Lamotrigine blocks the initiation and expression of repeated high-dose methamphetamine-induced prepulse inhibition deficit in rats

Abstract

Our group developed a new psychostimulant animal model reflecting some clinical aspects of schizophrenia better than the conventional model does. In this model, long-lasting prepulse inhibition (PPI) deficit at the basement state is induced via repeated administration of methamphetamine (METH, 2.5 mg/kg) without challenge injection of this psychostimulant. This study elucidates the effects of lamotrigine (LTG, 30 mg/kg) on the initiation and expression of a steady-state PPI deficit induced by the repeated METH administration. We assessed the effect of coadministration of LTG and METH on the initiation of PPI deficit. The LTG was injected 120 min after each METH injection for 5 times on every alternate day and for an additional 5 times every day, amounting to a total of 10 times. After 11-13 days of the withdrawal period, we measured PPI using the SR-LAB system. Using other animals after 20 min of LTG injection, we subsequently examined the effect of a single injection of LTG on the expression of PPI deficit caused by the repeated METH administration.The LTG blocked the initiation of PPI deficit induced by the repeated METH administration at 68 dB of prepulse intensity, but had no effect on the startle amplitude. The LTG prevented the initiation and expression of neuroplastic PPI deficit detected at the baseline state without any METH challenge injection, which was induced by the repeated administration of this psychostimulant.Results suggest that LTG is useful for blocking progressive deterioration of neurocognitive function and recovering the neurocognitive deficit in schizophrenia.3

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats

“…In addition, a clinical trial demonstrated that administration of LTG along with stable clozapine exhibited a beneficial effect on the psychopathological symptoms of clozapine-resistant schizophrenic patients [32]. Our recent report described that prepulse inhibition deficit induced by repeated METH is prevented by repeated LTG co-administration and that it is recovered by acute LTG administration [24]. However, the effects of LTG on METH-induced glutamate release and apoptosis remain unknown.…”

“…Vehicles for METH and LTG were saline (1 ml/kg) and approximately 0.002 N HCl in distilled water (4 ml/kg), respectively. This study used dosages of METH (2.5 mg/kg) and LTG (30 mg/kg) that were chosen after considering the results obtained in previous studies [2,24].…”

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats

“…The respective vehicles for METH and LTG were saline (1 ml/kg) and approximately 0.002 N HCl in distilled water (4 ml/kg). This study used dosages of METH (2.5 mg/kg) and LTG (30 mg/kg) that were chosen after considering the results obtained from previous studies [15,16].…”

“…In an animal model, LTG plus clozapine decreased hyperlocomotion induced by the NMDA receptor antagonist phencyclidine in rats [25]. Our recent report described that prepulse inhibition deficit and the increase of TUNEL-positive cells in the mPFC induced by repeated administration of 2.5 mg/kg of METH are prevented by repeated co-administration of LTG [15,16]. Moreover, our group presented data showing that LTG inhibits increased extracellular glutamate levels in the mPFC induced by 2.5 mg/kg of METH [16].…”

“…That dosage, but not 1.0 mg/kg (which increases extracellular dopamine levels but not glutamate levels), can increase both extracellular glutamate and dopamine levels in the medial prefrontal cortex (mPFC) [1,2]. It induces schizophrenia-related behavioral and histological abnormalities including cross-sensitization to the NMDA receptor antagonist, a neuroplastic prepulse inhibition (PPI) deficit, and an apoptotic reaction in the mPFC [1,2,10,11,15,16].…”