Abstract
The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat.
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.).
Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D2/5-HT1A, D2/5-HT1B/1D and D2/α2-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.
Co-treatment with the α2-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 α2-adrenoceptor antagonists had no effect per se.
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.).
The present data strongly implicate α2-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.
Keywords: Catalepsy, yohimbine, RX 821002, clozapine, loxapine, neuroleptic drugs, α2-adrenoceptor antagonists
Full Text
The Full Text of this article is available as a PDF (359.3 KB).