypes within DA-innervated forebrain regions in brain stimulation reward (BSR). Thirty-two rats were implanted with electrodes in the ventral tegmental area (VTA) and cannulae aimed at the caudal nucleus accumbens (NAcc), the caudate-putamen (CP) or cortex. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding (thresholds). After BSR thresholds stabilized rats received treatments with DA agonists and their effects on thresholds were analyzed. Systemic treatments consisted of injections of (+)-amphetamine (1.0 mg/kg, i.p., 10 min before testing), the D₂ agonist quinpirole (1.0 mg/kg, i.p., 10 min before testing), the novel D₁ agonist A-77636 (3.0 mg/kg, s.c., 90 min before testing) or their vehicle (distilled H₂O). Central treatments consisted of microinjections of quinpirole (0.3 – 10.0 μg/0.5 μl) directly into the caudal NAcc, CP or cortex or A-77636 (30 μg/0.5 μl) into the caudal NAcc or CP. Results showed that all three agonists, when injected systemically, significantly reduced the threshold frequency required for VTA BSR, indicating a potentiative effect on reward. Central injections of quinpirole in the caudal NAcc, CP or cortex produced significant increases in BSR thresholds indicative of reduced rewarding efficacy of stimulation. Central injections of A-77636 into the caudal NAcc, but not the CP, were associated with a reduction in VTA BSR thresholds, suggesting an increase in reward. These results suggest that stimulation of D₁ or D₂ receptors enhances the rewarding effect of brain stimulation. In the case of the systemic quinpirole enhancement of reward, the present results suggest that this may not occur in the caudal NAcc, CP or cortex. Finally, the present results suggest that D₁ receptor stimulation in the caudal NAcc can facilitate reward-related learning.     

Iontophoresis of amphetamine in the neostriatum and nucleus accumbens of awake, unrestrained rats

When administered systemically to ambulant animals, amphetamine (AMPH) has both excitatory and inhibitory effects on single-unit activity in the neostriatum and nucleus accumbens. To determine the extent to which these results reflect a direct action of the drug, AMPH was applied iontophoretically to neostriatal and accumbal neurons under naturally occurring behavioral conditions. AMPH dose-dependently (5–40 nA) inhibited the vast majority of spontaneously active units. The inhibition, which was evident at low ejection currents (5–10 nA), had relatively short onset (4–12 s) and offset (6–24 s) latencies, and was positively correlated with basal firing rate. Even stronger dose-dependent inhibitory responses were recorded when neurons having no or a very low rate of spontaneous activity were tonically activated by continuous, low-current applications of glutamate (Glu). Systemic injection of either SCH-23390 (0.1 mg/kg) or haloperidol (0.2 mg/kg), relatively selective D₁ and D₂ receptor antagonists, respectively, blocked the AMPH-induced inhibition. Prolonged AMPH iontophoresis (2–3 min; 5–30 nA) inhibited both spontaneous impulse activity and Glu-induced excitations, resulting in a complete blockade of the Glu response at relatively high AMPH ejection currents (≥20 nA). Taken together, these results suggest that although dopamine is largely responsible for the inhibitory effects of iontophoretic AMPH, dopamine alone cannot account for the complex response of neostriatal and accumbal neurons to systemic AMPH administration.     

Heightened locomotor-activating effects of amphetamine administered into the nucleus accumbens in adolescent rats

There is a shift in sensitivity to systemically administered psychostimulants in adolescence, as evidenced by less amphetamine-induced locomotor activity in adolescent compared to adult rodents. Locomotor activating effects of amphetamine are dependent on drug actions in the core of the nucleus accumbens (NAc), but the contribution of this region to age differences in amphetamine sensitivity has not been studied directly. In the present study, we investigated the development of the NAc using targeted injections of amphetamine (0, 3, or 6 μg/side) directly into the NAc core in early (postnatal day 30; P30) or late (P45) adolescence, or in adulthood (P75). Locomotor activity was recorded during two 1 h sessions, 48 h apart. Amphetamine increased locomotor activity at all ages. P45 rats were more active than adults only at the 3 μg/side dose, but this difference was not significant when baseline activity was taken into account. In contrast, P30 rats were more active than adults at the 6 μg/side dose, indicating that the magnitude of the locomotor response is highest in early adolescence. Results of the present study are the first to directly show a developmental difference in the sensitivity of the NAc to amphetamine under conditions in which the influence of pharmacokinetic factors and regulatory brain regions is minimized.     

Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse perturb the normal functioning of this pathway. The nucleus accumbens (NAc) is a major terminal field of the mesolimbic dopamine neurons and modifications in neuronal structure and function in NAc accompany repeated exposure to psychomotor stimulants and other addictive drugs. Glutamatergic afferents to the NAc are thought to be crucial to the development of several aspects of addictive behavior, including behavioral sensitization and relapse to cocaine self-administration. Here we examine glutamatergic neurotransmission and synaptic plasticity in NAc neurons in vitro before and after repeated amphetamine treatment in vivo. We find that dopamine attenuates the response of NAc neurons to repetitive activation of glutamatergic afferents and thereby blocks long-term potentiation (LTP) induced by high-frequency afferent stimulation. Dopamine's effects are mimicked by dopamine receptor agonists and by amphetamine. In a second set of experiments, animals were treated with amphetamine daily for 6 days and brain slices were prepared after 8-10 days of withdrawal. In these slices, LTP in the NAc appears normal. However, acute exposure of such slices to amphetamine no longer modulates synaptic transmission or LTP induction. Thus, repeated exposure to amphetamine produces long-lasting changes in the modulation of glutamatergic synaptic transmission by amphetamine in the NAc. Our results support the notion that after psychostimulant exposure, excitatory synapses on NAc neurons alter their response to further psychostimulant for long periods of time.     

Shift from inhibition to excitation in the neostriatum but not in the nucleus accumbens following long-term amphetamine

Peripheral nerves of the shiverer mouse, which are characterized by the absence of major dense lines and myelin basic proteins in CNS myelin, were analyzed. From subcellular fractionation of sciatic nerves, it was found from the SDS-polyacrylamide gel electrophoresis that the Pl and Pr proteins equivalent to myelin basic protein of CNS and PM protein were missing in the shiverer in both P2A and P3A fractions in which PNS myelin is recovered. No extra bands were observed in any other fractions of the shiverer in place of the absence of the proteins. The activities of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) of P2A and P3A fractions were high, but that of the P3X fraction which floated over 0.32 M sucrose was the highest among the fractions examined in both the shiverer and the control. Developmental analysis of the protein profiles revealed that PO, Pl, Pr and PM proteins increased rapidly from the sixth day postnatally up to the twentieth day after birth in the control. No differences were observed between the shiverer and the control as for PO protein, but Pl, Pr and PM proteins were absent in the shiverer throughout the development. The CNPase activity of total homogenate of sciatic nerve fibers at birth in the control showed high activity comparable to that of the adult value, but there was no significant difference in activity between the control and the shiverer at any stage of development. Immunohistochemical reaction using peroxidase anti-peroxidase method showed that the myelin from the shiverer did not react with the MBP antiserum, while that of the control reacted positively. On the contrary, the myelin from both shiverer and the control reacted positively against P2 antibody.     

Behavioural sensitization and enhanced dopamine response in the nucleus accumbens after intravenous cocaine self-administration in mice

The behavioural effects of cocaine are enhanced in animals with a prior history of repeated cocaine administration. This phenomenon, referred to as sensitization, is also associated with an increase in cocaine-evoked extracellular dopamine levels in the nucleus accumbens. Behavioural and neurochemical sensitization has been demonstrated in rats with a prior history of cocaine self-administration and in those that had received experimenter-administered cocaine. Although it is clear that the repeated non-contingent administration also results in behavioural sensitization in the mouse, the issue of whether behavioural and neurochemical sensitization also occur in this species following intravenous cocaine self-administration has not been assessed. The present study used the technique of in vivo microdialysis in conjunction with operant self-administration to characterize cocaine-evoked locomotor activity and dopamine levels in the nucleus accumbens in mice with a prior history of intravenous cocaine self-administration or those that had received yoked infusions of cocaine. Mice that had received contingent or non-contingent infusions of cocaine exhibited an enhanced behavioural response to cocaine and increased cocaine-evoked dopamine levels in the nucleus accumbens. There was no difference between groups in the magnitude of this effect. Prior exposure to cocaine did not modify baseline dopamine levels in the nucleus accumbens. These data demonstrate that mice with previous cocaine self-administration experience show an enhanced behavioural and dopamine response to cocaine in the nucleus accumbens. Furthermore, control over cocaine infusion does not significantly alter the magnitude of the sensitized behavioural and presynaptic dopamine responses observed in response to a challenge dose of cocaine.     

NMDA receptors mediate the behavioral effects of amphetamine infused into the nucleus accumbens.

The present experiments examined glutamate-dopamine interactions within the nucleus accumbens in rats. It has been hypothesized that dopaminergic nerve terminals exert a modulatory influence on glutamate-mediated signals from corticolimbic areas. In the present studies, the effect of the selective NMDA (n-methyl-d-aspartate) antagonist AP5 (2-amino-5-phosphonopentanoic acid) on amphetamine-mediated behaviors was observed. In two behavioral paradigms, AP5 (0, 0.05, 0.5, 1.0 micrograms bilaterally) was microinjected immediately prior to amphetamine (5 micrograms bilaterally) in the nucleus accumbens. In the first experiment, the influence of AP5 on amphetamine-induced motor activity was examined. AP5 dose-dependently reduced the effectiveness of amphetamine in stimulating motor behavior. AP5 alone, paradoxically, tended to increase motor activity. In the second experiment, the effects of AP5 on amphetamine-potentiated responding (lever pressing) for conditioned reward (CR) were investigated. Normally, when amphetamine is infused into the nucleus accumbens, a marked potentiation of CR responding occurs. Prior infusion of AP5 also attenuated this behavioral effect of amphetamine. The results demonstrate that NMDA receptors within the nucleus accumbens mediate the behavioral consequences of increased dopamine release. They provide additional evidence for the involvement of limbic-striatal connections in the activating and reinforcing effects of psychostimulant drugs.     

