Dopamine neurons have autoreceptors of the D2 subtype located on their soma and dendrites. When activated by dopamine itself or by exogenous D2 agonists, such as apo-morphine, neuronal firing is attenuated. On the contrary, their antagonism with the prototypical antipsychotic drug haloperidol leads not only to an increased firing rate but also to a discharge pattern characterized by bursts that produce a greater release of dopamine than would the same number of action potentials occurring at regular intervals. Prolonged D2 antagonism leads to a depolarization of these neurons and thus a shutting off of their firing activity. Such a silencing of the mesolimbic-dopamine neurons likely plays an important role in mediating the antipsychotic response because it leads to a decrease of dopamine in post-synaptic structures, contributing to decreased dopamine neurotransmission. Because long-term administration of the atypical antipsychotic agent clozapine depolarizes mesolimbic-dopamine neurons without affecting substantia-nigra-dopamine neurons, which give rise to projections to the striatum, this differential activity may account for the lack of movement disorders of clozapine. In support of this possibility, typical antipsychotic agents such as haloperi-dol, which produce such extrapyramidal side effects, depolarize both populations of dopamine neurons.
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