The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats

RATIONALE: It has been suggested that the nucleus accumbens (NAcc) may be involved in heroin reward, and the core and shell regions respond differently following administration of a number of drugs of abuse. OBJECTIVE: The possible role of the NAcc core and shell subregions in the acquisition of heroin self-administration behaviour was investigated. METHODS: Rats were given selective excitotoxic lesions of either the nucleus accumbens core or shell before the acquisition of responding for i.v. heroin (0.04 mg/infusion) under a continuous reinforcement schedule in daily 3 h sessions. After sham-lesioned rats reached a stable baseline, a between-sessions heroin dose-response function was established. RESULTS: Rats with lesions of the NAcc shell did not differ significantly from sham controls in either the acquisition of heroin self-administration or in their heroin dose-response function. The NAcc core lesion group showed reduced levels of responding during the acquisition of heroin self-administration and a reduction in responding during the heroin dose-response function, although this behaviour was sensitive to changes in the dose of heroin. CONCLUSIONS: The NAcc shell does not appear to be critical for heroin self-administration, whereas the NAcc core, although apparently not essential in mediating the rewarding effect of i.v. heroin, may mediate processes that are of special importance during the acquisition of instrumental behaviour.     

Selective mu- and kappa-opioid receptor antagonists administered into the nucleus accumbens interfere with rapid tolerance to ethanol in rats

Background  Previous findings have shown that intra-accumbens injection of naltrexone, a non-selective opioid antagonist, blocks the acquisition of rapid tolerance to ethanol in rats. This study investigates the effects of intra-accumbens injection of the selective mu-, delta-, and kappa-opioid antagonists, respectively, naloxonazine, naltrindole, and nor-binaltorphimine, on rapid tolerance to ethanol. Methods  Male Wistar rats with guide cannulae directed to the shell or the core portions of the nucleus accumbens received a microinjection of naloxonazine (2–4 μg), naltrindole (2–4 μg), nor-binaltorphimine (2.5–5 μg), or vehicle. After 5 min, each group was divided in two groups that received ethanol (2.7 g/kg i.p.) or saline. Rats were then tested for motor coordination on the tilting plane apparatus. Twenty four hours later, all rats received a challenge dose of ethanol (2.7 g/kg i.p.) and were tested on the tilt plane again. Results  Repeated injections of ethanol caused a reduction in motor impairment suggesting the development of tolerance. However, rats injected with 4 μg naloxonazine into either core or shell portions of the nucleus accumbens did not exhibit tolerance when challenged with ethanol on day 2. Rats treated with 5 μg nor-binaltorphimine into accumbens core plus intraperitoneal saline on day 1 showed reduced motor impairment when challenged with ethanol on day 2, suggesting cross-tolerance to ethanol. Conclusions  Taken together, our results suggests that mu-opioid receptors in both shell and core portions of the nucleus accumbens, and possibly kappa-opioid in the core, participate in the modulation of rapid tolerance to ethanol.     

Decrease of glycogen synthase kinase 3β phosphorylation in the rat nucleus accumbens shell is necessary for amphetamine-induced conditioned locomotor activity

Phosphorylation levels of glycogen synthase kinase 3β (GSK3β) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3β phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3β activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3β in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3β plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3β phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3β inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.     

Electrolytic lesions of the medial nucleus accumbens shell selectively decrease ethanol consumption without altering preference in a limited access procedure in C57BL/6J mice

