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A role for the mesolimbic dopaminergic system in the pathophysiology of depression has become increasingly evident. Specifically, brain-derived neurotrophic factor (BDNF) has been shown to be elevated in the nucleus accumbens of depressed patients and to positively contribute to depression-like behaviour in rodents. The dopamine D1–D2 receptor heteromer exhibits significant expression in NAc and has also been shown to enhance BDNF expression and signalling in this region. We therefore examined the effects of D1–D2 heteromer stimulation in rats by SKF 83959, or its inactivation by a selective heteromer-disrupting TAT-D1 peptide on depression- and anxiety-like behaviours in non-stressed animals and in animals exposed to chronic unpredictable stress. SKF 83959 treatment significantly enhanced the latency to immobility in the forced swim test, increased the latency to drink condensed milk and reduced total milk consumption in the novelty-induced hypophagia test, and additionally reduced the total time spent in the open arms in the elevated plus maze test. These pro-depressant and anxiogenic effects of SKF 83959 were consistently abolished or attenuated by TAT-D1 peptide pre-treatment, signifying the behaviours were mediated by the D1–D2 heteromer. More importantly, in animals exposed to chronic unpredictable stress (CUS), TAT-D1 peptide treatment alone induced significant and rapid anxiolytic and antidepressant-like effects in two tests for CUS-induced anhedonia-like reactivity and in the novelty-suppressed feeding test. Together these findings indicate a positive role for the D1–D2 heteromer in mediating depression- and anxiety-like behaviours and suggest its possible value as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404Glu and 405Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmuno-precipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-pro-tein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment. [ABSTRACT FROM AUTHOR]