Vol. 292, Issue 2, 731-736, February 2000

Atypical Antipsychotics and Dopamine D₁ Receptor Agonism: An In Vivo Experimental Study Using Core Temperature Measurements in the Rat¹

Sandra Oerther and Sven Ahlenius

Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The study objectives were to examine the effects of the atypical antipsychotic drugs olanzapine, risperidone, and quetiapine on core temperature in the rat in relation to such effects produced by clozapine and to compare possible in vivo intrinsic efficacy of olanzapine, risperidone, and quetiapine at dopamine (DA) D₁ receptors with such effects previously shown for clozapine. Core temperature measurements were made in adult male Wistar rats maintained under standard laboratory conditions using a reversed 12-h daylight cycle. Clozapine (0-32 µmol/kg s.c.), olanzapine (0-32 µmol/kg s.c.), and risperidone (0-4 µmol/kg s.c.) all produced a dose-dependent hypothermia. Except for slight nondose-dependent hyperthermia, there were no effects of quetiapine (0-16 µmol/kg s.c. or i.p.) on the core temperature. The hypothermia produced by clozapine, but not that produced by equipotent doses of olanzapine or risperidone, was fully antagonized by pretreatment with the DA D₁ receptor antagonist SCH-23,390 (0.1 µmol/kg s.c.). On the other hand, quinpirole-induced hypothermia (4 µmol/kg s.c.) was partially antagonized by olanzapine (2 µmol/kg s.c.), risperidone (4 µmol/kg s.c.), and quetiapine (16 µmol/kg s.c.) but not by clozapine (1 µmol/kg s.c.). Clozapine preferentially stimulates DA D₁ receptors in comparison with olanzapine and risperidone, whereas olanzapine, risperidone, and quetiapine preferentially block DA D₂ receptors compared with clozapine. It is suggested that stimulation of DA D₁ receptors, presumably in the prefrontal cortex, is a distinguishing feature of clozapine responsible for its favorable profile on cognitive functioning in schizophrenia.