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

Abstract.

Rationale: Functional imaging studies have revealed overactivity of the hippocampus in schizophrenic patients. Neuropathological data indicate that hyperactivity of excitatory hippocampal afferents and decreased hippocampal GABA transmission contribute to this overactivity. In rats, excitation of the ventral hippocampus, e.g. by NMDA, results in hyperactivity and disruption of sensorimotor gating measured as prepulse inhibition (PPI) of the acoustic startle response, behavioral effects related to psychotic symptoms in humans. Objective: The present study examined whether disinhibition of the ventral hippocampus by the GABA_A antagonist picrotoxin would result in similar psychosis-related behavioral disturbances (hyperactivity, decreased PPI) as NMDA stimulation. Methods and results: Wistar rats received bilateral infusions of subconvulsive doses of picrotoxin (100 or 150 ng/0.5 µl per side) into the ventral hippocampus and were then immediately tested for open field locomotor activity or startle reactivity and PPI. Only the higher dose induced hyperactivity and decreased PPI. Both doses decreased acoustic startle reactivity to a similar extent. The decreased PPI appeared not to result from decreased startle reactivity, but was associated with a diminished potency of the prepulses to inhibit the startle reaction to the startle pulse, 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 NMDA stimulation. Thus, a concurrence of decreased GABAergic inhibition and increased afferent excitation in the hippocampus of schizophrenic patients might contribute to psychotic symptoms.