Dopamine receptors: Pharmacology and localization
Dopamine transmission in the nucleus accumbens has been widely reported to play a critical role in cocaine reinforcement, and elucidating the dopaminergic receptor mechanisms underlying cocaine-induced reinstatement of drug-seeking behavior will be a major focus of the experiments presented here. Dopamine signaling is mediated by specific membrane receptors belonging to the seven transmembrane domain G protein-coupled family of receptors. Five dopamine receptor subtypes, designated D1-D5, have been isolated. Each dopamine receptor subtype can be further categorized as D1-like (D1 and D5) or D2-like (D2, D3, and D4) based on sequence homology and pharmacology. Cloning studies have further demonstrated that the D2 receptor can be subdivided into short and long splice variants. The D1-like and D2-like receptors are biochemically and pharmacologically distinct entities. Within the mesolimbic reward pathway, the two receptor classes exert opposing intracellular effects via their associated heterotrimeric GTP-binding proteins (G proteins). D1-like receptors couple to stimulatory G proteins that activate adenylate cyclase, whereas D2-like receptors inhibit adenylate cyclase via Gia/ Goa signaling. Adenylate cyclase promotes 3’,5’-cyclic adenosine monophosphate (cATP) formation through ATP hydrolysis, and cAMP activates the catalytic subunits of cAMP-dependent protein kinase (PKA) to amplify the signaling cascade. Additionally, both dopamine receptor subtypes interact with signal transduction pathways other than adenylate cyclase. Activation of D1-like receptors reportedly activates phospholipase C (PLC), thus stimulating phosphatidylinositol hydrolysis and mobilizing intracellular calcium stores, while D2-like receptor stimulation enhances outward potassium conductance in a G-protein dependent manner and attenuates calcium influx via voltage-gated channels in vitro.
The dopamine receptor subtypes display markedly different patterns of regional and cellular distribution. The D1 and D2 receptors are the most abundant in the rat brain, and mRNA for these receptors are expressed in all regions receiving dopaminergic innervation. Specifically, both subtypes are highly enriched within the dorsal striatum, olfactory tubercle, and nucleus accumbens, with lower levels of expression in the hippocampus, neocortex, hypothalamus, and thalamus. Additionally, D1 mRNA levels are high in the frontal, visual and insular cortices, as well as extensively expressed in the amygdala, while D2 mRNA expression is moderate in the neocortex, but prominent in the substantia nigra and ventral tegmental area. Conversely, the D3, D4 and D5 receptors subtypes are more discretely distributed throughout the rodent brain. D3 receptor mRNA is preferentially localized to limbic areas, particularly the nucleus accumbens shell and Islands Calleja, as well as mesencephalic dopamine neurons. Moreover, D2 and D3 receptor subtypes are expressed by dopaminergic neurons in both axon terminal and somatodendritic regions, and function as autoreceptors to regulate dopamine release. D4 mRNA appears to be restricted solely to limbic regions, including the nucleus accumbens, hippocampus, amygdala and prefrontal cortex, whereas D5 receptor mRNA present in the hippocampus, hypothalamus, and certain thalamic nuclei, but exceedingly low in both the striatum and neocortex.
Within the striatal complex, considerable evidence from immunocytochemical and in situ hybridization studies suggest that the D1-like and D2-like receptors are segregated to distinct neuronal populations. Thus, D1-like receptors are enriched in striatal neurons co-expressing substance P and dynorphin that project to the ventral mesencephalon, whereas D2-like receptors are enriched in encephalin-containing striatal neurons that send efferents to the globus pallidus. However, recent data from molecular and electrophysiological investigations advocate a more complex synaptic organization in both the dorsal and ventral striatum, such that specific neuronal subpopulations exhibit receptor and peptide colocalization. Within the nucleus accumbens, efferents to the ventral tegmental area are strictly limited to neurons expressing D1 receptors and substance P. In contrast, accumbal projection neurons to the ventral pallidum fall into two categories: those that express strictly D1 or D2 receptors and those that co-express both dopamine receptor subtypes. Functionally, localization of D1-like and D2-like dopamine receptor subtypes to separate neuronal populations allows for a synergistic effect on overall basal ganglia output, though it appears that there also may be antagonistic interactions at the cellular level within a relatively small population of accumbal neurons
Anderson, S. M. (2005). The Role of Dopamine Receptor Signaling in the Rat Nucleus Accumbens in Cocaine-induced Reinstatement (Doctoral dissertation, Boston University).
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