5-HT MODULATION OF AUDITORY AND VISUAL SENSORIMOTOR GATING .1. EFFECTS OF 5-HT RELEASERS ON SOUND AND LIGHT PREPULSE INHIBITION IN WISTAR RATS

Increasing evidence suggests an important role for serotonin (5-HT) ne uron in the etiology and treatment of schizophrenia. The prepulse inhi bition paradigm is used as a model for sensorimotor gating processes t hat are disrupted in schizophrenia. The present study assessed the gen eral role of 5-HT in modulating auditory and visual prepulse inhibitio n in Wistar rats. A general overactivation of central serotonerigic pa thways was produced pharmacologically by four different agents which a ll shared the common property of releasing 5-HT, i.e., p-chloroampheta mine, 3,4-methylenedioxymethamphetamine, N-ethyl-3,4-methylenedioxymet hamphetamine, or fenfluramine. Within each test session, both sound an d light prepulses were sued to obtain a cross-modal assessment of audi tory and visual sensory gating processes. All four 5-HT releasing agen ts produced dose-related disruptions of auditory and visual prepulse i nhibition, with p-chloroamphetamine being the most potent. The release rs depressed baseline to varying degrees. The alpha(2)-adrenergic agon ist clonidine decreased baseline startle without substantially disrupt ing prepulse inhibition, demonstrating that the two effects were disso ciable. Using fenfluramine as the most selective 5-HT releaser, two ap proaches were used to demonstrate 5-HT mediation of its disruptive eff ect on prepulse inhibition. In the first approach, the selective 5-HT uptake blocker MDL 28,618A was used to prevent fenfluramine-induced 5- HT release. In the second approach, prior exposure to a neurotoxic dos e of p-chloroamphetamine (10 mg/kg) was used to produce a substantial, sustained depletion of cortical 5-HT, presumably reflecting the loss of 5-HT terminals. Both approaches reduced the disruptive effect of fe nfluramine on auditory and visual prepulse inhibition, thereby demonst rating 5-HT mediation of these effects. Neither manipulation significa ntly affected the depressant effect of fenfluramine on startle baselin e, demonstrating that the baseline-reducing and prepulse inhibition-re ducing effects of fenfluramine could be dissociated. MDL 28,618A alone did not affect prepulse inhibition or basal startle levels, demonstra ting an important functional difference between pharmacologically indu ced 5-HT uptake blockade and 5-HT release. In summary, these data indi cate that serotonergic overactivation can disrupt auditory and visual sensorimotor gating as measured using sound and light prepulse inhibit ion in rats. These data support a potential role of excessive 5-HT act ivity as a contributing factor to disrupted sensory gating processes s een in schizophrenia and possibly other neuropsychiatric disorders.