Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

Abstract

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.

Mood stabilizers increase prepulse inhibition in DBA/2NCrl mice

“…Topiramate, alone and after apomorphine, increased PPI at 32, 58, and 100 mg/kg (i.p.) in Sprague-Dawley rats (Frau et al 2007). In the present study, topiramate was efficacious in DBA/2 mice at 100 and 300 mg/kg (i.p.).…”

“…The mood stabilizers were inconsistently active in most of the PPI models (Brody et al 2003;Ong et al 2005), with the exception of the model of apomorphineinduced PPI decreases in ddY mice and Sprague-Dawley rats (Umeda et al 2006;Frau et al 2007). Lithium, topiramate, carbamazepine, and valproic acid increased PPI in the apomorphine-induced models; lamotrigine was not tested.…”

“…The mood stabilizers were tested in PPI in several mouse strains, as well as in Sprague-Dawley rats (Table 1; Brody et al 2003;Ong et al 2005;Umeda et al 2006;Frau et al 2007). The mood stabilizers were inconsistently active in most of the PPI models (Brody et al 2003;Ong et al 2005), with the exception of the model of apomorphineinduced PPI decreases in ddY mice and Sprague-Dawley rats (Umeda et al 2006;Frau et al 2007).…”

“…The negative results in the NMDA antagonist models were quite disappointing, in light of the recent glutamatergic dysfunction hypotheses of schizophrenia and bipolar disorder and the presumed action of some of the mood stabilizers (e.g., lithium, valproic acid, and lamotrigine) on the glutamatergic system (Marino and Conn 2002;Coyle 2006;Sanacora et al 2008). PPI was only increased in the apomorphine models by the mood stabilizers (Umeda et al 2006;Frau et al 2007). This study was performed to evaluate the effects of mood stabilizers on PPI in the DBA/2 mouse model of naturally low PPI and to determine whether the model would be predictive of efficacy for a therapeutic class other than typical and atypical antipsychotics.…”

“…These studies examined the effects of mood stabilizers alone on PPI, as well as their effects on PPI decreased by dopaminergic stimulants (the dopamine D 1 /D 2 receptor agonist apomorphine or the dopamine transporter inhibitor amphetamine) or by noncompetitive NMDA receptor antagonists (ketamine or dizocilpine; Brody et al 2003;Ong et al 2005;Umeda et al 2006;Frau et al 2007). As a whole, the mood stabilizers demonstrated inconsistent results in increasing PPI in these studies.…”