Precursor Availability and Function of Midbrain Dopaminergic Neurons

Abstract

Midbrain dopamine (DA) neurons were once thought of as a very homogeneous population of neurons with similar biochemical, physiological, and pharmacological properties and regulatory controls. However, it is now known that these midbrain neurons are quite heterogeneous and are comprised of several distinct subsets. Biochemical and electrophysiological studies have demonstrated that certain mesocortical DA neurons, in contrast to the intensively-studied nigrostriatal and mesolimbic DA neurons, appear to lack impulse-regulating somatodendritic and synthesis-modulating nerve terminal autoreceptors (1). The absence or insensitivity of this important class of receptors on mesoprefrontal and mesocingulate DA neurons may, in part, explain some of the unique biochemical and electrophysiological properties of these two subpopulations of midbrain neurons (2). For example, the mesoprefrontal and mesocingulate DA neurons appear to have a faster firing rate, exhibit more bursting, and have a more rapid turnover of transmitter than those DA neurons innervating the striatum, nucleus accumbens, and pyriform cortex. The mesoprefrontal and mesocingulate DA neurons also exhibit diminished biochemical and electrophysiological responsiveness to DA agonists and antagonists. Chronic administration of antipsychotic drugs leads to the development of biochemical tolerance in those midbrain DA neurons possessing autoreceptors, but not in the systems lacking autoreceptors. Transmitter synthesis is also readily influenced by altered availability of the dopamine precursor tyrosine in those midbrain DA neurons lacking autoreceptors; this observation is perhaps related to the enhanced rate of physiological activity of this subpopulation of midbrain DA neurons.