title: Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced  hyperthermia by harmaline and the involvement of activation  of 5-HT1A and 5-HT2A receptors.
abstract: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214-8033, USA.
authors.forename: Xi-Ling
authors.initials: XL
authors.lastname: Jiang
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Shen
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005334:Fever / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D006246:Harmaline / Q000494:pharmacology*; D008297:Male; D008732:Methoxydimethyltryptamines / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology
chemical_list: D008732:Methoxydimethyltryptamines; D008996:Monoamine Oxidase Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A; D006246:Harmaline; D019389:Cytochrome P-450 CYP2D6