title: Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response.
abstract: Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling sensory stimulus is inhibited by a preceding sensory stimulus of a lower intensity. The current experiment used tactile startle rather than acoustic startle to determine the generality of PPI across sensory modalities. PPI is easily modeled in experimental animals and serves as a useful method for determining the neural bases for sensorimotor plasticity, which can be disturbed in sensory modulation disorders. In the current study, female Sprague-Dawley rats were tested for tactile startle PPI after an auditory pre-pulse. The glutamate NMDA receptor antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly total blockade of the PPI effect (p<0.0005). The antipsychotic drug clozapine (1.25 mg/kg, p<0.001 and 2.5 mg/kg p<0.05) significantly attenuated the dizocilpine-induced PPI impairment. Interestingly, the lower clozapine dose did not by self enhance PPI and the higher clozapine dose when given alone caused a significant (p<0.05) PPI impairment relative to control. Nicotine (0.2 and 0.4 mg/kg) did not significantly interact with the other treatments, though the higher nicotine dose did show a trend toward attenuating the PPI impairment caused by the high clozapine dose. These effects were replicated in a second experiment of clozapine-dizocilpine interactions without nicotine treatment. This study shows that PPI of tactile startle is dramatically impaired by blocking NMDA activation and that the prototypic atypical antipsychotic drug clozapine can correct this deficit. This may be relevant to the action of clozapine in attenuating sensory gating deficits in schizophrenia and may point to new avenues of treatment for sensory modulation disorders in which there is excessive tactile response.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. edlevin@duke.edu
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: D Patrick
authors.initials: DP
authors.lastname: Caldwell
authors.forename: Charles
authors.initials: C
authors.lastname: Perraut
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D009538:Nicotine / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D009538:Nicotine; D003024:Clozapine