Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording.

Acute administration of the antipsychotic drug haloperidol causes an increase in the firing rate and in the proportion of spontaneously active dopamine neurons in the substantia nigra. In contrast, repeated administration of haloperidol for 21 days results in a dramatic decrease in the number of dopamine neurons displaying spontaneous electrophysiological activity. In vivo intracellular recordings revealed that these nonfiring dopamine neurons have a membrane potential significantly more depolarized than dopamine neurons in control rats, although their input resistances were equivalent. Neurons displaying this depolarization block could not be activated by depolarizing current injection, but could be made to fire in response to hyperpolarization of the membrane. Furthermore, administration of autoreceptor-selective doses of the direct acting dopamine agonist apomorphine hyperpolarized inactivated dopamine neurons in treated rats, resulting in initiation of spontaneous activity. Thus, repeated administration of neuroleptics appears to cause a feedback excitatory drive to nigral dopamine neurons of sufficient magnitude to depolarize the membrane beyond the spike generating region. As a result, a tonic depolarization blockade of spontaneous spike activity is induced.