The role of α 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 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 D 2 /5‐HT 1A , D 2 /5‐HT 1B/1D and D 2 /α 2 ‐receptor affinity (K D ) 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 D 2 to 5‐HT 2A , 5‐HT 2C or D 1 did not reflect the grouping of cataleptic and non‐cataleptic compounds. 4 Co‐treatment with the α 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 α 2 ‐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 D 1 receptor antagonist, SCH 23390 (1 mg kg −1  s.c.), while, like clozapine, both compounds abolished the response to the 5‐HT 2A receptor antagonist, MDL 100,151 (3 mg kg −1  s.c.). 6 The present data strongly implicate α 2 ‐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.British Journal of Pharmacology (1998) 124 , 1550–1556; doi: 10.1038/sj.bjp.0701975