Hyperactivity, decreased startle reactivity, and disrupted prepulse inhibition following disinhibition of the rat ventral hippocampus by the GABA(A) receptor antagonist picrotoxin

Rationale: Functional imaging studies have revealed overactivity of the hip pocampus in schizophrenic patients. Neuropathological data indicate that hy peractivity of excitatory hippocampal afferents and decreased hippocampal G ABA transmission contribute to this overactivity. In rats, excitation of th e ventral hippocampus, e.g. by NMDA, results in hyperactivity and disruptio n of sensorimotor gating measured as prepulse inhibition (PPI) of the acous tic startle response, behavioral effects related to psychotic symptoms in h umans. Objective: The present study examined whether disinhibition of the v entral hippocampus by the GABAA antagonist picrotoxin would result in simil ar psychosis-related behavioral disturbances (hyperactivity, decreased PPI) as NMDA stimulation. Methods and results: Wistar rats received bilateral i nfusions of subconvulsive doses of picrotoxin (100 or 150 ng/0.5 mul per si de) into the ventral hippocampus and were then immediately tested for open field locomotor activity or startle reactivity and PPI. Only the higher dos e induced hyperactivity and decreased PPI. Both doses decreased acoustic st artle reactivity to a similar extent. The decreased PPI appeared not to res ult from decreased startle reactivity, but was associated with a diminished potency of the prepulses to inhibit the startle reaction to the startle pu lse, indicating a sensorimotor gating deficit. All effects were temporary, i.e. disappeared when the rats were tested 24 h after infusion. Conclusions : Decreased GABAergic inhibition in the ventral hippocampus of rats yielded psychosis-related behavioral effects, very similar to those induced by NMD A stimulation. Thus, a concurrence of decreased GABAergic inhibition and in creased afferent excitation in the hippocampus of schizophrenic patients mi ght contribute to psychotic symptoms.