Methamphetamine self-Administration in mice decreases GIRK channel-mediated currents in midbrain dopamine neurons

Background: Methamphetamine is a psychomotor stimulant with abuse liability and a substrate for catecholamine uptake transporters. Acute methamphetamine elevates extracellular dopamine, which in the midbrain can activate D2 autoreceptors to increase a G-protein gated inwardly rectifying potassium (GIRK) conductance that inhibits dopamine neuron firing. These studies examined the neurophysiological consequences of methamphetamine selfadministration on GIRK channel-mediated currents in dopaminergic neurons in the substantia nigra and ventral tegmental area. Methods: Male DBA/2J mice were trained to self-Administer intravenous methamphetamine. A dose response was conducted as well as extinction and cue-induced reinstatement. In a second study, after at least 2 weeks of stable self-Administration of methamphetamine, electrophysiological brain slice recordings were conducted on dopamine neurons from self-Administering and control mice. Results: In the first experiment, ad libitum-fed, nonfood-Trained mice exhibited a significant increase in intake and locomotion following self-Administration as the concentration of methamphetamine per infusion was increased (0.0015- 0.15 mg/kg/infusion). Mice exhibited extinction in responding and cue-induced reinstatement. In the second experiment, dopamine cells in both the substantia nigra and ventral tegmental area from adult mice with a history of methamphetamine self-Administration exhibited significantly smaller D2 and GABAB receptor-mediated currents compared with control mice, regardless of whether their daily self-Administration sessions had been 1 or 4 hours. Interestingly, the effects of methamphetamine self-Administration were not present when intracellular calcium was chelated by including BAPTA in the recording pipette. Conclusions: Our results suggest that methamphetamine self-Administration decreases GIRK channel-mediated currents in dopaminergic neurons and that this effect may be calcium dependent.