title: Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat.
abstract: Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.
authors.affiliation: PK/PD section, DMPK&BAC, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. sandra.visser@astrazeneca.com
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.forename: Susanna
authors.initials: S
authors.lastname: Pozarek
authors.forename: Sofia
authors.initials: S
authors.lastname: Martinsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Forsberg
authors.forename: Svante B
authors.initials: SB
authors.lastname: Ross
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D002719:Chlormethiazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D010852:Picrotoxin / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001640:Bicuculline; D002719:Chlormethiazole; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D009118:Muscimol; D010852:Picrotoxin; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists