Abstract
Dopamine D3 receptors have a pre- and postsynaptic localization in brain stem nuclei, limbic parts of the striatum, and cortex. Their widespread influence on dopamine release, on dopaminergic function, and on several other neurotransmitters makes them attractive targets for therapeutic intervention. The signaling pathways of D3 receptors are distinct from those of other members of the D2-like receptor family. There is increasing evidence that D3 receptors can form heteromers with dopamine D1, D2, and probably other G-protein-coupled receptors. The functional consequences remain to be characterized in more detail but might open new interesting pharmacological insight and opportunities. In terms of behavioral function, D3 receptors are involved in cognitive, social, and motor functions, as well as in filtering and sensitization processes. Although the role of D3 receptor blockade for alleviating positive symptoms is still unsettled, selective D3 receptor antagonism has therapeutic features for schizophrenia and beyond as demonstrated by several animal models: improved cognitive function, emotional processing, executive function, flexibility, and social behavior. D3 receptor antagonism seems to contribute to atypicality of clinically used antipsychotics by reducing extrapyramidal motor symptoms; has no direct influence on prolactin release; and does not cause anhedonia, weight gain, or metabolic dysfunctions. Unfortunately, clinical data with new, selective D3 antagonists are still incomplete; their cognitive effects have only been communicated in part. In vitro, virtually all clinically used antipsychotics are not D2-selective but also have affinity for D3 receptors. The exact D3 receptor occupancies achieved in patients, particularly in cortical areas, are largely unknown, mainly because only nonselective or agonist PET tracers are currently available. It is unlikely that a degree of D3 receptor antagonism optimal for antipsychotic and cognitive function can be achieved with existing antipsychotics. Therefore, selective D3 antagonism represents a promising mechanism still to be fully exploited for the treatment of schizophrenia, cognitive deficits in schizophrenia, and comorbid conditions such as substance abuse.
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Gross, G., Drescher, K. (2012). The Role of Dopamine D3 Receptors in Antipsychotic Activity and Cognitive Functions. In: Geyer, M., Gross, G. (eds) Novel Antischizophrenia Treatments. Handbook of Experimental Pharmacology, vol 213. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25758-2_7
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