[The role of serotonin in the behavioral changes induced in the rat by cyclazocine].

Abstract

Cyclazocine is a benzomorphan derivative, considered as a mixed kappa and and sigma opioid receptor agonist. In experimental study with rats, cyclazocine is known to increase locomotor activity and to produce a bizarre behavioral syndrome including head swaying, backward walking, circling. The present study was undertaken to investigate the effects of various drugs modifying the serotoninergic neuronal systems, upon the locomotor activity and the abnormal behaviors induced by cyclazocine. Pretreatment with p-chlorophenylalanine (PCPA, 400 mg/kg, 72, 48, 24 hr) resulted in an inhibition of the three abnormal behaviors. Pretreatment with p-chloromethylamphetamine (PCMA, 15 mg/kg, 24 hr) antagonized head swaying, backward walking and markedly enhanced locomotor activity. In the contrary, pretreatment with PCMA (2.5 mg/kg, 15 min) resulted in enhanced abnormal behavioral responses to cyclazocine. L-tryptophan (50 mg/kg), 5-hydroxytryptophan (5-HTP, 50 mg/kg), or pargyline (50 mg/kg) inhibited abnormal behaviors and decreased locomotor activity. Serotonin antagonists with affinity fir both 5-HT1 and 5-HT2 receptors, metergoline (0.25-1 mg/kg), methysergide (1-5 mg/kg), amitriptyline (5-20 mg/kg), dl-propranolol (10-40 mg/kg) blocked head swaying and backward walking; only methysergide inhibited circling. All these drugs, except methysergide, markedly enhanced the cyclazocine-induced locomotor activity. In contrast, ketanserine (0.5-2 mg/kg) and pirenperone (0.05-0.2 mg/kg), serotonin antagonists with selective affinity for 5-HT2 receptors had no effects on the abnormal behaviors and locomotor activity. Taken together, these results suggest that a serotoninergic mediation is involved in the cyclazocine-induced abnormal behaviors, and that serotonin exerts an inhibitory control on the locomotor activity produced by the drug. These effects are probably associated with 5-HT1 receptors. Further experiments have shown that the drugs having being able to potentiate cyclazocine-induced locomotor activity, similarly potentiate the locomotor activity induced by levallorphan, morphinan derivative with cyclazocine-like properties but do not enhance the hyperactivity produced by a low dose of morphine. The data reported here, provide a contribution to the informations concerning the neuromediation of the effects of mixed kappa and sigma agonists and allow to compare the mechanism of action of cyclazocine with those of other psychotomimetic drugs.