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

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.

Keywords: Accumbens; Calcium signaling; Dopamine; Dopamine transporter; Methamphetamine; Striatum; Voltammetry.