Sigma (σ) receptor ligand, AC927 (N-phenethylpiperidine oxalate), attenuates methamphetamine-induced hyperthermia and serotonin damage in mice.
Methamphetamine interacts with sigma (σ) receptors and AC927, a selective σ receptor ligand, protects against methamphetamine-induced dopaminergic neurotoxicity. In the present study, the effects of AC927 on methamphetamine-induced hyperthermia and striatal serotonergic neurotoxicity were evaluated. Male, Swiss Webster mice were injected (i.p.) every 2 h, for a total of four times, with one of the following treatments: Saline+Saline; Saline+Methamphetamine (5 mg/kg); AC927 (5, 10, 20 mg/kg)+Methamphetamine (5 mg/kg); or AC927 (5, 10, 20 mg/kg)+Saline. Pretreatment with AC927 (10 mg/kg) significantly attenuated methamphetamine-induced striatal serotonin depletions, striatal serotonin transporter reductions, and hyperthermia. At the doses tested, AC927 itself had no significant effects on serotonin levels, serotonin transporter expression, or body temperature. To evaluate the effects of higher ambient temperature on methamphetamine-induced neurotoxicity, groups of mice were treated at 37 °C. Overall, there was an inverse correlation between the body temperature of the animals and striatal serotonin levels. Together, the data suggest that AC927 (10 mg/kg) protects against methamphetamine-induced neurotoxicity. The reduction of methamphetamine-induced hyperthermia by AC927 may contribute to the observed neuroprotection in vivo.
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
Michael J
MJ
Seminerio
Nidhi
N
Kaushal
Jamaluddin
J
Shaikh
Jason D
JD
Huber
Andrew
A
Coop
Rae R
RR
Matsumoto
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008024:Ligands; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D010070:Oxalates / Q000378:metabolism* / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology*; D017480:Receptors, sigma / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D008024:Ligands; C470324:N-phenethylpiperidine oxalate; D018696:Neuroprotective Agents; D010070:Oxalates; D010880:Piperidines; D017480:Receptors, sigma; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D008694:Methamphetamine