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Some dopamine neurons may be more impulsive than others: Why differences in receptors and transporters can affect dopamine function in Parkinson's disease

The mesencephalic dopamine system is heterogeneous in its functions, and subregions of the dopamine neuron area have distinct connections and functional impacts. Consequently, treatments that selectively affect one subregion can lead to unique pathophysiological consequences. There are two major groups of dopamine neurons that reside in substantial nigra pars compacta (SNC) and the ventral tegmental area (VTA). The SNC itself is divided into dorsal and ventral tiers: the dorsal tier is contiguous with the VTA and innervates more limbic-related regions, and the ventral tier projects to dorsolateral caudate and putamen regions that are preferentially involved in habit formation and motor functions. Patients with Parkinson’s disease (PD) who are treated with dopamine agonists to compensate for depletion in the motor systems often develop dysfunctions in reward-based learning, including impulse control disorders. The increased susceptibility to impulse control disorders may be related to the fact that the degeneration of the dopamine system in PD is not uniform. The SNC dopamine neurons, particularly those in the ventral tier, are preferentially vulnerable to degeneration, which is thought to underlie the motor deficits. In contrast, the dorsal SNC and VTA are preferentially spared. One of the major treatments for PD is dopamine replacement therapy, which is accomplished via the administration of drugs that increase dopamine stimulation, such as L-dopa or direct dopamine agonists, at doses sufficient to compensate for the damaged dopamine system in the SNC. However, because the medial SNC and VTA system are relatively spared, intact neurons could be over-stimulated as the dopamine agonist works across the entire system, with the consequence that pathologically high levels of dopamine receptor stimulation in limbic regions could occur. Such over-stimulation may increase the likelihood of PD patients to develop impulse control disorders, such as pathological gambling, compulsive shopping, and hypersexuality. There are different types of dopamine receptors that have different and often opposing actions in the modulation of these systems. Members of the D1-like receptor family (D1 and D5 receptors) tend to facilitate firing in postsynaptic targets of the dopamine system, whereas members of the D2-like receptor family (D2, D3, and D4 receptors) inhibit postsynaptic neurons but also potently inhibit dopamine neuron firing via activation of dopamine receptors on the dopamine neurons themselves. These self-regulatory receptors are known as autoreceptors, and they play an essential role in the regulation of synaptic dopamine levels. Because of the complicated nature of the dopamine system, it is critical to characterize the distribution of the dopamine receptors and transporters, because this may differentially impact system function, which can predispose a patient to dopamine replacement therapy-induced pathological consequences. The study by Reyes and colleagues in this issue of Movement Disorders characterizes the distribution of dopamine receptors and transporters in postmortem brains obtained from healthy aged humans. More specifically, the authors compared the differential density of expression in the VTA and the medial SNC (together termed the “midbrain impulse control region”), as well as in the dorsal and ventral SNC, with the latter being the region primarily affected by degeneration early in PD. Their report indicates that D1, D2, D3, and D5 dopamine receptors were localized in midbrain dopamine neurons, and there were no differences between cell groups in the intensity of expression of the D3 or D5 subclasses of receptors. Within the impulse control region, the medial SNC had the highest density of D1 and D2 receptor staining, which was greater than 2.5-fold higher that that in the VTA. Most human midbrain dopamine neurons (>90%) contain dopamine transporter (DAT) and vesicular monoamine transporter (VMAT). Regional -*Correspondence to: Dr. Anthony A. Grace, Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, PA 15260; graceaa@pitt.edu