DEFICIENT SENSORIMOTOR GATING AFTER 6-HYDROXYDOPAMINE LESION OF THE RAT MEDIAL PREFRONTAL CORTEX IS REVERSED BY HALOPERIDOL

The present study sought to test the hypothesis that dopamine in the p refrontal cortex exerts an inhibitory influence on subcortical dopamin e systems and that depletion of prefrontal dopamine may affect behavio ur via an increase in dopamine release in the basal ganglia. We used p repulse inhibition of the acoustic startle response, i.e. the inhibiti on of the acoustic startle response by a preceding non-startling stimu lus, as the behavioural test, because this phenomenon of sensorimotor gating is modified in opposite directions by dopamine in the prefronta l cortex and in the basal ganglia. Rats were tested for prepulse inhib ition before and after injections of the neurotoxin 6-hydroxydopamine into the medial prefrontal cortex. We attempted to differentiate the c ontributions of prefrontal dopamine and noradrenaline by pretreating t he animals with desipramine (6-OHDA(DMI) rats) or bupropion (6-OHDA(BU P) rats), selective inhibitors of noradrenaline and dopamine reuptake respectively. 6-Hydroxydopamine lesion reduced prefrontal dopamine by 90% and noradrenaline by 80% in 6-OHDA(DMI) rats, while prefrontal dop amine was reduced by 54% and noradrenaline by 95% in 6-OHDA(BUP) rats. The ability of an acoustic prepulse (75 dB, 10 kHz) to inhibit the re sponse to a startle pulse (100 dB noise burst) was maintained in sham- lesioned rats and in 6-OHDA(BUP) rats. However, there was a marked red uction of prepulse inhibition (by 26%) in the 6-OHDA(DMI) rats. System ic administration of the dopamine antagonist haloperidol (0.05 mg/kg), which did not affect prepulse inhibition in sham-lesioned and in 6-OH DA(BUP) rats, antagonized the lesion-induced deficit in prepulse inhib ition in 6-OHDA(DMI) rats. These results suggest that prefrontal dopam ine is involved in prepulse inhibition of the acoustic startle respons e. The haloperidol-induced antagonism of the deficit in prepulse inhib ition observed in 6-OHDA(DMI) rats is compatible with the view that pr efrontal dopamine depletion led to overactivity of subcortical dopamin e systems involved in prepulse inhibition, i.e. in the nucleus accumbe ns and/or anteromedial striatum. The significance of prefrontal noradr enaline depletion, which may have partially counteracted the effects o f dopamine depletion on prepulse inhibition, is also discussed. Since prepulse inhibition is impaired in schizophrenics, the present finding s lend support to the theory of prefrontal dopamine hypofunction in th e aetiology of schizophrenia.