Substantia nigra of the rat contains a dopamine sensitive adenylate cyclase

Abstract

A LARGE body of evidence exists to support the hypothesis that most antipsychotic drugs exert their specific actions by antagonising the effects of dopamine at postsynaptic receptors within the central nervous system^1–3. More recent evidence suggests that postsynaptic dopamine receptors may occur not only at sites of axon terminals, but also within the region of the cell bodies which give rise to the ascending dopaminergic projections. Iontophoretic application of dopamine to dopamine-containing neurone cell bodies in the zona compacta of the substantia nigra, inhibits firing of these cells⁴. Fluorescent histochemical examination of the substantia nigra with the glyoxylic acid technique has shown that dendrites arising from cell bodies of the zona compacta contain intensely fluorescent varicosities, and that these occur both in compacta and reticulata regions of the substantia nigra⁵. These varicosities may form the anatomical basis for a mechanism of self-inhibition whereby dopamine released from dendritic varicosities on stimulation subsequently inhibits the firing of the dopamine neurones themselves⁶. Direct support for the role of dendrites in the release of dopamine has been obtained by showing that slices of substantia nigra labelled by exposure to ³H-dopamine will release labelled dopamine when depolarised by high potassium concentrations⁷. We set out to explore further the hypothesis of self-inhibitory control by looking for biochemical evidence of a dopamine response in this region of the brain. Homogenates of tissues containing dopaminergic axon terminals respond to low concentrations of dopamine by increased production of cyclic AMP^8–12. We now provide evidence that a similar dopamine sensitive adenylate cyclase is present in the rat substantia nigra, and that it is potently antagonised by antipsychotic drugs.