Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat

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 μmol/kg and the effect returned to ∼50% in 32 days. The γ-aminobutyric acidA (GABAA) receptor agonist muscimol induced hypothermia at 88 μmol/kg without any (cross-) tolerance. GABAA receptor antagonists, bicuculline (5.4 μmol/kg) and picrotoxin (3.3 μmol/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 μmol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine1A (5-HT1A) 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 GABAA or 5-HT1A receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.