The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat.
1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2.The close structural analogues of clozapine, loxapine (0.1 mg kg(-1) s.c.) and iso-clozapine (1 and 3 mg kg(-1) s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, iso-loxapine (up to 10 mg kg(-1) s.c.) did not produce catalepsy, but at a dose of 1 mg kg(-1) significantly inhibited catalepsy induced by loxapine (0.3 mg kg(-1) s.c.). 3. Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D2/5-HT1A, D2/5-HT1B/1D and D2/alpha2-receptor affinity (KD) ratios: i.e. 30-100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and iso-loxapine. The ratios of affinities for D2 to 5-HT2A, 5-HT2C or D1 did not reflect the grouping of cataleptic and non-cataleptic compounds. 4. Co-treatment with the alpha2-adrenoceptor antagonists, yohimbine (1-10 mg kg(-1) s.c.), RX 821002 (1-10 mg kg(-1) s.c.) and MK-912 (0.3 and 1 mg kg(-1) s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg(-1)). Yohimbine (1-10 mg kg(-1) s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg(-1) s.c.). The alpha2-adrenoceptor antagonists had no effect per se. 5. Neither yohimbine (10 mg kg(-1)) nor RX821002 (3 mg kg(-1)) altered the cataleptic response to the D1 receptor antagonist, SCH 23390 (1 mg kg(-1) s.c.), while, like clozapine, both compounds abolished the response to the 5-HT2A receptor antagonist, MDL 100,151 (3 mg kg(-1) s.c.). 6. The present data strongly implicate alpha2-adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.
Kalkman
H O
HO
Nervous Systems Research, Novartis Pharma AG, Basel, Switzerland.
Neumann
V
V
Hoyer
D
D
Tricklebank
M D
MD
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology; D002375:Catalepsy / Q000517:prevention & control*; D003024:Clozapine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D006801:Humans; D008152:Loxapine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D001552:Benzazepines; C115236:MDL 100,151; D011725:Pyridines; D012702:Serotonin Antagonists; D003024:Clozapine; D008152:Loxapine