Lamotrigine effects sensorimotor gating in WAG/Rij rats

Introduction

Prepulse inhibition (PPI) is a condition in which a weaker prestimulus, which is prepulse, inhibits the reaction of a species to a following strong startling stimulus, which is the pulse. It can be measured in many kinds ranging from rats to humans and the stimuli types are mostly acoustic. The most sensible way to measure PPI is to use muscular reactions, which are normally diminished as a result of the impaired central nervous system functions. When the pulse stimulus is preceded by a weak prepulse stimulus, the motor reflexes can be reduced.[1] Deficits in PPI occur due to the inability of the nervous system to filter out the unnecessary information, and have been linked to abnormalities of sensorimotor gating.[2] Although PPI deficits are mostly seen in schizophrenia, this is not the only situation that may cause such an impairment. PPI has been found to be disrupted in many neuropsychiatric conditions, such as, panic disorder,[3] obsessive-compulsive disorder,[4] Huntington's disease,[5] attention deficit disorder, nocturnal enuresis,[6] and Tourette's syndrome.[7] In this study, the subjects were WAG/Rij (Wistar Albino Glaxo from Rijswijk) rats, which are the widely used genetic model of absence epilepsy. Altough the pathophysiology of absence epilepsy is not fully understood, an abnormally excitable cortex interacted with the thalamus, and brain stem reticular formation is an accepted concept for the formation of absence seizures. The role of the thalamo-cortico-thalamic network in rats, in the occurence of absence seizures, is reported in previous studies.[8] PPI is potently regulated by neural circuitry within the limbic system, frontal cortex, basal ganglia, and pons.[9] Deficits of PPI are not typical to a particular disease, but rather are related to disruptions in certain, yet undefinable brain circuits. In this study, we have compared male WAG-Rij rats (genetically absence epileptic rats) with male Wistar rats, in order to clarify if there is a deficiency in sensorimotor gating in absence epilepsy and examine the effects of lamotrigine (15,30 mg/kg, i.p.) on this phenomenon. Lamotrigine is an anticonvulsant drug used in the treatment of absence epilepsy. Its mechanism of action is based on sodium (Na+)-channel antagonism and inhibition of glutamate release in the brain.[10] Another mechanism of action of lamotrigine is to increase gamma-amino-butyric acid (GABA) release.[11] Lamotrigine may be considered as a treatment option for schizophrenia, as it is known that dysfunctional glutamatergic neurotransmission has a role in the pathophysiology of schizophrenia.[12] It has been seen that lamotrigine, similar to phenytoin,[11] decreases the background release of the major excitatory transmitter glutamate, while increasing the release of the major inhibitory transmitter GABA at synapses in an area of the temporal lobe, which is highly susceptible to epileptogenesis. The combination of these two effects should lead to a powerful idea of excitability in the cortical networks, and may underlie the effectiveness of lamotrigine against partial and generalized seizures. Epilepsy and sensorimotor gating is now yielding to a multifactorial view, in which the monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits.

Materials and Methods

Results

Effects of lamotrigine (15, 30 mg/kg) on startle amplitude (g)

The startle amplitude was low in WAG/Rij rats compared to Wistar control rats, (P=0.0002, t:4,86). The startle amplitudes of Wistar rats and WAG/Rij rats were uninfluenced by lamotrigine treatment (P=0,85, F:0,1523) [Figure 1].

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Figure 1

The effects of lamotrigine on the startle amplitude of Wistar rats and WAG/Rij rats (P=0,85, F:0,1523). Each column represents the mean±SEM of 6 – 7 animals.*P=0.0002, compared to the Wistar control (t:4,86)

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Effects of lamotrigine (15, 30 mg/kg) on prepulse inhibition (%)

Compaired to Wistar control rats, the PPI% was significantly low in WAG/Rij rats. (P<0.0001, t:9,612). Even as lamotrigine (15, 30 mg/kg) had no effect on the PPI% of Wistar contol rats (P=0.82, F:0,19), the PPI% of lamotrigine-treated (15, 30 mg/kg) WAG/Rij rats showed a significant elevation (P<0.0001, F:861,24) [Figure 2].

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Figure 2

Effects of lamotrigine on prepulse inhibition% of Wistar rats and WAG/Rij rats. And P<0.0001 (F:861, 24). Each column represents the mean±SEM of 6 – 7 animals. *P<0.0001 compared to Wistar control (t:9,612)

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Discussion

Our results demonstrated that, first, the PPI percent value is depleted in WAG/Rij rats compared to Wistar rats, which means that sensorimotor gating is impaired in WAG/Rij rats. Second, lamotrigine treatment (15 mg/ kg and 30 mg/kg) reversed the diminished PPI% of WAG/Rij rats.

