ABSTRACT
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 Ca2+ release from intracellular stores, which may be responsible for METH-induced DA increases. OBJECTIVES: The role of intracellular and extracellular Ca2+ in METH-induced DA increases and associated behavior was tested. METHODS: METH-induced Ca2+ release was measured in hNPC-derived DA cells using ratiometric Ca2+ 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 Ca2+ was removed through pharmacological blockade of Ca2+ permeable channels (Cd2+ and IP3 sensitive channels), intracellular Ca2+ chelation (BAPTA-AM), or non-inclusion (zero Ca2+). 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 Ca2+ release in DA-mediated behaviors. RESULTS: Reducing Ca2+ extracellular levels and Ca2+ release from intracellular stores prevented intracellular Ca2+ release. Intracellular Ca2+ chelation and blocking intracellular Ca2+ release reduced METH effects on voltammetric measures of dopamine. Blocking intracellular Ca2+ release via 2-APB resulted in increased METH-induced circling behavior. CONCLUSIONS: METH induces NAc DA release through intracellular Ca2+ activity. Blocking intracellular Ca2+ release prevents METH effects on DA signals and related behavior.
