Elsevier

Neuroscience Letters

Volume 211, Issue 1, 14 June 1996, Pages 21-24
Neuroscience Letters

Clozapine-induced potentiation of synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits

https://doi.org/10.1016/0304-3940(96)12709-9Get rights and content

Abstract

To examine the contribution of N-methyl-d-aspartate (NMDA) receptors in the mechanisms underlying the action of antipsychotics, we investigated the effects of a representative atypical antipsychotic, clozapine (CLZ), on the induction of long-term potentiation (LTP) in the perforant path-dentate gyrus pathway in 15 chronically prepared rabbits. Eventually, neither low (10 mg/kg) nor high (20 mg/kg) doses of CLZ intraperitoneally injected had any effects on LTP induction. However, the high dose CLZ always potentiated the ordinary synaptic responses induced by single stimulations before the LTP induction. The present study indicates a new finding, the presence of ‘CLZ-induced potentiation’, although it needs further investigation whether NMDA receptors contribute to this potentiation.

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    Thus, while clozapine's partial agonist affinity for the serotonin 5-HT1A receptor is unlikely to contribute to a therapeutic mechanism via the local serotonin 5-HT1A receptor, local application of the selective serotonin 5-HT2A receptor antagonist M100907 (100 nM) in a hippocampal slice preparation study reportedly potentiates CA1 LTP (Wang & Arvanov, 1998), suggesting that clozapine's strong antagonist affinity for the serotonin 5-HT2A receptor may at least in part its reported ability to reverse the cognitive deficit. Acute clozapine (20 mg/kg, i.p.) is reported to potentiate the responsiveness of the perforant pathway-DG synapse mediated by a single stimulation prior to LTP, a finding which may contribute at least in part to clozapine's ability to reverse the cognitive deficit (Kubota et al., 1996). Acute clozapine (20 mg/kg, i.p.) is also associated with a 13-fold increase in rat hippocampal pregnenolone levels (Marx et al., 2006) while chronic clozapine (0.33 mg/ml in drinking water, one month, consumption not reported) is associated with a ~15% decrease in local hippocampal kynurenic acid levels (Ceresoli-Borroni et al., 2006).

  • Effects of antipsychotic D2 antagonists on long-term potentiation in animals and implications for human studies

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    Of these six, two found that acute clozapine facilitated LTP (Gemperle et al., 2003; Matsumoto et al., 2008). Three found that clozapine increased EPSP slope and spike amplitude but did not affect the magnitude of potentiation caused by tetanization (Kubota et al., 1996, 2000, 2008), and one found that chronic but not acute clozapine impaired LTP, though this effect was only significant from 50 to 60 min after tetanization (Gemperle and Olpe, 2004). Both studies performed in mutant animals with impaired LTP found that clozapine reversed these deficits (Delotterie et al., 2010; Xu et al., 2009).

  • Effects of zotepine on excitatory synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits

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    We previously found that clozapine, 20 mg/kg intraperitoneally injected, potentiated the excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path in chronically prepared rabbits. We called this phenomenon ‘clozapine-induced potentiation’ (Kubota et al., 1996). Further, in a recent study, we found that a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, at 1.0 mg/kg completely prevented the clozapine-induced potentiation (Kubota et al., 2000).

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