Abstract
Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.
Highlights
The dopaminergic system undergoes a delayed maturation in the brain, suggesting important stabilizing and integrating functions on neural circuits (Grace, 2016; Ohira, 2020)
This review aims at providing a summary of the most recent advances in dopamine receptors (DR) control in SCZ with focus on DR—glutamate NMDA interactions across the genetic, intracellula,r and synaptic aspects of the disease. (Rampino et al, 2018)
The aspects of DR research described hereby are strictly related to SCZ or risk genes associated with it
Summary
The dopaminergic system undergoes a delayed maturation in the brain, suggesting important stabilizing and integrating functions on neural circuits (Grace, 2016; Ohira, 2020). Schizophrenia (SCZ) is associated with dopamine (DA) neurotransmission alterations during puberty and adult life causing deficits in motivation, cognition and sensory functions (Simpson and Kellendonk, 2017; Abi-Dargham, 2018; Grace and Gomes, 2019; Sonnenschein and Grace, 2020). A summary of the most recent experimental evidence linking SCZ to DA alterations can be found in Table 1 (McCutcheon et al, 2020). Recent studies are questioning the causal role of DA in SCZ in favor of a more “NMDA hypofunction hypothesis” of the disease. The limited SCZ genetic links to dopamine receptors (DR) and
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