The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

Br J Pharmacol. 1998 Aug;124(7):1550-6. doi: 10.1038/sj.bjp.0701975.

Abstract

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.

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Antipsychotic Agents / antagonists & inhibitors
  • Antipsychotic Agents / therapeutic use*
  • Benzazepines / pharmacology
  • Catalepsy / prevention & control*
  • Clozapine / analogs & derivatives
  • Clozapine / antagonists & inhibitors
  • Clozapine / therapeutic use*
  • Humans
  • Loxapine / analogs & derivatives
  • Loxapine / antagonists & inhibitors
  • Loxapine / therapeutic use
  • Male
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Serotonin Antagonists / pharmacology

Substances

  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Antipsychotic Agents
  • Benzazepines
  • MDL 100,151
  • Pyridines
  • Serotonin Antagonists
  • Clozapine
  • Loxapine