Preferential blockade by clozapine of hyperlocomotion induced by non-competitive NMDA antagonist MK-801.

Effect of clozapine on MK-801-induced hyperlocomotion and stereotypy as well as open field behavior was studied. Clozapine (0.1-7.5 mg/kg) dose-dependently blocked MK-801(0.5 mg/kg)-induced stereotypy. Both total and ambulatory responses were blocked by even the lower doses (0.1-0.5 mg/kg) of clozapine. In open field test, clozapine selectively blocked hyperambulation induced by MK-801 (0.1 mg/kg) whereas it potentiated MK-801 (0.1 mg/kg)-induced stereotypy at all the doses used. Haloperidol (0.25 and 0.5 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) showed a dose-dependent effect on MK-801-induced behaviors while sulpiride (25 and 50 mg/kg) failed to modify MK-801-induced open field behavior. This study supports the preferential effect of clozapine on dopamine receptors located in mesolimbic area and further suggests the possibility of using open field behavior induced by MK-801 as a model for studying atypical antipsychotics.

Influence of chronic prenatal and postnatal administration of naltrexone in locomotor activity induce by morphine in mice

The influence of chronica pre- and postnatal naltrexone exposure on the sensitivity of off spring to the locomotor effects of morphine was investigated i C-57 Black mice. Pregnant mice were injected subcutaneously (sc) with either saline (0.1 ml/10 g) or naltrexone (10 mg/kg) twice daily during gestation and throughout lactation, 21 days postpartum. One, three and seven weeks after bith, male offspring were tested for locomotor activity. At 7 weeks of age, dose-response curves were obtained with morphine (10, 31.6, and 100 mg/kg) and amphetamine (0.31, 10 and 31.6 mg/kg) in naltrexone-pretreated and in saline-treated animals. Naltrexone exposure during gestation and lactation resulted in an augmented sensitivity of offspring to the locomotor activity increasing effects of morphine. In these animals, the dose-response relationship for the effect of morphine on locomotor activity was displaced to the left about threefold. In contrast, naltrexone exposure did not alter the sensitivity of offspring to amphetamine. It was also found that ofsspring of naltrexone-treated animals have significantly greater spontaneous locomotor activity than that of the offspring of saline treated mothers. The increased locomotor activity persisted for at least 4 weeks after the last injection of naltrexone. These findings indicate that chronic opioid receptor blockade during gestation and early portnatal development induces supersensitivity to the locomotor effects of morphine and is associated with long-lasting behavioral alterations

Reversal of diazepam withdrawal induced hyperactivity in mice by BR 16-A (Mentat), a herbal preparation.

Abrupt cessation of chronic treatment of diazepam (20 mg/kg/day for 21 days) produced withdrawal reactions. BR 16-A, a multicomponent herbal preparation shown to reverse the withdrawal reactions to opiates was studied against diazepam induced withdrawal reactions in mice. Acute dose of diazepam (20 mg/kg) produced a decrease in the ambulatory and total activity. However, chronic administration for 21 days produced tolerance and no significant change in the ambulatory and total activity. On abrupt termination of diazepam treatment after 21 days, the animals showed anxiety and excitement as there was an increase in ambulatory and total activity. The withdrawal excitement was highest at 72 hr of the last dose of diazepam. Concomittant administration of BR 16-A (100 and 500 mg/kg) reversed the acute effect of diazepam in a dose dependent manner. Similarly, chronic administration of BR 16-A (100 and 500 mg/kg/day for 21 days) with diazepam (20 mg/kg/day for 21 days) also reversed the withdrawal induced hyperambulation and total activity. Chronic administration of BR 16-A per se had no significant effect on the ambulatory and total activity, however, in acute doses, BR 16-A (100 and 500 mg/kg) produced a dose dependent increase in the ambulatory and total activity. BR 16-A with its CNS profile of activity could be a useful preparation in the management of substances of abuse.