The central extended amygdala (cExtA) is a limbic region proposed to play a key role in drug and alcohol addiction and to contain the medial nucleus accumbens shell (MNAc shell). The aim of this study was to examine the involvement of the MNAc shell in ethanol and sucrose consumption in a limited and free access procedure in the C57BL/6J (B6) mouse. Separate groups of mice received bilateral electrolytic lesions of the MNAc shell or sham surgery, and following recovery from surgery, were allowed to voluntarily consume ethanol (15% v/v) in a 2 h limited access 2-bottle-choice procedure. Following 1 week of limited access ethanol consumption, mice were given 1 week of limited access sucrose consumption. A separate group of lesioned and sham mice were given free access (24 h) to ethanol in a 2-bottle choice procedure and were run in parallel to the mice receiving limited access consumption. Electrolytic lesions of the MNAc shell decreased ethanol (but not sucrose) consumption in a limited access procedure, but did not alter free access ethanol consumption. These results suggest that the MNAc shell is a component of the underlying neural circuitry contributing to limited access alcohol consumption in the B6 mouse.     

CB1 receptors modulate the intake of a sweetened-fat diet in response to mu-opioid receptor stimulation of the nucleus accumbens

Previous research has demonstrated that concurrent systemic administration of CB₁ cannabinoid and mu-opioid receptor agonists increases feeding in rats. However, the possible neural loci of this cooperative effect have yet to be identified. These studies tested whether the nucleus accumbens shell may be one site of the interactive effects of opioid and cannabinoid ligands on feeding. Injection of the mu-opioid agonist DAMGO (at 0, 0.025, 0.25, or 2.5 µg/0.5 µl/side) directly into the rat nucleus accumbens shell increased feeding on a sweetened-fat diet, and this effect was blocked by pretreatment with either the mu-opioid antagonist naltrexone (20 µg/0.5 µl/side) or the CB₁ antagonist SR141716 (0.5 µg/0.5 µl/side). Activation of nucleus accumbens shell CB₁ receptors with WIN55212-2 alone (at 0.1 or 0.5 µg/0.5 µl/side) had no apparent effect on food intake. However, local injections of the low dose of DAMGO (.025 µg/0.5 µl/side) in this region along with WIN55212-2 (at 0.25 or 0.50 µg/0.5 µl/side) increased feeding above that induced by DAMGO alone. These data suggest an important modulatory role for cannabinoid receptors in the expression of feeding behaviors in response to mu-opioid receptor activation of the nucleus accumbens shell.     

The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement

RATIONALE: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and -taking behaviour. However, the importance of the "core" and "shell" subdivisions of the NAcc in heroin-seeking and -taking behaviour remains unclear. OBJECTIVES: To investigate the function of the NAcc core and shell in heroin self-administration and heroin-seeking behaviour. METHODS: Male rats were trained to self-administer heroin (0.12 mg/kg per infusion) under a continuous reinforcement (CRF) schedule. After responding stabilised, rats were given excitotoxic (or sham) lesions of either the NAcc core or shell and after recovery were assessed for their retention of heroin self-administration under CRF. At this point a second-order schedule of reinforcement was introduced, commencing at FR10 (FR1:S) and terminating at FR10 (FR10:S), in which ten lever presses resulted in presentation of the heroin-associated CS+, and completion of ten such units resulted in drug infusion. RESULTS: Within 7 days, all groups re-acquired responding for heroin under CRF at rates similar to their pre-lesion performance. However, rats with lesions of the NAcc core, but not shell, were severely impaired in the acquisition of heroin-seeking behaviour. CONCLUSIONS: These results indicate an important role for the core of the NAcc in the acquisition of heroin-seeking behaviour under the control of drug-associated stimuli.     

Control of within-binge cocaine-seeking by dopamine and glutamate in the core of nucleus accumbens

