Methamphetamine increases dopamine release in the nucleus accumbens through calcium-dependent processes

Rationale Methamphetamine (METH) enhances exocytotic dopamine (DA) signals and induces DA transporter (DAT)-mediated efflux in brain striatal regions such as the nucleus accumbens (NAc). Blocking sigma receptors prevents METH-induced DA increases. Sigma receptor activation induces Ca 2+ release from intracellular stores, which may be responsible for METH-induced DA increases. Objectives The role of intracellular and extracellular Ca 2+ in METH-induced DA increases and associated behavior was tested. Methods METH-induced Ca 2+ release was measured in hNPC-derived DA cells using ratiometric Ca 2+ imaging. In mouse brain slices, fast-scan cyclic voltammetry was used to measure METH effects on two measures of dopamine: electrically stimulated and DAT-mediated efflux. Intracellular and extracellular Ca 2+ was removed through pharmacological blockade of Ca 2+ permeable channels (Cd 2+ and IP3 sensitive channels), intracellular Ca 2+ chelation (BAPTA-AM), or non-inclusion (zero Ca 2+ ). Lastly, METH effects on dopamine-mediated locomotor behavior were tested in rats. Rats received intra-NAc injections of ACSF or 2-aminoethoxydiphenyl borate (2-APB; IP3 receptor blocker) and intraperitoneal METH (5 mg/kg) to test the role of intracellular Ca 2+ release in DA-mediated behaviors. Results Reducing Ca 2+ extracellular levels and Ca 2+ release from intracellular stores prevented intracellular Ca 2+ release. Intracellular Ca 2+ chelation and blocking intracellular Ca 2+ release reduced METH effects on voltammetric measures of dopamine. Blocking intracellular Ca 2+ release via 2-APB resulted in increased METH-induced circling behavior. Conclusions METH induces NAc DA release through intracellular Ca 2+ activity. Blocking intracellular Ca 2+ release prevents METH effects on DA signals and related behavior.