This study combines a specific kind of animal model of absence epilepsy (WAG/Rij rats) with naive rats, using the sensorimotor gating phenomenon, to experimentally address the hypothesis that disruption of PPI may develop in WAG/Rij rats. Using the acoustic startle test, we found evidence for the occurrence of PPI impairment in WAG/Rij rats compared to Wistar control rats. Our study has opened a gate to the idea that WAG-Rij rats can be used to investigate biological questions related to the co-morbidity of psychosis and epilepsy.

Clinical disorders with some specific neuroanatomical localizations that address the neural circuit regulation of PPI have been reported in previous studies. In Huntington's disease, diminished PPI may be associated with the degeneration of striatal GABA ergic cells.[5] In Parkinson's disease, the diminished PPI produced by the apomorphine challenge, is suggestive of an enhanced striatal dopamine receptor regulation of PPI.[16] Diminished PPI in patients with temporal lobe epilepsy, with psychosis, and in patients with non-epileptic seizures, suggests some role of the temporal lobe in the regulation of PPI.[17] A study has shown that GABA (B1) heterozygote animals show enhanced PPI responses compared to the controls, suggesting that GABA (B1)-deficient mice exhibit increased sensorimotor gating mechanisms.[18] Absence epilepsy is classified as a generalized seizure type and it has been widely assumed that the thalamus is the generator of this seizure activity. Many studies have been carried out in order to identify the neural circuit regulation of PPI of the startle in rats. In preclinical studies, the brain regions implicated in the regulation of PPI have been probed and defined, for instance, the mediodorsal thalamus[19] and prefrontal cortex[20] are some of the important brain structures. The WAG/Rij albino rat strain is considered to be an appropriate genetic animal model for absence epilepsy.[21] Absence seizures are activated by hyperventilation and occasionally by photic stimulation. Some investigators have concluded that absence seizures are not truly generalized, but rather have selective cortical networks, mainly the ventromedial frontal areas and the somatosensory cortex. The thalamus, especially the reticular nucleus, plays a major role and the frontal cortex, mainly the dorsolateral and orbital frontal areas are important in these seizures.[22] The involvement of the thalamus in limbic epileptogenesis has recently drawn attention to the connectivity between the nuclei of the thalamus and limbic structures. The thalamo-limbic circuits are thought to regulate limbic seizure activity, whereas, the thalamocortical circuits are involved in the expression and generation of spike and slow wave discharges in the absence of epilepsy models. During absence seizures, abnormal rhythms are produced by the interaction between the thalamus and cortex. In a way, the thalamo-cortical circuits have a role in the generation of spike and slow wave discharges in absence epilepsy.[23] The thalamus is an obligatory station through which nearly all sensory information must pass, before reaching the cerebral cortex. One of the major functions of the thalamus is the selective control of the flow of sensory-motor information to the cerebral cortex during different states of the sleep-wake cycle and arousal. This is controlled through the actions of various neurotransmitter systems in the brainstem, hypothalamus, and cerebral cortex.[24] In a similar manner, the limbic and cortico-pallido-striato-thalamic circuitry is thought to be responsible for modulation of PPI in the rat by supporting our findings, and this might be related to impairment of PPI in the absence of epileptic rats. Lamotrigine has the ability to reduce glutamate release, prevent ketamine-induced deficits in PPI in mice, which supports the fact that it exerts its effect through the glutamergic system.[25] The therapeutic effect of lamotrigine on absence seizures may not be related to a main change in a certain neurotransmitter, such as, reduced glutamate, but may have a complex effect that needs to be searched for in further studies. Furthermore, the improvement of PPI impairment via lamotrigine in absence epileptic rats may be related to the thalamocortical system, which is a probable therapeutic target of this anticonvulsant drug.[26] This suggests that lamotrigine, an anticonvulsant, mood stabilizer, may have an undefinable affect, beyond stabilizing voltage-sensitive sodium channels, on absence epileptic rats that could make it effective in PPI impairment. The results of this study demonstrate that PPI disrupted in WAG/Rij rats and this disruption could be reversed by lamotrigine. This at least, in part, may be used to investigate the comorbidity of psychosis and epilepsy.