title: Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.
abstract: Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Baladi
authors.affiliation: Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Newman
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Nielsen
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA; School of Dentistry, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA. Electronic address: fleckenstein@hsc.utah.edu.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Fleckenstein
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005334:Fever / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine
keywords: D(3) antagonist; Dopamine D(3) receptors; Dopamine transporter; Methamphetamine; PG01037; Serotonin transporter