Dopaminergic neurons: Role of presynaptic receptors in the regulation of transmitter biosynthesis

Abstract

1. 1. Presynaptic dopamine receptors appear to modulate the increase of dopamine synthesis which is observed after both cessation and an increase in impulse flow. Stimulation of presynaptic receptors limits synthesis in both cases by suppressing the activation of tyrosine hydroxylase. 2. 2. Two in vivo models for studying presynaptic receptors are described. In one, impulse flow is abolished by mechanical lesion of the dopaminergic fibers or by administration of γ-butyrolactone, a drug which reversibly inhibits all impulse flow. In the second model, dopaminergic fibers are stimulated at supra-physiological rates. Once the rate of impulse flow is experimentally stablized by either of these methods, various dopaminergic agonists and antagonists are administered. The observed drug-induced changes of dopamine synthesis activity must then be the result of their interaction with receptors on the terminals since the drugs can no longer affect the rate of impulse flow. 3. 3. Using these in vivo models, it was found that dopamine agonists depress synthesis; dopamine antagonists reverse the effects of the agonists. In the stimulation model dopamine antagonists further enhance synthesis above the stimulation-induced increase, presumably by blocking the effects of released dopamine. These pharmacological studies suggest that by responding to the amount of dopamine present in the synaptic cleft, presynaptic receptors may function to modulate changes in transmitter synthesis which normally occur in response to alterations in impulse flow. Some evidence is presented which is consistent with the hypothesis that these changes may be mediated by the ability of presynaptic receptors to gate calcium entry into the dopamine terminals. 4. 4. The two in vivo models have been utilized to demonstrate that presynaptic receptors in different brain regions vary in sensitivity to agonists. Like postsynaptic receptors, presynaptic receptors become supersensitive after chronic treatment and withdrawal of antipsychotic drugs. Some antipsychotic drugs such as clozapine and pimozide were found to be less effective than other antipsychotic drugs in blocking presynaptic receptors. These results suggest that pre- and postsynaptic dopamine receptors may not be identical. The pharmacological implications of the above observations as well as the possible physiological role played by presynaptic receptors are discussed.