Neurochemical actions of ethylketocyclazocine and ketocyclazocine in different regions of rat brain.

The effects of ethylketocyclazocine (EKC) and ketocyclazocine (KC), benzomorphan derivatives proposed as kappa opioid receptor agonists, were studied by measuring changes in the levels of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), and their major metabolites, DOPAC, HVA, MHPG-SO4, 5-HIAA, in different regions of rat brain. Doses ranging from 1 to 10 mg/kg were tested. EKC decreased the levels of DOPAC and HVA in striatum, and increased DA concentrations, EKC markedly increased the levels of MHPG-SO4 in hypothalamus, but not in cortex, midbrain and pons-medulla. There was a non-significant decrease in NA concentrations. EKC increased the levels of 5-HIAA in hypothalamus and also in cortex, midbrain and pons-medulla, while the levels of 5-HT were increased. On the whole, similar neurochemical effects were observed after KC administration. These data were discussed in relation to the behavioral actions caused in rats by EKC and KC, including the increase in food intake, and they raise the possibility that the hypothalamic noradrenergic system participate in feeding behavior of these drugs.

[The role of serotonin in the behavioral changes induced in the rat by cyclazocine]. / Rôle de la sérotonine dans les modifications comportementales produites chez le rat par la cyclazocine.

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.

Effects of acute administration of cyclazocine on the metabolism of biogenic amines in different regions of rat brain.

The effects of cyclazocine on the metabolism of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in regions of rat brain were studied by measuring changes in the levels of the monoamines and their major metabolites. Doses ranging from 4-32 mg/kg were tested. Rats were sacrificed 1 or 2 h after administration of the drug, according to the experiment. Administration of cyclazocine significantly decreased DA concentration and increased the levels of DOPAC and HVA in striatum. Cyclazocine decreased the levels of NA, and markedly increased the levels of MHPG-SP4 and 5-HIAA in cortex, hypothalamus, midbrain and pons-medulla, while little change in 5-HT concentration, except a decrease after the highest dose, was observed. These changes in the metabolism of the monoamines differed in their amplitude and temporal nature. The possible roles of dopaminergic, noradrenergic and serotoninergic neurons in different brain regions are discussed in relation to modifications of locomotor activity and the induction of bizarre behavior resulting from cyclazocine administration in rats. These investigations may add to the understanding of the mechanism of psychotomimetic effects produced in man by this drug.