Neural mechanisms underlying release-mode-specific abnormalities in dopamine neural activity in a schizophrenia-like model

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, we demonstrate that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. We examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or NMDA), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs. Significance I discovered that the hypo-NMDA function occurs in midbrain dopaminergic neurons of a schizophrenia-like model instead of the cerebral cortex, which has been the focus of attention so far. This suggests that the schizophrenia glutamate hypothesis may interact with the dopamine hypothesis. Furthermore, it was elucidated that a subpopulation of dorsal raphe serotonergic neurons inhibits VTA dopaminergic neurons in the resting state, resulting in promotion of social behavior. 5HT2 receptor-mediated regulation of inhibitory inputs to the dopaminergic neurons underlies this serotonergic regulation. In the schizophrenia-like model, this regulation by 5HT2 receptors is impaired. Chronic administration of an atypical antipsychotic ameliorates this abnormality. Therefore, this result may represent a mechanism underlying the differential efficacy between atypical and typical antipsychotics.