Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice.
In humans, phencyclidine (PCP) is known to produce a syndrome of behavioral effects which have many characteristics in common with schizophrenia. Therefore, antagonism of PCP effects might be evidence for antipsychotic efficacy of a compound. In the present studies, the effects of the D2-like antagonist haloperidol, the mixed D2-like/5-HT2 antagonists olanzapine and clozapine, and a series of 5-HT receptor subtype selective antagonists on the hyperlocomotion produced by PCP were evaluated in mice. PCP (0.3-10 mg/kg) produced a dose-related increase in locomotor activity, with a peak effect at 3.0 mg/kg. The D2-like antagonist haloperidol produced a dose-related decrease in locomotor activity when administered alone, and blocked the hyperactivity effects of PCP over the same dose-range (minimal effective dose, MED = 0.3 mg/kg for both effects). In contrast, olanzapine and clozapine reversed the hyperlocomotion effects of PCP at doses (MED = 0.03 and 0.3 mg/kg, respectively) approximately 30- and 10-fold, respectively, below those that decreased activity when administered alone (MED = 1.0 and 3.0 mg/kg, respectively). The selective 5-HT2 antagonist LY53857 (0.3-3.0 mg/kg) administered alone had no effect on locomotor activity but reversed (MED = 0.1 mg/kg) the effects of PCP. Similarly, the selective 5-HT2A/2C antagonist ritanserin (0.001-1.0 mg/kg) alone had no effect on locomotor activity, but reversed (MED = 0.01 mg/kg) the effects of PCP. The selective 5-HT2A antagonists ketanserin (MED = 3.0 mg/kg) and MDL 100,907 (MED = 0.3 mg/kg) produced dose-related decreases in locomotor activity and ketanserin (MED = 0.1 mg/kg) and MDL 100,907 (MED = 0.003 mg/kg) reversed the effects of PCP. The selective 5-HT3 antagonist zatosetron (0.01-10 mg/kg) and the selective 5-HT1A antagonist WAY 100,635 (0.001-3 mg/kg) were without effects on spontaneous locomotor activity. Zatosetron reversed the effects of 3.0 mg/kg PCP at the nonselective dose of 10 mg/kg whereas WAY 100,635 (0.001-1 mg/kg) did not affect PCP-induced hyperlocomotion. The present results indicate that PCP increases locomotor activity, at least in part, due to actions at 5-HT2A, but not 5-HT3 or 5-HT1A, receptors. Further, the present findings support the hypothesis that antagonism at 5-HT2A receptors contributes to the in vivo actions of atypical antipsychotics such as olanzapine and clozapine.
Gleason
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SD
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Shannon
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HE
D000818:Animals; D001569:Benzodiazepines; D003024:Clozapine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D000077152:Olanzapine; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*
D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D010890:Pirenzepine; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine