lithium-chloride and ezogabine

Retigabine is a novel compound with anticonvulsant efficacy. Preclinical studies have indicated that the compound, like other anticonvulsants may also have antimanic efficacy. Bipolar disorder is characterized by episodes of depression and mania, which show a progressively faster recurrence and an increase in severity with time. Recurrence of episodes in bipolar disorders is suggested to reflect a process of sensitization. Repeated intermittent administration of amphetamine in rodents gives rise to a behavioral sensitization phenomena argued to have similarities to the sensitization found in humans. The aims were therefore to explore the predictive validity of the amphetamine sensitization model as a behavioral model of mania by testing the effect of a range of antimanic drugs and to evaluate the effect of retigabine on the sensitized amphetamine response. Furthermore, since withdrawal from prolonged use of amphetamine in humans can result in depression symptoms it was explored if a state of anhedonia could be assessed by testing saccharine preference before and during the withdrawal period of the model. The tested antimanic drugs (lithium, valproate, carbamazepine and lamotrigine) all attenuated the sensitized locomotor activity induced and with the exception of valproate the found effects seemed not to be due to sedation. Interestingly, retigabine also attenuated the induced locomotor activity with a lowest effective dose at 1.0mg/kg, whereas basal locomotor activity was only reduced at 8.0mg/kg, suggesting a genuine calming and antimanic-like efficacy of the compound. In addition, saccharine preference data suggest that withdrawal from the d-amphetamine pre-treatment regimen may induce depression-like behavior indicating that both manic and depression-like behavior is expressed in this mouse model.

Topics: Amphetamine; Analysis of Variance; Animals; Anticonvulsants; Antimanic Agents; Behavior, Animal; Bipolar Disorder; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Food Preferences; Lithium Chloride; Male; Mice; Motor Activity; Phenylenediamines; Saccharin; Treatment Outcome

Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were therefore (1) to confirm previous findings with lithium and lamotrigine, and (2) to evaluate the effect of the novel compound retigabine on AMPH+CDP-induced hyperactivity in rats. In all experiments, co-administration of AMPH and CDP induced a significant increase (191-295%) in locomotor activity. Lithium chloride (0.9 mg/kg) and lamotrigine (20 mg/kg), which are known to effectively stabilize mood in humans, both significantly decreased AMPH+CDP-induced locomotor activity without affecting basal locomotor activity. The results furthermore indicate that retigabine, like lithium and lamotrigine, significantly and dose-dependently attenuates the induced hyperactivity at a lowest effective dose of 1.0 mg/kg, whereas basal locomotor activity is reduced only at doses 4.0 mg/kg. In conclusion, retigabine was found to have an antimanic-like effect in the AMPH+CDP-induced hyperactivity model, suggesting a potential role for retigabine in the treatment of mania and possibly in the management of bipolar disorder.

Topics: Amphetamine; Animals; Anticonvulsants; Behavior, Animal; Bipolar Disorder; Carbamates; Chlordiazepoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Lamotrigine; Lithium Chloride; Male; Motor Activity; Phenylenediamines; Rats; Rats, Wistar; Triazines