Elsevier

Behavioural Brain Research

Volume 207, Issue 1, 11 February 2010, Pages 78-83
Behavioural Brain Research

Research report
Antimanic efficacy of retigabine in a proposed mouse model of bipolar disorder

https://doi.org/10.1016/j.bbr.2009.09.040Get rights and content

Abstract

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 1.0 mg/kg, whereas basal locomotor activity was only reduced at 8.0 mg/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.

Introduction

Retigabine was discovered in the 1980s as a part of the National Institute of Neurological Disorders and Stroke Anticonvulsants Screening project and is currently being developed as an adjunctive treatment for partial-onset seizures in patients with epilepsy. As an anticonvulsant, retigabine acts by a novel mechanism of action that involves opening of neuronal KCNQ 2–5 (Kv7.2-5) voltage-activated potassium channels. Opening of KCNQ channels leads to neuronal hyperpolarization and stabilization of the membrane potential, which suggests that retigabine may be particularly efficacious to treat CNS disorders that are linked to hyperexcitability [4], [27]. In vitro, retigabine increases the open-probability of homotetrameric KCNQ 4 and 5 channels as well as heterotetrameric KCNQ 2/3 and KCNQ 3/5 channels. At high doses, retigabine also potentiates GABA-evoked currents and may also possess weaker sodium and calcium channel blocking activity [20], [31]. Retigabine has shown effect in a range of preclinical epilepsy, pain and anxiety models including the amygdala kindling model [28]. However, if viewed in the framework of Post and collaborators [17], [18] who used the kindling model as a heuristic model for the clinical and theoretical implications of antiepileptic drugs in bipolar disorder, this result may also suggest a potential for retigabine in the treatment of bipolar disorder. Indeed, we previously showed antimanic efficacy of retigabine in a rat model of mania [2]. Interestingly, single nucleotide polymorphisms within the KCNQ2 gene has been associated with bipolar disorder in a collection of DNA samples from 315 unrelated bipolar disorder patients and 300 control individuals [1]. Bipolar disorder is a severe chronic mood disorder associated with poor clinical outcome, social and occupational dysfunction as well as high suicide rate. The disorder is characterized by episodes of depression and mania, which show a progressive recurrence and an increase in severity with time [10], [21], [24], [25]. Pharmacological treatment options for mania include lithium, anticonvulsants (e.g. valproate or carbamazepine) and antipsychotics [3].

Today, there is no animal model that covers the full spectrum of bipolar disorder; rather separate models of mania and depression are used. Behavioral models of mania are often based on stimulant-induced increased locomotor activity. Indeed, the use of amphetamine in humans can induce euphoria, increased activity, increased libido, and impaired ability to concentrate and sleep, which are all characteristic symptoms of a manic episode. In rodents, a single administration of amphetamine produces increased locomotor activity and also rewarding effects [23] while repeated dosing with amphetamine increases the behavioral response over time. This phenomenon is called behavioral sensitization and is a process whereby repeated intermittent administration of a psychostimulant results in a time-dependent, enduring and progressively greater or more rapid behavioral response [19]. Also recurrence of episodes in psychiatric disorders, such as bipolar disorder, is suggested to reflect a process of sensitization. On the contrary, withdrawal from especially prolonged use of amphetamine can result in feelings of depression, fatigue and decreased energy in humans [12], [14]. It could therefore be suggested that withdrawal from repeated amphetamine administration, which produces amphetamine sensitization, could also result in depression-like behavior in the mouse [11]. Anhedonia, a decreased ability to experience pleasure, is a core symptom of depression which can be expressed in rodents by decrease in intake of palatable solutions, typically sucrose or saccharine [26].

Therefore the aims of present study were to (1) explore the predictive validity of amphetamine sensitization as a behavioral model of mania by testing the effect of a range of antimanic drugs and (2) to evaluate the antimanic-like effect of retigabine in this model and furthermore (3) to explore if a state of anhedonia could be assessed in the model by testing saccharine preference during the withdrawal period of the model.

Section snippets

Animals

Male NMRI mice (Charles River, Germany) 21–27 days old were group-housed (4–6 mice per cage) in makrolon cages (20 cm × 35 cm × 15 cm) enriched with two plastic houses and nesting material. The animals were kept at room temperature (20 °C ± 2) in a 12-h light/dark cycle (lights on at 06:00 a.m.) with free access to food and water. The mice were allowed to acclimatize to the animal facility for 4–7 days prior to the initiation of experiments. The animals were taken to the experimental room (locomotor

Amphetamine sensitization

Two-way ANOVA revealed a significant interaction between pre-treatment and challenge in all experiments (lithium: F1,87 = 45.7; valproate: F1,41 = 6.6; carbamazepine: F1,43 = 12.4; and lamotrigine F1,43 = 27.6, P's < 0.014). That is, an acute d-amphetamine challenge (0.9 mg/kg) resulted in a 196–234% increase in locomotor activity selectively in mice pre-treated with d-amphetamine (1.8 mg/kg, 5 days). Lithium treatment (0.1–1.0 mEq/kg) decreased the sensitized locomotor activity (F4,73 = 7.5, P < 0.001). Post

Discussion

The results obtained in the present studies show that lithium, valproate, carbamazepine and lamotrigine treatment all significantly decreased the sensitized locomotor response to an acute amphetamine challenge, in animals pre-treated with amphetamine. With the exception of valproate, which affected basal activity at all tested doses, these effects cannot be explained by sedation but seem to represent a true calming effect of the compounds. In view of the wide clinical use of these compounds in

Conflicts of interest

None.

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