br Localization of D receptors in striatum
Localization of D2 receptors in striatum One characteristic of D2Rs that has complicated their study is their expression in multiple neuronal populations within striatum, both pre- and postsynaptically (Beaulieu and Gainetdinov, 2011). In addition to spiny projection neurons (SPNs), which are the principal Adapalene of the striatum, D2R expression has been demonstrated in cholinergic interneurons (CINs), as well as in axon terminals of DA and cortical neurons, all of which are key players in controlling striatal output and behavior.
Associations between striatal D2Rs and disease Various disorders that are known to involve dysfunction of the dopamine system also exhibit D2R alterations in striatum. In some cases, D2R involvement has been inferred from the ability of D2R-based drugs to successfully treat disease symptoms or to generate side effects (Seeman, 2002). Other studies have compared changes in the binding of D2R-selective radioligands in striatum of patients to healthy controls (Laruelle, 1998; Volkow et al., 2009). While the uncovered associations cannot establish causation, they have set the stage for the interrogation of D2R function and expression levels as potential contributors to disease etiology.
Establishing causality with regional and cellular specificity Given the complex regulation, expression patterns and distribution of D2Rs across —and even within— different striatal cells, it is difficult to reconcile the heterogeneity of symptoms in these disorders with simple bidirectional changes in D2R binding potential or gene expression in striatum (Fig. 1). Many other questions remain in the way of clarifying the role of D2R in striatal function and dysfunction. What specific symptom domains are most closely tied to D2R alterations? Are the changes premorbid or do they result from a lifetime of the disorder? Are there critical developmental windows in which D2R alterations could result in long-term adaptations or impairments? In which cell(s) does the disease-relevant changes in D2R function occur? Have D2Rs in sparse neuronal populations been overlooked with traditional methods? What are the underlying cellular and circuit mechanisms by which D2Rs alter striatal function, and how specific are the alterations to certain disorders? How do D2R drugs work? Can some D2R drug side effects be explained by off-target actions on striatal D2Rs? Could superior D2R-based therapeutics be developed that account for regional, cellular, and intracellular diversity?
Summary and conclusions Since the first demonstration that DA was a neurotransmitter more than 60 years ago, many discoveries have been made that critically link D2Rs to striatal function. In fact, within five years of the cloning of the rat Drd2 gene in 1988 (Bunzow et al., 1988), the annual number of publications involving D2Rs tripled, and has remained steady since. In that time, valuable insights from human brain imaging studies combined with the power of genetics and pharmacology in animal models have cemented the notion that striatal D2Rs are directly involved in shaping the structure and the function of neural circuits to mediate a host of dopamine-related behaviors. Likewise, technical advances that enable cell-selective targeting of D2R are beginning to offer a clearer view of D2R function in different neuron populations. However, many challenges and exciting new questions remain to be addressed. While D2Rs in SPNs and dopamine neurons have received considerable attention, relatively less is known about D2Rs in cholinergic interneurons and their region-specific contributions to dopamine-dependent behaviors. Moreover, D2Rs in cortical neurons, particularly at corticostriatal synapses, may have important behavioral and therapeutic implications (Cui et al., 2018; Urs et al., 2016), yet they also remain poorly understood. Current evidence about cell-selective actions of striatal D2Rs stems primarily from D2R deletion throughout striatum or from local D2R overexpression, but the use of cell- and region-specific knockdown approaches in the adult brain has been limited and should be considered. Moreover, methods that afford flexible temporal control of D2R expression throughout the lifespan of an animal (Cazorla et al., 2014; Kellendonk et al., 2006) would be well-suited to probe the developmental consequences of D2R alterations. Adaptations of techniques like optogenetics and chemogenetics to the D2R, as done with a D1R opsin chimera (Gunaydin et al., 2014), could enhance experimental control over D2R activation/inhibition in a cell-targeted fashion. Techniques that enable dissection of somatodendritic vs axonal functions of D2Rs may unveil distinct sub-cellular roles in behavior (Stachniak et al., 2014).