Separable roles of the nucleus accumbens core and shell in context- and cue-induced alcohol-seeking.

Conditioned responding to drug-predictive discrete cues can be strongly modulated by drug-associated contexts. We tested the hypothesis that differential recruitment of the nucleus accumbens (NAc) core and shell mediates responding to drug cues in a drug vs non-drug context. Rats were trained to discriminate between two 10-s auditory stimuli: one stimulus (CS+) was paired with ethanol (10% v/v; 0.2 ml; oral) whereas the other (CS-) was not. Training occurred in operant conditioning chambers distinguished by contextual stimuli, and resulted in increased entries into the ethanol delivery port during the CS+ when compared with the CS-. In experiment 1, port entries were then extinguished in a second context by withholding ethanol, after which context-induced renewal of ethanol-seeking was tested by presenting both stimuli without ethanol in the previous training context. This manipulation stimulated strong responding to the CS+ in rats pretreated with saline in the core (n=9) or shell (n=10), which was attenuated by pharmacologically inactivating (muscimol/baclofen; 0.1/1.0 mM; 0.3 microl/side) either subregion pretest. In experiment 2, after discrimination, training rats were habituated to a different context in which ethanol and both stimuli were withheld. Cue-induced ethanol-seeking was then elicited by presenting the CS+ and CS- without ethanol in the different context. Saline-pretreated rats responded more to the CS+ than the CS- (core n=8; shell n=9), and inactivating the core but not shell attenuated this effect. These data highlight an important role for the core in cue-induced ethanol-seeking, and suggest that the shell is required to mediate the influence of contexts on conditioned ethanol-seeking.

Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats.

RATIONALE: Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect. OBJECTIVES: We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues. METHODS: Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 microg/side), into the nucleus accumbens core or shell. RESULTS: Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell. CONCLUSION: These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context.

Reinstated ethanol-seeking in rats is modulated by environmental context and requires the nucleus accumbens core.

The reinstatement of ethanol (EtOH)-seeking induced by an EtOH-predictive light-tone stimulus is enhanced in an environment associated with prior EtOH self-administration (SA) compared with a context associated with EtOH unavailability (Tsiang & Janak, 2006). Here we hypothesized that EtOH-seeking would be elicited by the conditioned sensory stimulus properties of EtOH and that this reinstatement would be similarly modulated by context. We also determined whether pharmacologically inactivating the nucleus accumbens (NAc), a key structure in relapse circuitry, would attenuate reinstated EtOH-seeking. Rats lever-pressed for oral EtOH (10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory and tactile stimuli. Responding was then extinguished by withholding EtOH in a different context. EtOH-seeking, expressed as elevated responding without EtOH delivery, was subsequently tested by presenting an oral EtOH prime (two aliquots of 0.1 mL EtOH) in either the extinction or the prior EtOH-SA context. Rats received a microinfusion (0.3 microL/hemisphere) of saline or GABA agonists (muscimol/baclofen) into the NAc core or shell immediately before the reinstatement test. Robust EtOH-seeking was observed in the prior EtOH-SA but not the extinction context in saline-pretreated rats. This effect was significantly attenuated by inactivating the NAc core but not shell. Conversely, NAc shell inactivation significantly elevated lever-pressing in the extinction context. These data suggest that the sensory stimulus properties of oral EtOH can reinstate EtOH-seeking when experienced in the appropriate context and that functional activity in the NAc core is required for this effect. In contrast, the shell may normally inhibit incorrect behavioral responses.

Context-induced relapse of conditioned behavioral responding to ethanol cues in rats.

BACKGROUND: The environmental context in which drug-conditioned cues are encountered could modulate the capacity of such cues to trigger relapse in abstinent addicts. We explored this hypothesis using a behavioral animal model. METHODS: Rats were trained to discriminate between two auditory stimuli; the first (CS+) was paired with 10% ethanol and the second (CS-) was presented without ethanol. Training occurred in operant conditioning chambers equipped with distinct contextual stimuli, and entries into the ethanol delivery port during the stimuli were measured. Behavior was then extinguished by presenting both stimuli without ethanol in a second, different context. Context-dependent renewal of port entries was tested by presenting the CS+ and CS- without ethanol in the original training context. RESULTS: At test, port entries during the CS+ increased compared with extinction levels, while responding during the CS- remained unchanged (n = 11). This effect was attenuated after multiple extinction sessions in three distinct contexts (n = 18), compared with an equivalent number of extinction sessions in a single unique context (n = 16). Context-dependent renewal of port entries was also observed to a CS+ paired with 14% sucrose (n = 7) but not to a CS+ paired with 2% sucrose (n = 8). CONCLUSIONS: Environmental contexts can trigger the relapse of behavioral responding to ethanol- and sucrose-predictive cues in rats. For ethanol, this effect can be reduced by extinguishing responses to the ethanol cue in multiple distinct contexts, a manipulation that could increase the efficacy of cue-reactivity treatments for addiction.

Time-courses of Fos expression in rat hippocampus and neocortex following acquisition and recall of a socially transmitted food preference.

The present study examined expression of the immediate-early gene, c-Fos, following acquisition, 48-h (recent) recall, and 1-week (remote) recall of a socially transmitted food preference (STFP) in multiple brain regions implicated in learning and memory. In comparisons with controls, trained Long-Evans rats had increased Fos immunoreactivity in the ventral hippocampus following acquisition and recent recall. In the parahippocampal cortices, Fos was increased in the lateral entorhinal cortex after acquisition. In the orbitofrontal cortex, increased Fos immunoreactivity was observed in the lateral orbital cortex following both recent and remote recall and in the ventral orbital cortex following remote recall, indicating a role for the orbitofrontal cortex in the remote recall of STFP memory. In contrast, in the medial prefrontal cortex, increased Fos-ir was found following acquisition in the prelimbic cortex and following recent recall in the prelimbic and infralimbic cortices. No differences in Fos expression were found between trained rats and controls in the dorsal hippocampus, posterior parietal cortex, or amygdala. The present findings support a time-limited role of the hippocampus in the acquisition and recall of STFP memory and implicate neocortical regions involved in STFP acquisition, recent, and remote recall.

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes.

RATIONALE: Corticotropin-releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established. OBJECTIVES: We used selective CRF receptor antagonists to determine the receptor subtypes involved in the anxiogenic-like and aversive effects CRF in the BNST. MATERIALS AND METHODS: Male Long-Evans rats were bilaterally infused with CRF (0.2 or 1.0 nmol) either alone or in combination with the CRF1 receptor antagonist CP154,526 or the CRF2 receptor antagonist anti-sauvagine 30 (AS30) before behavioral testing in the elevated plus maze or place conditioning paradigms. RESULTS: Intra-BNST administration of CRF produced a dose-dependent reduction in open arm entries and open arm time in the elevated plus maze, indicating an anxiogenic-like effect. These effects were inhibited by co-infusion of CP154,526 but not of AS30, indicating that the anxiogenic-like effects of CRF in the BNST are mediated by CRF1 receptors. Place conditioning with intra-BNST administration of CRF produced a dose-dependent aversion to the CRF-paired environment that was prevented by co-infusion of either CP154,526 or AS30, indicating that both CRF receptor subtypes mediate the aversive effects of this peptide. Intra-BNST infusions of the CRF receptor antagonists alone produced no effects in either behavioral paradigm. CONCLUSIONS: CRF1 receptors in the BNST mediate the anxiogenic-like effects of CRF in this region, whereas both CRF1 and CRF2 receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST.