5-HT MODULATION OF AUDITORY AND VISUAL SENSORIMOTOR GATING .2. EFFECTS OF THE 5-HT2A ANTAGONIST MDL-100,907 ON DISRUPTION OF SOUND AND LIGHT PREPULSE INHIBITION PRODUCED BY 5-HT AGONISTS IN WISTAR RATS

Increasing evidence suggests an important role of 5-HT, and 5-HT2A rec eptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor g ating processes that are disrupted in schizophrenia. The present study used the selective seroronin(2A) (5-HT2A) antagonist and putative ant ipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A re ceptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D-2 antagonist haloperidol was used to evaluate a p ossible interaction with dopamine neurons. Sound or light prepulses we re used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT relea sing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that M DL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibit ion. In the second study, the direct acting 5-HT2A/2C receptor agonist /hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-3-aminopropane (DOI) con sistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysi s demonstrated that MDL 100,907 potently antagonized DOI disrupted aud itory prepulse inhibition, with an ED(50) of 0.04 mg/kg, IP DOI did no t consistently disrupt visual prepulse inhibition. In summary, these d ata indicate that, at least under the conditions of the present studie s, the disruptions of auditory prepulse inhibition produced by fenflur amine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furt hermore, these disruptions do not involve direct or indirect stimulati on of D-2 receptors. The identity of the 5-HT receptor(s) underlying t he disruptive effects of fenfluramine or MDMA on visual prepulse inhib ition has not yet been identified. MDL 100.907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor cone disrupts sen sory gating processes.