Basolateral amygdala regulation of cocaine-seeking behavior: New insights from studies investigating multiple phases of addiction

The basolateral amygdala (BLA) is a heterogenous brain structure comprised of rostral (rBLA) and caudal (cBLA) subregions. One goal of this dissertation was to investigate if dopamine D1 receptors within the rBLA and cBLA differentially regulate cocaine-seeking behavior during distinct phases of addiction in rats. The D1 receptor agonist SKF 81297 (Experiment 1) and the D1 receptor antagonist SCH 23390 (Experiment 2) were infused bilaterally into the cBLA or rBLA. Using a model of intravenous drug self-administration and relapse, cocaine-seeking behavior was studied during maintenance and reinstatement tests. Results demonstrated that the D 1 agonist increased, and the D1 antagonist decreased, cocaine-seeking behavior during maintenance tests when infused into the cBLA but not the rBLA. During reinstatement tests the D1 agonist increased, and the D 1 antagonist decreased, cocaine-seeking behavior when infused into the rBLA but not the cBLA. Thus, dissociable regulation of cocaine-seeking behavior by the dopamine D1 receptor depended on the phase of addiction and BLA subregion. Control studies demonstrated that behaviorally effective doses of SKF 81297 and SCH 23390 did not alter food-maintained responding, indicating that drug-induced changes in cocaine-seeking behavior were not due to non-specific factors. A second goal was to identify the neurocircuitry underlying reinstatement of cocaine-seeking behavior in rats (Experiment 3). Simultaneous lidocaine inactivation of the rBLA in one hemisphere and prelimbic prefrontal cortex (plPFC) in the contralateral hemisphere attenuated reinstatement of cocaine-seeking behavior relative to vehicle treatment. Unilateral inactivation of each site alone did not modify responding. Fos protein expression, a marker for neuronal activation, was enhanced bilaterally in the nucleus accumbens (NAcc) core, but not in the NAcc shell, in rats manipulated asymmetrically and undergoing reinstatement testing. Findings suggest that the rBLA, p1PFC, and NAcc core connect serially to regulate reinstatement of cocaine-seeking behavior. By implication, different therapeutic approaches may be necessary for reducing cocaine-seeking behavior in abstinent addicts vs. active users because separate neurocircuits are involved in regulating behavior during different phases of addiction.