Effect of the new antiepileptic drug retigabine in a rodent model of mania

Abstract

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.

Introduction

Retigabine (N-[2-Amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester) was discovered in the 1980s as a part of the National Institute of Neurological Disorders and Stroke Anticonvulsants Screening Program [1]. Retigabine is the first KCNQ opener to have entered clinical development and is currently in phase 3 clinical trials as an adjunctive treatment for partial-onset seizures in patients with epilepsy. KCNQ channels are voltage-dependent potassium channels composed of homo- and heterotetrameric complexes of five different KCNQ subunits (KCNQ1–5, K_V7.1–7.5). With the exception of KCNQ1, all other KCNQ subunits are expressed in various cell types of the nervous system, including hippocampal and cortical neurons, as well as dorsal root ganglion neurons [2], [3], [4]. The mechanism of action of retigabine involves increasing the probability of neuronal KCNQ2–5 voltage-dependent potassium channel opening leading to hyperpolarization of the neuron [5]. In this manner, retigabine functions as a brake on repetitive action potential discharges and as a regulator of the excitability of various peripheral and central neuronal populations [6]. Furthermore, mutations in the KCNQ2 and KCNQ3 genes have been associated with benign familial neonatal convulsions [7]. As a consequence, positive KCNQ channel modulation, in particular, has been focused on as a target with the potential to treat central nervous system diseases in which inhibition of neuronal activity is warranted, including epilepsy, anxiety, pain, and migraine [8].

Single-nucleotide polymorphisms within the KCNQ2 gene have also been associated with bipolar disorder in a collection of DNA samples from 315 unrelated patients with bipolar disorder and 300 control individuals [9]. Bipolar disorder is a severe chronic mood disorder that is characterized by episodes of major depression and mania/hypomania [10]. Pharmacological treatment options to dampen acute manic symptoms or prevent new episodes include lithium, various anticonvulsants, and antipsychotics [11]. Because patients diagnosed with mania often experience clinical benefit from treatment with anticonvulsant drugs, and because the KCNQ2 gene has been implicated in bipolar disorder, it was hypothesized that retigabine, in addition to its anticonvulsant efficacy [12], [13], may also possess antimanic-like activity. Currently, there is no animal model that covers the full symptomatic spectrum of bipolar disorder. Rather, separate animal models of either mania or depression symptoms are used [14], [15]. Behavioral models of mania are often based on assessing increased locomotor activity as a simplified means of modeling core manic symptoms in humans that all reflect excessive activity exemplified by, for example, decreased need for sleep, increased sexual drive, pressure of speech, and racing thoughts [10], [14]. An appropriate combination of amphetamine (AMPH) and chlordiazepoxide (CDP) is known to induce a characteristically repetitive and mania-like form of locomotor hyperactivity in rats placed in an unfamiliar environment [16], [17]. It has since been shown that AMPH + CDP-induced hyperactivity behavior in rats and mice is sensitive to lithium, carbamazepine, valproic acid, and lamotrigine [18], [19], [20], [21], and the model has consequently been proposed as a suitable model for studying the potential antimanic-like activity of novel compounds [18], [19], [20], [21]. The aims of the present study 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.