Neurodegeneration in autoimmune MRL-lpr mice as revealed by Fluoro Jade B staining

As in many humans suffering from lupus erythematosus, the development of systemic autoimmunity and inflammation in Fas-deficient MRL-lpr mice is accompanied by CNS dysfunction of unknown etiology. Experimental studies revealed infiltration of lymphoid cells into the choroid plexus, reduced neuronal complexity, retarded brain growth, and enlargement of cerebral ventricles. Moreover, an increased presence of cells with nicked-DNA (TUNEL+ cells) in the periventricular areas suggested accelerated apoptosis in brain cells of MRL-lpr mice. However, direct evidence that the dying cells were neurons was lacking. For this purpose, we presently use Fluoro-Jade B (FJB), a novel fluorescent dye which has high affinity for dying neurons (both apoptotic and necrotic). As expected, in comparison to the control groups, the brains of diseased, 5-month-old MRL-lpr mice showed increased numbers of FJB-positive (+) cells in cortical and periventricular regions. The FJB+ cells were significantly more numerous than TUNEL+ cells, and only approximately 7% co-localized with TUNEL. Immunostaining for CD4 and CD8 markers did not correlate with the number of FJB+ cells, suggesting that T-lymphocyte infiltration into the brain tissue is not a reliable predictor of neuronal demise. Conversely, indices of systemic autoimmunity (splenomegaly and high serum anti-nuclear antibody levels) were associated with increased FJB+ cell numbers in brains of autoimmune MRL-lpr mice, supporting the causal link between autoimmunity and neurodegeneration. Taken together, the above results suggest that factors other than T-cell infiltration and cell death mechanisms other than Fas-mediated apoptosis dominate neuronal degeneration in lupus-prone MRL-lpr mice.     

Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens.

We reported previously that environmental novelty enhances the acute psychomotor activating effects of amphetamine, its ability to induce behavioral sensitization, and its ability to induce c-fos mRNA in the striatum and other structures, relative to when amphetamine is given in the home cage. The purpose of the present experiment was 2-fold: to determine (1) whether environmental novelty has a similar effect on the ability of cocaine to induce c-fos mRNA, and (2) whether this effect is seen in neurologically-intact rats (in previous experiments we studied the intact hemisphere of rats with a unilateral 6-OHDA lesion). In the dorsal portion of the caudate putamen, core and shell of the nucleus accumbens, and in several cortical regions, both amphetamine (1.5 mg/kg) and cocaine (15 mg/kg) induced higher levels of c-fos mRNA expression when administered in a novel environment, relative to when they were administered in the home cage. The ability of environmental context to modulate psychostimulant drug-induced immediate early gene expression may be related to its ability to modulate forms of drug experience-dependent plasticity, such as behavioral sensitization.     

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level.     

Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine

A robust increase in dopaminergic transmission in the nucleus accumbens (NAc) shell has been reported to be consistently associated with the long-term expression of behavioural sensitization to drugs of abuse. However, little is known about how this affects the neuronal network of the NAc. We made cellular recordings in NAc slices of saline- and amphetamine-pretreated adult rats and found that expression of behavioural sensitization was associated with long-lasting changes in the basal firing pattern of cholinergic interneurons up to 3 weeks after the last drug injection. Consequently, upon amphetamine sensitization, an inhibiting effect of the nicotinic receptor blocker mecamylamine on the amplitudes of spontaneous GABAergic synaptic currents as well as on the failure rate of electrically evoked GABAergic currents was found that was not present under control conditions. Thus, behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors that, in turn, stimulate the GABAergic synaptic transmission within the NAc shell. This is a new mechanism by which drugs of abuse may induce alterations in the processing and integration of NAc inputs involved in psychomotor sensitization.     

Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine.

The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.     

Pairing mild stress with increased serotonin-1B receptor expression in the nucleus accumbens increases susceptibility to amphetamine

Both serotonin-1B (5-HT_1B) receptors and stress modulate the behavioral and neurobiological effects of psychostimulant drugs. In order to examine how these factors interact to influence the development of behaviors associated with addiction, we used viral-mediated gene transfer to transiently increase expression of 5-HT_1B receptors in the nucleus accumbens (NAc) shell along with exposure to repeated mild stress (novelty + saline injection) in rats. Once the viral-mediated increases in gene expression had dissipated, the resulting effects of this 5-HT_1B/stress pairing on the acute locomotor response to amphetamine and on the development of psychomotor sensitization were examined. We report that the increasing expression of 5-HT_1B receptors on the terminals of NAc shell neurons that project to the ventral tegmental area and repeatedly exposing rats to mild stress subsequently enhance the acute locomotor-activating effects of amphetamine. In addition, the development of psychomotor sensitization (both locomotor activity and stereotypy components) is facilitated. These results suggest that serotonin signaling through NAc 5-HT_1B heteroreceptors can interact with stress to increase susceptibility to the enduring forms of drug-induced plasticity that are associated with addiction.