Rationale  Dopamine and glutamate are thought to interact in the ventral striatum and to play important roles there in the cocaine-seeking of cocaine-experienced animals. Objectives  We sought to determine the relative roles of the two transmitters in the two major zones of the nucleus accumbens (NAS), the core and shell subregions. Methods  We assessed the effects of dopamine and glutamate receptor blockade in the core and shell on intravenous cocaine self-administration in rats. Trained animals were allowed to self-administer cocaine for an initial hour, and then D1-type or D2-type dopamine receptor blockers or NMDA-type or AMPA-type glutamate receptor blockers were infused by reverse microdialysis into one of the two regions for an additional 3 h of testing. Results  The D1-type antagonist SCH23390 and the D2-type antagonist raclopride each increased cocaine intake whereas the AMPA-type antagonist CNQX decreased responding when infused into the core. SCH23390 increased cocaine intake less strongly when infused into the shell, while raclopride and CNQX were each ineffective when infused into the shell. The NMDA-antagonist CPP failed to affect cocaine self-administration when infused into either site. Conclusions  These findings implicate the core of NAS in the maintenance of established cocaine self-administration in trained animals, despite the fact that the reinforcement of responding in untrained animals appears to results from cocaine actions in the olfactory tubercle and medial shell and not the core of accumbens.     

Distinct contributions of dopamine receptors in the nucleus accumbens core or shell to established cocaine reinforcement under a second-order schedule

Nucleus accumbens dopamine is implicated in the primary and conditioned reinforcing properties of abused drugs. In the present study, specific impairments in responding for intravenous cocaine (0.3 mg/inf/0.1 ml/5 s) under a fixed-ratio 1 (FR-1) or second-order schedule (FI 15 min (FR10:S)) were investigated following infusion of the dopamine antagonist, α-flupenthixol, into either the nucleus accumbens core or shell. Infusion of α-flupenthixol into the core decreased cocaine intake under the FR-1 and second-order schedules. By comparison, blockade of nucleus accumbens shell dopamine receptors increased cocaine intake under the FR-1 schedule. Under the second-order schedule, cocaine intake and the number of responses was decreased. Effects on responding were more apparent after self-administered cocaine, when impairments in the latency to receive cocaine infusions were no longer evident. These results are discussed with reference to a role for nucleus accumbens shell dopamine in instrumental responding, and a role of nucleus accumbens core dopamine in incentive motivation, perhaps under the control of contextual stimuli.     

Contralateral turning elicited by unilateral stimulation of dopamine D2 and D1 receptors in the nucleus accumbens of rats is due to stimulation of these receptors in the shell,but not the core,of this nucleus

The goal of this study was to determine whether dopamine D₂ and/or D₁ receptors in the shell and the core of the nucleus accumbens of rats have a differential role in turning behaviour. Unilateral injection of a mixture of the dopamine D₂ receptor agonist quinpirole (10 µg) and the dopamine D₁ receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7, 8-diol (SKF 38393, 5 µg) into the shell of the nucleus accumbens produced contralateral turning, when doses which per se were ineffective were injected. This effect was far greater than that found after similar injections into the core of the nucleus accumbens. The effect elicited from the shell was significantly attenuated by prior administration of either the dopamine D₂ receptor antagonistl-sulpiride (25 ng/0.5 µl) or the dopamine D₁ receptor antagonist (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol (SCH 23390, 0.5 µg/0.5 µl) into the same region. These data together with the fact thatl-sulpiride is known to be a valid tool to differentiate the involvement of distinct regions within the shell underlie the conclusion that dopamine D₂ and D₁ receptors in the shell, but not the core, of the nucleus accumbens play a critical role in the contralateral turning induced by unilateral injection of dopamine receptor agonists into this nucleus. The results are discussed in view of the known output pathways of the shell.     

Role of protein kinase C epsilon (PKCɛ) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell

