Differential and long-lasting changes in neurotransmission in the amygdala of male Wistar rats during extended amphetamine abstinence

Abstract

Amphetamine addiction is associated with maladaptive actions that promotes continued use despite negative consequences, and a high risk of relapse even after protracted abstinence. Considering the role of the amygdala in regulating incentive motivation and reward-based behavior, the aim of this study was to assess neuroadaptations in subregions of the amygdala elicited by a brief period of discontinuous amphetamine exposure (2.0 mg/kg/day, 5 days) followed by abstinence (2 weeks, 1 month, 3 months) in male Wistar rats. Electrophysiological field potential recordings demonstrated that repeated amphetamine exposure significantly depressed evoked populations spikes in the basolateral amygdala (BLA). Evoked populations spikes were normalized after three months abstinence, but one challenge dose of amphetamine (0.5 mg/kg) was sufficient to reinstate synaptic depression in animals previously receiving amphetamine. In the central nucleus of the amygdala (CeA), amphetamine produced a long-lasting hyperexcitability that sustained even after three months abstinence. In the CeA, there were no significant differences between treatment groups following bath perfusion of the GABAA receptor antagonist bicuculline, indicating that amphetamine acts by reducing the inhibitory tone. Recordings performed in brain subregions interlinked with the amygdala, including medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens shell (nAc), revealed no significant neuroadaptations after two weeks abstinence. However, synaptic output was significantly depressed in the nAc after one- and three-month abstinence. In conclusion, the data presented here shows that five days of discontinuous exposure to amphetamine is sufficient to produce long-lasting neuroadaptations, which may contribute to compulsive drug taking and increase the risk for relapse.