Research reportAntimanic efficacy of retigabine in a proposed mouse model of bipolar disorder
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.
References (31)
- et al.
Effect of the new antiepileptic drug retigabine in a rodent model of mania
Epilepsy Behav
(2008) - et al.
The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine
Eur J Pharmacol
(2007) - et al.
On the impact of episode sensitization on the course of recurrent affective disorders
J Psychiatr Res
(2001) Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants
Drug Alcohol Depend
(1995)- et al.
Clinical definitions of sensitisation in affective disorder: a case register study of prevalence and prediction
J Affect Disord
(1998) The KCNQ channel activator retigabine blocks haloperidol-induced c-Fos expression in the striatum of the rat
Neurosci Lett
(2004)- et al.
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res Brain Res Rev
(1993) - et al.
Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans
Biol Psychiatry
(1998) - et al.
Lack of enhanced response to repeated d-amphetamine challenge in first-episode psychosis: implications for a sensitization model of psychosis in humans
Biol Psychiatry
(1997) - et al.
D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures
Eur J Pharmacol
(1996)
PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder
Pharmacogenomics J
Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology
J Psychopharmacol
The therapeutic potential of neuronal KCNQ channel modulators
Expert Opin Ther Targets
The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat
J Pharmacol Exp Ther
Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS
J Physiol
Cited by (49)
The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: Relevance for bipolar disorder
2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryQuestioning the predictive validity of the amphetamine-induced hyperactivity model for screening mood stabilizing drugs
2019, Behavioural Brain ResearchCitation Excerpt :Interestingly, the current data also show that lithium has no effects on amphetamine sensitization. Psychostimulant sensitization was suggested to be a better model for mania-like state compared with the acute amphetamine model [46,47] and was used to evaluate different compounds across the years. Yet, the current study demonstrates that lithium has no effects on the expression of amphetamine locomotor sensitization and that at least for ICR mice; the model may not have pharmacological validity.
The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats
2017, Epilepsy and BehaviorCitation Excerpt :In addition, a neuroprotective activity of retigabine has been observed in in vitro and in vivo models [4,5]. For this reason, mainly preclinical studies have been conducted in order to evaluate the efficacy of retigabine in the treatment of diseases associated with impaired neuronal activity, like neuropathic pain [6], osteoarthritis pain [7], dystonia and dyskinesia [8], anxiety [9], bipolar disorder [10], bladder hypersensitive disorder [11], and addiction [12]. However, the complex impact of retigabine on various neurotransmission systems induces not only beneficial effects but also may increase the risk of side effects associated with central disorders.
Animal Models of Mania: Essential Tools to Better Understand Bipolar Disorder
2017, Animal Models for the Study of Human Disease: Second Edition