title: Dopamine D(3) receptor as a new pharmacological target for the treatment of depression.
abstract: A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the "monoaminergic hypothesis" of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine D3 receptor in some brain areas and BDNF induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D3 receptors. These preclinical and clinical data are discussed in the present review.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Leggio
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Platania
authors.affiliation: CEITEC (Central European Institute of Technology) Masaryk University, Brno, Czech Republic.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Micale
authors.affiliation: Department of Educational Sciences, University of Catania, Catania, Italy; IRCCS Associazione Oasi Maria S.S. - Institute for Research on Mental Retardation and Brain Aging, 94018 Troina, Enna, Italy. Electronic address: carafil@hotmail.com.
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000382:microbiology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
chemical_list: D050637:Receptors, Dopamine D3; D004298:Dopamine
keywords: Aripiprazole; Brain-derived neurotrophic factor; Depression; Dopamine D(3) receptor; Partial agonist; Treatment-resistant depression