Compulsive alcohol seeking and relapse: Central role of conditioning factors associated with alleviation of withdrawal states by alcohol

Background and Purpose Learned associations between environmental stimuli and drugs of abuse represent a major factor in the chronically relapsing nature of drug addiction. In drug dependent subjects these associations must be presumed to include associations linked to reversal of adverse withdrawal states by drug use-"withdrawal-associated learning" (WDL). However, their significance in drug seeking has received little experimental scrutiny. Experimental Approach Using alcohol as a drug of abuse, the behavioural consequences of WDL were investigated in animal models of relapse and compulsive drug seeking by comparing the effects of WD L-associated stimuli versus stimuli associated with alcohol without WDL experience in nondependent and post-dependent rats. Brain sites activated by exposure to the respective stimuli were identified by c-fos immunohistochemistry. Key Results (1) WDL-associated stimuli elicited significant alcohol seeking. In rats with WDL experience, stimuli associated with alcohol in the nondependent state no longer elicited robust alcohol seeking. (2) Responding elicited by WDL-associated stimuli, but not stimuli conditioned to alcohol in the nondependent state, was resistant to footshock punishment and increased response effort requirements for presentation of WDL-related stimuli. (3) Stimuli conditioned to alcohol in rats with a dependence but not WDL history did not sustain punished responding or tolerance of increased effort. (4) The central nucleus of the amygdala was identified as a site selectively responsive to WDL stimulus exposure. Conclusion and Implications Environmental stimuli associated with reversal of adverse withdrawal states by alcohol elicit compulsive-like alcohol seeking and establish WDL as a major, not well-recognized factor, in relapse vulnerability.