title: Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle.
abstract: Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 dB prestimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.
authors.affiliation: Department of Psychiatry, University of California, San Diego, School of Medicine, La Jolla 92093.
authors.forename: V A
authors.initials: VA
authors.lastname: Keith
authors.forename: R S
authors.initials: RS
authors.lastname: Mansbach
authors.forename: M A
authors.initials: MA
authors.lastname: Geyer
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D008144:Loudness Perception / Q000187:drug effects / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D014110:Touch / Q000187:drug effects / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol