• Energy Research

In four experiments we studied the impact of retrieval-extinction training on the extinction and reinstatement of alcoholic beer seeking. Experiment 1 showed that preceding daily extinction sessions with a brief (10 min) extinction session (retrieval-extinction) attenuated the context-induced reinstatement of alcoholic beer seeking, thereby replicating and extending the findings of Xue et al. (2012). Experiment 2 then showed that the retrieval-extinction manipulation could attenuate the reinstatement produced by reversible inactivation of the nucleus accumbens shell prior to test. Experiment 3 showed that a modified extinction protocol that involved a reversed retrieval (i.e., extinction then retrieval) was also able to attenuate context-induced reinstatement. Finally, experiment 4 showed that the extinction-retrieval manipulation facilitated the reacquisition of alcoholic beer seeking as evidenced by increased breakpoints and responses during tests under a progressive ratio schedule. Taken together, these findings show that retrieval-extinction training protocols can alter the propensity to reinstate extinguished drug seeking but that these alterations are not always protective. These findings are inconsistent with accounts of the retrieval-extinction manipulation in terms of memory reconsolidation and deepened extinction. Instead, they are consistent with the notion that this manipulation increases the sensitivity of animals to the contingencies in effect during testing.

AbstractThe contexts where drugs are self‐administered have important control over relapse and extinction of drug‐seeking behavior. The nucleus accumbens shell (AcbSh) is essential to this contextual control over drug‐seeking behavior. It has been consistently implicated in both the expression of context‐induced reinstatement and the expression of extinction, across a variety of drug classes and other rewards. Here, we review the evidence linking AcbSh to the extinction and reinstatement of drug seeking. We consider whether this dual role can be linked to known heterogeneities in AcbSh cell types, their major afferents, and their major efferents. We show that although these heterogeneities are each important and can determine extinction vs. reinstatement, they do not seem adequate to explain the body of findings from the behavioral literature. Rather, we suggest that this functional specialization of AcbSh may be more profitably viewed in terms of the segregation and compartmentalization of AcbSh channels.

Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell types, and projections, by which AcbSh serves these dual roles are unknown. Here, we show that contextual control over relapse and abstinence is embedded within distinct output circuits of dopamine 1 receptor (Drd1) expressing AcbSh neurons. We report anatomical and functional segregation of Drd1 AcbSh output pathways during context-induced reinstatement and extinction of alcohol seeking. The AcbSh→ventral tegmental area (VTA) pathway promotes relapse via projections to VTA Gad1 neurons. The AcbSh→lateral hypothalamus (LH) pathway promotes extinction via projections to LH Gad1 neurons. Targeting these opposing AcbSh circuit contributions may reduce propensity to relapse to, and promote abstinence from, drug use.

Following a Pavlovian pairing procedure, alcohol-paired cues come to elicit behavioral responses that lead to alcohol consumption. Here we used an optogenetic approach to activate basolateral amygdala (BLA) axonal terminals targeting the shell of nucleus accumbens (AcbSh) and investigated a possible influence over cue-conditioned alcohol seeking and alcohol drinking, based on the demonstrated roles of these areas in behavioral responding to Pavlovian cues and in feeding behavior. Rats were trained to anticipate alcohol or sucrose following the onset of a discrete conditioned stimulus (CS). Channelrhodopsin-mediated activation of the BLA-to-AcbSh pathway concurrent with each CS disrupted cued alcohol seeking. Activation of the same pathway caused rapid cessation of alcohol drinking from a sipper tube. Neither effect was accompanied by an overall change in locomotion. Finally, the suppressive effect of photoactivation on cued-triggered seeking was also evidenced in animals trained with sucrose. Together these findings suggest that photoactivation of BLA terminals in the AcbSh can override the conditioned motivational properties of reward-predictive cues as well as unconditioned consummatory responses necessary for alcohol drinking. The findings provide evidence for a limbic-striatal influence over motivated behavior for orally consumed rewards, including alcohol.

Neurobiological mechanisms that influence behavior in the presence of alcohol-associated stimuli involve processes that organize behavior during the presence of these cues, and separately, regulation of behavior in their absence. However, little is known about anatomical structures that might mediate this regulation. Here we examined nucleus accumbens shell (AcbSh) as a possible neural substrate mediating behavior modulation triggered by the presence and absence of alcohol-associated environmental cues and contexts. We also examined subregions of basal amygdala nuclei- rostral basolateral (BLA) and basal posterior (BAP)- as they provide a major source of glutamatergic input to the AcbSh. Animals were trained to associate an auditory conditioning stimulus with alcohol in a discriminative context and then subsequently tested for conditioned port-entries across contexts either previously associated or not associated with alcohol. We found that, on test to the alcohol cue alone, AcbSh inactivation prevented conditioned port-entries in contexts that either were associated with alcohol or were novel, while also increasing unconditioned port-entries during the intertrial intervals. When tested to alcohol-reinforced cues, AcbSh inactivation produced more cue-trial omissions and elevated unconditioned port-entries. Interestingly, BLA and BAP inactivation produced dissociable effects. BAP but not BLA increased unconditioned port-entries, while both manipulations prevented conditioned port-entries during the alcohol-cue. We conclude that AcbSh is necessary for modulating control over behavior otherwise guided by the presence of alcohol-predictive environmental stimuli and contexts. Moreover, this role may involve integration of functionally segregated inputs from rostral and posterior portions of basal amygdala nuclei.

We investigated the impact of cocaine- and amphetamine-regulated transcript (CART) in the nucleus accumbens shell (AcbSh) on context-induced reinstatement of alcoholic beer-seeking. Rats were trained to respond for 4% (vol/vol) alcoholic beer in one context (A) followed by extinction in a second context (B). Rats were subsequently tested for renewal of extinguished responding in the training context (A). Return to the training context elicited responding (reinstatement), whereas intra-AcbSh injections of CART (55-102) attenuated reinstatement without affecting general behavioral activity (Experiment 1). CART (55-102) attenuated reinstatement dose-dependently across the 0.025 - 2.5 μg range (Experiment 2), and no effect was observed with the inactive CART (1-27) fragment (Experiment 3). Together, these findings suggest that intra-AcbSh CART (55-102) modulates the impact of drug-associated environments on reward seeking behavior.