Rationale  The type 5 metabotropic glutamate receptor (mGluR5) and the epsilon isoform of protein kinase C (PKCɛ) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCɛ-dependent mechanism. Objectives  We explored the potential neuroanatomical substrates of regulation of ethanol reinforcement by this mGluR5-PKCɛ signaling pathway by infusing selective inhibitors of these proteins into the shell or core region of the nucleus accumbens (NAc). Methods  Male Wistar rats were trained to self-administer ethanol intravenously and received intra-NAc infusions of vehicle or the selective mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) alone and in combination with a PKCɛ translocation inhibitor (ɛV1–2) or a scrambled control peptide (sɛV1–2). The effects of intra-NAc MTEP on food-reinforced responding and open-field locomotor activity were also determined. Results  MTEP (1 μg/μl) had no effect on ethanol or food reinforcement or locomotor activity when infused into either region. MTEP (3 μg/μl) reduced ethanol reinforcement when infused into the NAc shell but not the core, and this effect was reversed by ɛV1–2 (1 μg/μl) but not sɛV1–2 (1 μg/μl). In both regions, this concentration of MTEP did not alter food-reinforced responding or locomotor activity, and infusion of ɛV1–2 alone did not alter ethanol reinforcement. MTEP (10 μg/μl) reduced locomotor activity when infused into the shell; therefore, this concentration was not further tested on responding for ethanol or food. Conclusions  Blockade of mGluR5 receptors in the NAc shell reduces ethanol reinforcement via a PKCɛ-dependent mechanism.     

The selective κ-opioid receptor antagonist JDTic attenuates the alcohol deprivation effect in rats

The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective κ-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 µg/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell κ-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, κ-antagonism could be a valuable adjunct in ethanol relapse prevention.     

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 microg) 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.     

The decreased cyclic-AMP dependent-protein kinase A function in the nucleus accumbens: a role in alcohol drinking but not in anxiety-like behaviors in rats.

The nucleus accumbens (NAc) brain structures have been implicated in the reward and reinforcing properties of ethanol. The present study investigated the role of nucleus accumbal cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling in alcohol drinking and anxiety-like behaviors of rats. It was found that infusion of PKA inhibitor (Rp-cAMP) into the NAc shell significantly increased the alcohol but not the sucrose intake, without modulating the anxiety-like behaviors, as measured by elevated plus maze test in rats. PKA inhibitor infusion into the NAc shell significantly decreased the protein levels of alpha-catalytic subunit of PKA (PKA-Calpha) and phosphorylated cAMP response element-binding protein (p-CREB) as well as decreased the protein levels of neuropeptide Y (NPY) in the shell but not in the NAc core of rats. On the other hand, infusion of PKA activator (Sp-cAMP) or NPY alone into the NAc shell did not produce any changes in alcohol intake; however, when these agents were coinfused with PKA inhibitor, they significantly attenuated the increases in alcohol preference induced by pharmacological inhibition of PKA. Interestingly, PKA activator coinfusion with PKA inhibitor into the NAc shell significantly normalized the PKA inhibitor-induced decreases in the protein levels of PKA-Calpha and p-CREB as well as of NPY in the NAc shell of rats. Taken together, these results provide the first evidence that decreased PKA function in the NAc shell is involved in alcohol drinking but not in anxiety-like behaviors of rats. Furthermore, decreased function of PKA may regulate alcohol drinking behaviors via CREB-mediated decreased expression of NPY in the NAc shell of rats.     

Increases in food intake or food-seeking behavior induced by GABAergic,opioid, or dopaminergic stimulation of the nucleus accumbens: is it hunger?

Rationale Previous work has shown that stimulation of GABAergic, opioid, or dopaminergic systems within the nucleus accumbens modulates food intake and food-seeking behavior. However, it is not known whether such stimulation mimics a motivational state of food deprivation that commonly enables animals to learn a new operant response to obtain food.Objectives In order to address this question, acquisition of lever pressing for food in hungry animals was compared with acquisition in non-food-deprived rats subjected to various nucleus accumbens drug treatments.Methods All animals were given the opportunity to learn an instrumental response (a lever press) to obtain a food pellet. Prior to training, ad lib-fed rats were infused with the -aminobutyric acid (GABA)_A agonist muscimol (100 ng/0.5 µl per side) or the mu-opioid receptor agonist d-Ala², N-me-Phe⁴, Gly-ol⁵-enkephalin (DAMGO, 0.25 µg/0.5 µl per side), or saline into the nucleus accumbens shell (AcbSh). The indirect dopamine agonist amphetamine (10 µg/0.5 µl per side) was infused into the AcbSh or nucleus accumbens core (AcbC) of ad lib-fed rats. An additional group was food deprived and infused with saline in the AcbSh. Chow and sugar pellet intake responses after drug treatments were also evaluated in free-feeding tests.Results Muscimol, DAMGO, or amphetamine did not facilitate acquisition of lever pressing for food, despite clearly increasing food intake in free-feeding tests. In contrast, food-deprived animals rapidly learned the task.Conclusions These findings suggest that pharmacological stimulation of any of these neurochemical systems in isolation is insufficient to enable acquisition of a food-reinforced operant task. Thus, these selective processes, while likely involved in control of food intake and food-seeking behavior, appear unable to recapitulate the conditions necessary to mimic the state of negative energy balance.     

Effects of bromocriptine on self-administration of sweetened ethanol solutions in rats

The effect of bromocriptine (BRO), a D₂ receptor agonist, on chronic oral ethanol (ETOH) self-administration was tested in a home-cage environment. Male Wistar rats (n = 77) were food deprived for 24 h. Then, a period of 15 days of limited-access (1h/day) to food and to a sweetened ETOH solution was started [3% w/v of glucose and several concentrations of ETOH depending upon the group: 0% (control group), 1.5%, 5% or 10% v/v]. Later, another period started in which rats were maintained in a free-choice, two-bottle situation with food, tap-water and the sweetened solution available for 24 h/day, for 14 days. Following this period, BRO (5 mg/kg, SC) was administered, once daily, for 5 days, in the same continuous free-access conditions. ETOH consumption was also studied for 4 days after the last BRO injection. BRO increased ETOH self-administration throughout the 5-day period, regardless of the ETOH concentration available, in the rats with previous higher ETOH intake, without effect in the control animals. In the control rats, water intake was increased, whereas in the group that had access to the lowest ETOH concentration a decrease in water consumption was found. The enhanced ETOH drinking was maintained after BRO treatment for the animals with previous higher ETOH intake. BRO effects on water consumption were also maintained. These data suggest that BRO can potentiate ETOH intake and provide further support for the role of dopamine (DA) systems in mediating volitional oral intake of ETOH. Received: 25 January 1996 / Final version: 12 June 1996     

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

Whether metabotropic glutamate 7 (mGluR7) -activation enhances or diminishes the reinforcing properties of psychostimulants remains unclear. We have previously shown that systemic mGluR7 activation reduced alcohol consumption and preference as well as locomotor-stimulating and rewarding properties of ethanol. In this study, we further examined the contribution of mGluR7 on the effect of ethanol within the nucleus accumbens (NAcc), a neural target for many drugs of abuse. Using short hairpin RNA (shRNA)-expressing lentiviral vectors (LV) to alter locally the activity of mGluR7 in male rats, we have shown that blocking mGluR7 expression increased ethanol consumption and preference in a two-bottle choice drinking paradigm with no effect either on saccharin or on quinine used for taste discrimination. In addition, mGluR7 knockdown increases preference for environments previously paired with low doses of ethanol in the conditioned place preference (CPP) test, as it shifted the dose–response curve for ethanol CPP to the left, indicating alterations in the rewarding effects of alcohol. More importantly, mGluR7 blockade in the dorsal striatum (DS) neither affected ethanol consumption nor ethanol-elicited CPP. These results show that levels of mGluR7 in the NAcc regulate responsiveness to alcohol. Taken together, these findings clearly demonstrate that mGluR7 signaling within the NAcc is a key modulator of functional responses to ethanol and offer an important target for regulating the addictive effects of alcohol.     

Differential effects of ethanol in the nucleus accumbens shell of alcohol-preferring (P), alcohol-non-preferring (NP) and Wistar rats: A proteomics study

The objective of this study was to determine the effects of ethanol injections on protein expression in the nucleus accumbens shell (ACB-sh) of alcohol-preferring (P), alcohol-non-preferring (NP) and Wistar (W) rats. Rats were injected for 5 consecutive days with either saline or 1 g/kg ethanol; 24 h after the last injection, rats were killed and brains obtained. Micro-punch samples of the ACB-sh were homogenized; extracted proteins were subjected to trypsin digestion and analyzed with a liquid chromatography-mass spectrometer procedure. Ethanol changed expression levels (1.15-fold or higher) of 128 proteins in NP rats, 22 proteins in P, and 28 proteins in W rats. Few of the changes observed with ethanol treatment for NP rats were observed for P and W rats. Many of the changes occurred in calcium-calmodulin signaling systems, G-protein signaling systems, synaptic structure and histones. Approximately half the changes observed in the ACB-sh of P rats were also observed for W rats. Overall, the results indicate a unique response to ethanol of the ACB-sh of NP rats compared to P and W rats; this unique response may reflect changes in neuronal function in the ACB-sh that could contribute to the low alcohol drinking behavior of the NP line.     

Systemic and intra-accumbens microinjections of naltrexone interfere with tolerance to ethanol in rats

Rationale Evidence suggests a role for the opioid system in the control of ethanol reinforcement and drinking. Previous findings have shown that naltrexone, an opioid antagonist that decreases ethanol consumption in humans and experimental animals, reduces the acquisition of acute ethanol tolerance in rats. However, there are few data regarding the role of the opioid system in the acquisition of ethanol tolerance, particularly in brain areas involved in the rewarding actions of ethanol. Objectives This study investigates the effects of systemic and of intra-accumbens injections of naltrexone on the development of rapid tolerance to ethanol. Methods Wistar rats received intraperitoneal injections of naltrexone (0.1–3.0 mg/kg) or microinjections into the core or shell portions of the nucleus accumbens (5–20 μg) before ethanol (2.7 g/kg i.p.). The animals were tested for motor coordination on the tilting plane apparatus. Tolerance was assessed 24 h later by administering the same dose of ethanol to all animals and retesting them on the tilting plane. Results The second injection of ethanol resulted in less motor incoordination on Day 2, suggesting the development of rapid tolerance. Pretreatment with naltrexone, either i.p. (0.3 and 0.6 mg/kg) or intra-accumbens (5–20 μg), on Day 1, blocked the development of rapid tolerance to the motor-incoordinating effects of ethanol on Day 2 without affecting the motor performance of the animals on Day 1. Conclusions The results suggest that the opioid system may be involved in the development of ethanol tolerance, and that the nucleus accumbens may play a role in this phenomenon.     

Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer.

Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providing a model of some aspects of long-term drug addiction. The purpose of the present study was to investigate the effects of inactivating the dorsal striatum (DStr), nucleus accumbens (NAcc) core, or NAcc shell on different types of responding, each maintained by drug-paired conditioned reinforcers. Inactivations were achieved by infusing a combination of baclofen and muscimol prior to (1) persistent responding for a drug-paired conditioned reinforcer, (2) reacquisition of this instrumental response after extinction by omission of the contingent conditioned stimulus (CS), or (3) CS (cue)-induced reinstatement of the original (and different) instrumental response that had previously delivered cocaine. Inactivation of the DStr attenuated persistent responding for a cocaine-paired conditioned reinforcer, as well as its reacquisition after extinction of this response, while the only effect of inactivation of the NAcc shell was to increase CS (cue)-induced reinstatement of the extinguished instrumental response that had previously delivered cocaine. Inactivation of the NAcc core affected all measures of responding maintained by drug-paired conditioned reinforcers. These results are discussed with reference to the neural systems involved in different aspects of responding maintained by drug-paired conditioned reinforcers.