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.
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Acknowledgments
The authors would like to acknowledge Chris Schow, Gilbert Marchant, Spencer McCarthy, Seth Stapley, Austin Elwood, Sadie Karratti-Abordo, and Chena Bryan for their technical assistance during experiments.
Funding
This work is funded by the National Research Foundation of Korea (NRF; 2016R1D1A1B03935206 to EYJ) and the National Institute of Drug Abuse (NIDA; R01DA035958 to SCS and R03DA033904 to MAA).
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Experimental protocols were approved by the Brigham Young University Institutional Animal Care and Use Committee and Korea Institute of Toxicology according to NIH guidelines.
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Yorgason, J.T., Hedges, D.M., Obray, J.D. et al. Methamphetamine increases dopamine release in the nucleus accumbens through calcium-dependent processes. Psychopharmacology 237, 1317–1330 (2020). https://doi.org/10.1007/s00213-020-05459-2
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DOI: https://doi.org/10.1007/s00213-020-05459-2