The Potent Effect of Environmental Context on Relapse to Alcohol-Seeking After Extinction

Abstract

Environments in which the pharmacological effects of alcohol have been experienced become potent triggers for relapse in abstinent humans. Animal models developed to study the effect of environmental contexts on relapse to alcohol-seeking behavior demonstrate that alcohol-seeking is renewed by exposure to an alcohol-associated context, following the extinction of alcohol-seeking in a different context. Hence, contexts in which alcohol conditioning and extinction learning occur can be critical determinants for whether or not alcohol-seeking behavior is observed. This review summarizes preclinical research to date examining the role of alcohol contexts on the reinstatement of extinguished responding for alcohol. Behavioral studies have elucidated factors that are important for eliciting context-dependent relapse, and have uncovered novel interactions between alcohol-seeking driven by discrete alcohol cues in different contexts. Neuropharmacological studies provide substantial evidence for a role of dopaminergic systems in context-dependent reinstatement, and growing support for opioidergic mechanisms as well. Several key limbic brain regions have been identified in the modulation of alcohol-seeking by context, supporting a proposed neural circuit that includes the hippocampus, nucleus accumbens, basolateral amygdala, lateral hypothalamus, and the paraventricular thalamus.

Fig. (1). Context-dependent reinstatement of alcohol-seeking

This schematic illustrates the use of distinct sensory features (floor texture, odors, distinctive visual features on the walls) used to create distinct training, extinction, and testing environments, or contexts. Training is conducted in Context A, and responding is extinguished in Context B. The reinstatement of responding can be tested in the the original training context (the ABA design) or in a new, novel context (the ABC design).

Fig. (2). The alcohol training context reinstates alcohol-seeking after extinction in a different context

A) Rats (N=8) were trained to lever press for alcohol in Context A (black bars) and extinguished in Context B (white bars). Twenty-four hours after the last extinction session (Extinction), subjects underwent the first reinstatement test in Context A (Reinstatement Test Day 1). Two and three weeks later, subjects were tested again for reinstatement of the operant response in Context A (Reinstatement Test Days 14 and 21), and in Context B 15 days after the first reinstatement test (Day 15). No reward was delivered for any of the tests. Depicted are mean alcohol lever presses +/− S.E.M. B) A separate group of rats (N=6) was trained to lever press for sucrose in Context A (gray bars) and extinguished in Context B (white bars). Reinstatement was tested as described in (A). Depicted are mean sucrose lever presses +/− S.E.M. * P < 0.01 as compared to extinction and # P < 0.01 as compared to Reinstatement Test Day 15. Adapted from [30] with permission.

Fig. (3). Context-dependent reinstatement of alcohol-seeking depends upon the full configuration of stimuli that comprise the context

A) Mean (+/− S.E.M.) alcohol lever and inactive lever presses during the final 5 days of self-administration (Self-Admin) and during four different reinstatement tests including the full configuration of stimuli of the ethanol context (Full Context), the alcohol context without the olfactory stimulus (No Odor), the olfactory stimulus alone presented in a novel context (Odor Only), and the same Novel context without the olfactory stimulus. The mean responding in the extinction context the last day of extinction before each test is also depicted. No alcohol was delivered during the reinstatement tests, and the order of reinstatement tests was counter-balanced across subjects. N=6. **P<0.001, *P<0.05 as compared to Extinction responding; ##P<0.005, #P<0.05 as compared to reinstatement in the full context. B) Mean (+/−) S.E.M. entries into the alcohol port by the same subjects as in Fig. (4A). Interestingly, there is a significant increase in port entries only during a reinstatement test with the Full Context. **P<0.005, as compared to extinction responding. Adapted from [31] with permission.

Fig. (4). Dopamine in the nucleus accumbens in required for context-dependent alcohol-seeking

Panels depict Mean (± S.E.M) responses on the active lever at the end of extinction (white bar) and after microinfusion of the D1 dopamine receptor antagonist, SCH 23390, into the nucleus accumbens (NAC; filled bars). Comparison of responding during extinction and responding after vehicle (0) reveals the context-dependent reinstatement effect; comparison of the different doses from 0 to 0.6 reveals the dose-dependent effect of SCH 23390 on this reinstatement. The top panel depicts combined data from the core and shell subregions as there were no statistical differences in the effects of SCH 23390 after infusion into the subregions (Overall NAC). Data from each subregion are shown in the smaller figures, below. At test, active lever responding produced the light-noise stimulus without alcohol. ^^ p<0.01, ^ p<0.05 significantly different from saline. Adapted from [34].

Fig. (5). Proposed neural circuitry implicated in context-dependent reinstatement of responding for alcohol

In this highly simplified schematic, the NAc core is proposed as a requisite final common output for alcohol-seeking. The influence of context is proposed to have access to the NAc core through multiple routes: First, through direct projections from the hippocampus (HIPP) to the NAc shell; the NAc shell may then influence the NAc core via projections from the ventral tegmental area (VTA) that influence dopamine projections back to the NAc core. Second, contextual information from the hippocampus (HIPP) may be carried by projections that terminate at the cell body regions of other excitatory inputs to the NAc core, such as the basolateral amygdala (BLA), where this contextual information may modulate the processing of information regarding conditioned stimuli. The information provided by the paraventricular thalamus (PVth) is not clear at the present time. Likewise, the role of NAc shell projections to the lateral hypothalamus (LH) in alcohol-seeking is not defined. See text for relevant research findings and further discussion.