Serotonergic neurotransmission mediates hypothermia induced by the N-phenylpiperazine antipsychotic prototypes LASSBio-579 and LASSBio-581.
Previous studies have demonstrated that LASSBio-579 and LASSBio-581, two N-phenylpiperazine derivatives designed for the treatment of schizophrenia, are presynaptic dopamine D(2) receptor agonists that induce a hypothermic effect in mice that is not mediated by dopamine receptor activation. The aim of the present study was to investigate possible serotonergic mechanisms underlying hypothermia induced by LASSBio-579 and LASSBio-581 in CF1 mice. The reduction in core temperature was dose-dependent (15-60 mg/kg, i.p.) and occurred by the oral route (30 mg/kg). Pretreatment with haloperidol (4 mg/kg, i.p.) resulted in a synergistic hypothermic effect. Pretreatment with (+/-)DOI (0.25 mg/kg, i.p.), a serotonin 5-HT(2A/C) receptor agonist, reduced the hypothermic effect induced by LASSBio-579 and LASSBio-581 at 15 and 30 mg/kg, i.p. In contrast, (+/-)DOI enhanced the hypothermia induced by both compounds at 60 mg/kg, i.p. The serotonin 5-HT1A antagonist WAY 100635 (0.05 mg/kg, s.c.) abolished the hypothermia induced by LASSBio-579 and diminished the hypothermia induced by LASSBio-581. Pretreatment with LASSBio579 (30 and 60 mg/kg, i.p.) and LASSBio-581 (60 mg/kg, i.p.) reduced the number of head-twitches induced by (+/-)DOI (2.5 mg/kg, i.p.). The ear-scratch response induced by (+/-)DOI was inhibited by both LASSBio-579 and LASSBio-581 at 60 mg/kg, i.p. These results indicate that LASSBio-579 and LASSBio-581 have mechanisms of action through the serotonergic neurotransmitter system.
Neves
Gilda
G
Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Kliemann
Michele
M
Betti
Andresa H
AH
Conrado
Daniela J
DJ
Tasso
Leandro
L
Fraga
Carlos A M
CA
Barreiro
Eliezer J
EJ
Teresa Dalla Costa
Rates
Stela M K
SM
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D014150:Antipsychotic Agents; C518328:LASSBio-579; C490224:LASSBio-581; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D006220:Haloperidol; C031503:phenylpiperazine