Sustained inhibitory transmission but dysfunctional dopamine D2 receptor signaling in dorsal striatal subregions following protracted abstinence from amphetamine

Abstract

Behavioral sensitization to amphetamine is a complex phenomenon that engages several neurotransmitter systems and brain regions. While dysregulated signaling in the mesolimbic dopamine system repeatedly has been linked to behavioral sensitization, later research has implicated dorsal striatal circuits and GABAergic neurotransmission in contributing to behavioral transformation elicited by amphetamine. The aim of this study was thus to determine if repeated amphetamine exposure followed by abstinence would alter inhibitory neurotransmission in dorsal striatal subregions. To this end, male Wistar rats received amphetamine (2.0 mg/kg) in an intermittent manner for a total of five days. Behavioral sensitization to amphetamine was measured in locomotor-activity boxes, while neuroadaptations were recorded in the dorsolateral (DLS) and dorsomedial striatum (DMS) using ex vivo electrophysiology at different timepoints of amphetamine abstinence (2 weeks, 4–5 weeks, 10–11 weeks). Data show that repeated drug-exposure produces behavioral sensitization to the locomotor-stimulatory properties of amphetamine, which sustains for at least ten weeks. Electrophysiological recordings demonstrated a long-lasting suppression of evoked population spikes in both striatal subregions. Furthermore, following ten weeks of abstinence, the responsiveness to a dopamine D2 receptor agonist was significantly impaired in brain slices from rats previously receiving amphetamine. However, neither the frequency nor the amplitude of spontaneous inhibitory currents was affected by treatment at any of the time points analyzed. In conclusion, passive administration of amphetamine initiates long-lasting neuroadaptations in brain regions associated with goal-directed behavior and habitual performance, but these transformations do not appear to be driven by changes in GABAergic neurotransmission.