Role of the amygdala in drug-associated cue responses and drug-seeking

Abstract

Learning and memory appear to be critical aspects of drug abuse phenomena; playing a role in craving and relapse. These studies are directed toward understanding how learning and memory systems may interact with classical reward circuitry. They assess the role of the basolateral complex of the amygdala (BLC) in responses to drug-associated cues and drug-seeking behavior; addressing the hypotheses that (1) the BLC is necessary for responses to drug-associated cues as measured by intracranial self-stimulation (ICSS) and (2) that activation of the BLC is sufficient to induce reinstatement of drug-seeking in rats. We have developed a method for establishment of baseline behavior, the pairing of drug exposure (cocaine 10 mg/kg, morphine 5 mg/kg) with unique cues, and finally testing the effect of cue exposure on ICSS responding within the same apparatus. Cues previously paired with drug exposure decreased ICSS thresholds when presented in the absence of drug. This is suggestive of a Pavlovian conditioning phenomenon in which the reward circuitry is modulated by drug-associated cues. A study conducted in exactly the same manner, but with animals pre-treated with microinjections of the excitotoxin quinolinic acid into the BLC, established that the BLC is required for cocaine-associated cues to modulate ICSS behavior without affecting baseline ICSS responding. Sham treated animals were unaffected. In animals, the BLC has been shown to be necessary for cocaine-seeking behavior elicited by cocaine-associated cues. It has not been determined whether BLC activation is sufficient to reinstate cocaine-seeking. To address this possibility, electrical stimulation of the BLC was tested as a trigger to induce reinstatement of cocaine-seeking in rats. Rats were catheterized and trained to respond for cocaine. Once baseline criteria were met, lever-pressing behavior was extinguished by substitution of saline for cocaine. Upon extinction, animals were subjected to brief electrical stimulation of the BLC. 20 Hz electrical stimulation of the BLC produced reinstatement of cocaine-seeking while 2 Hz stimulation did not. Electrical stimulation of cerebellar and medial forebrain bundle as control areas did not reinstate cocaine-seeking. BLC stimulation is therefore sufficient to reinstate cocaine-seeking behavior in a frequency-dependent and anatomically selective manner.