Acute and chronic administration of clozapine produces greater proconvulsant actions than haloperidol on focal hippocampal seizures in freely moving rats

Abstract

In this study, we assessed the effects of the acute (a single injection) and repeated (once daily injections for 21 days) administration of the atypical antipsychotic drug clozapine (1.5, 5, or 15 mg/kg i.p.) and the typical antipsychotic drug haloperidol (0.15, 0.5, and 1.5 mg/kg, i.p.) on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold (PNT) and the primary afterdischarge duration (ADD), respectively. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the PNT and significantly increased the primary ADD, indicating a proconvulsant action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose-dependent, proconvulsant effects by significantly decreasing the PNT and by significantly increasing the primary ADD. In contrast to clozapine, the acute administration of haloperidol did not significantly alter the PNT or the primary ADD. The repeated administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the primary ADD, but did not alter the PNT. Overall, clozapine produces a greater proconvulsant action than haloperidol in an animal model of hippocampal seizures.

Acute Clozapine Suppresses Synchronized Pyramidal Synaptic Network Activity by Increasing Inhibition in the Ferret Prefrontal Cortex

“…The condition of the bicuculline-treated tissue may be akin to the loss of GABAergic synapses onto PFC pyramidal neurons and the associated changes in GABA A receptors presented in postmortem schizophrenic brains. The enhancement of recurrent excitation under this condition may thus be the cause of the proconvulsant effects of clozapine in human patients (Denney and Stevens 1995;Minabe et al 1998;Stevens et al 1996) because seizure activity is usually accompanied with impaired inhibitory functions (Avoli et al 2002;Cossart et al 2005;Hablitz 2004;Wong et al 1986). Indeed, disinhibition of in vitro cortical slice by blockade of GABA A receptors could disrupt the neuronal network and induce synchronized epileptiform burst.…”

Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

“…Rats were always tested 30 min after drugs or vehicle administration (see Table 1 for experimental scheme). Doses of the drugs were selected from our preliminary experiments and previous studies [20,[40][41][42]. As higher doses of most of antipsychotics and other drugs used in our preliminary studies and in previous reports caused sedation and/or impairment of motor coordination [43], such doses were not used.…”

“…Clozapine displays strong affinity for several dopamine receptor subtypes and it has been proposed that such changes have selectivity for mesolimbic dopamine receptors, which might account for its proconvulsant effects [41]. However, clozapine is an antagonist with a high affinity at α2-adrenoceptors [66,85]; this mechanism may also be responsible for proconvulsant effects on audiogenic seizures in GEPRs, as previously described for other compounds acting on α2-adrenoceptors [86].…”

Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex

“…Finally, it has been suggested that clozapine's "pro-convulsant" effect may be one of the important mechanisms responsible for its therapeutic action (Denney and Stevens 1995;Minabe et al 1998;Stevens 1995;Stevens et al 1996). Clozapine has the collective abilities to block GABA A receptors moderately (Korpi et al 1995;Michel and Trudeau 2000;Squires and Saederup 1998); to lower the level of GABA released in PFC (Bourdelais and Deutch 1994); to promote activity-dependent release of glutamate and dopamine in PFC (Daly and Moghaddam 1993;Hértel et al 1996;Kuroki et al 1999;Nomikos et al 1994;Pehek and Yamamoto 1994;Youngren et al 1999); and to potentiate postsynaptic D1 receptor-dependent NMDA receptor functions (present study).…”