Deficient Sensorimotor Gating After 6‐Hydroxydopamine Lesion of the Rat medial Prefrontal Cortex is Reversed by Haloperidol

Abstract

The present study sought to test the hypothesis that dopamine in the prefrontal cortex exerts an inhibitory influence on subcortical dopamine systems and that depletion of prefrontal dopamine may affect behaviour via an increase in dopamine release in the basal ganglia. We used prepulse inhibition of the acoustic startle response, i.e. the inhibition of the acoustic startle response by a preceding non-startling stimulus, as the behavioural test, because this phenomenon of sensorimotor gating is modified in opposite directions by dopamine in the prefrontal cortex and in the basal ganglia. Rats were tested for prepulse inhibition before and after injections of the neurotoxin 6-hydroxydopamine into the medial prefrontal cortex. We attempted to differentiate the contributions of prefrontal dopamine and noradrenaline by pretreating the animals with desipramine (6-OHDA_DMI rats) or bupropion (6-OHDA_BUP 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 dopamine 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 response 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 reduction of prepulse inhibition (by 26%) in the 6-OHDA_DMI rats. Systemic administration of the dopamine antagonist haloperidol (0.05 mg/kg), which did not affect prepulse inhibition in sham-lesioned and in 6-OHDA_BUP rats, antagonized the lesion-induced deficit in prepulse inhibition in 6-OHDA_DMI rats. These results suggest that prefrontal dopamine is involved in prepulse inhibition of the acoustic startle response. The haloperidol-induced antagonism of the deficit in prepulse inhibition observed in 6-OHDA_DMI rats is compatible with the view that prefrontal dopamine depletion led to overactivity of subcortical dopamine systems involved in prepulse inhibition, i.e. in the nucleus accumbens and/or anteromedial striatum. The significance of prefrontal noradrenaline depletion, which may have partially counteracted the effects of dopamine depletion on prepulse inhibition, is also discussed. Since prepulse inhibition is impaired in schizophrenics, the present findings lend support to the theory of prefrontal dopamine hypofunction in the aetiology of schizophrenia.