THE ROLE OF ALPHA(2)-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 atypic al neuroleptic agent, clozapine, has been investigated in the rat. 2 T he 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 ra ts. In contrast, clozapine and the regio-isomer of loxapine, iso-cloza pine (up to 10 mg kg(-1) s.c.) did not produce catalepsy, but at a dos e of 1 mg kg(-1) significantly inhibited catalepsy induced by loxapine (0.3 mg kg(-1) s.c.). 3 Radioligand binding assays showed that catale ptogenic potential was most clearly predicted by the D-2/5-HT1A, D-2/5 -HT1B/1D and D-2/alpha(2)-receptor affinity (K-D) ratios: i.e. 30-100- fold higher ratios were calculated for loxapine and iso-clozapine, whe reas the ratios were less than 1 for clozapine and isoloxapine. The ra tios of affinities for D-2 to 5-HT2A, 5-HT2C or D-1 did not reflect th e grouping of cataleptic and non-cataleptic compounds. 4 Co-treatment with the alpha(2)-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 alpha(2)-adrenoceptor antagonists had no effect per se. 5 Neithe r yohimbine (10 mg kg(-1)) nor RX821002 (3 mg kg(-1)) altered the cata leptic response to the D-1 receptor antagonist, SCH 23390 (1 mg kg(-1) s.c.), while, like clozapine, both compounds abolished the response t o the 5-HT2A receptor antagonist, MDL 100,151 (3 mg kg(-1) s.c.). 6 Th e present data strongly implicate alpha(2)-adrenoceptor blockade in th e anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.