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Stimulatory coupling of dopamine D1 (D1R) and adenosine A2A receptors (A2AR) to adenylyl cyclase within the striatum is mediated through a specific Gαolfβ2γ7 heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gαolfβ2γ7 heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which the Gng7 gene was deleted in either the D1R-or A2AR/D2R-expressing MSNs. We show that conditional loss of γ7 disrupts the cell type-specific assembly of the Gαolfβ2γ7 heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D1Rs or A2ARs in coordinating motor behaviors, including in vivo responses to psychostimulants. We reveal that Gαolfβ2γ7/cAMP signal in D1R-MSNs does not impact spontaneous and amphetamine-induced locomotor behaviors in male and female mice, while its loss in A2AR/D2R-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additionally, Gαolfβ2γ7/cAMP signal in either D1R- or A2AR/D2R-expressing MSNs is not required for the activation of PKA signaling by amphetamine. Finally, we show that Gαolfβ2γ7 signaling acting downstream of D1Rs is selectively implicated in the acute locomotor-enhancing effects of morphine. Collectively, these results support the general notion that receptors use specific Gαβγ proteins to direct the fidelity of downstream signaling pathways and to elicit a diverse repertoire of cellular functions. Specifically, these findings highlight the critical role for the γ7 protein in determining the cellular level, and hence, the function of the Gαolfβ2γ7 heterotrimer in several disease states associated with dysfunctional striatal signaling. [ABSTRACT FROM AUTHOR]

Stimulatory coupling of dopamine D 1 (D 1 R) and adenosine A 2A receptors (A 2A R) to adenylyl cyclase within the striatum is mediated through a specific Gα olf β 2 γ 7 heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gα olf β 2 γ 7 heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which the Gng7 gene was deleted in either the D 1 R- or A 2A R/D 2 R-expressing MSNs. We show that conditional loss of γ 7 disrupts the cell type-specific assembly of the Gα olf β 2 γ 7 heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D 1 Rs or A 2A Rs in coordinating motor behaviors, including in vivo responses to psychostimulants. We reveal that Gα olf β 2 γ 7 /cAMP signal in D 1 R-MSNs does not impact spontaneous and amphetamine-induced locomotor behaviors in male and female mice, while its loss in A 2A R/D 2 R-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additionally, Gα olf β 2 γ 7 /cAMP signal in either D 1 R- or A 2A R/D 2 R-expressing MSNs is not required for the activation of PKA signaling by amphetamine. Finally, we show that Gα olf β 2 γ 7 signaling acting downstream of D 1 Rs is selectively implicated in the acute locomotor-enhancing effects of morphine. Collectively, these results support the general notion that receptors use specific Gαβγ proteins to direct the fidelity of downstream signaling pathways and to elicit a diverse repertoire of cellular functions. Specifically, these findings highlight the critical role for the γ 7 protein in determining the cellular level, and hence, the function of the Gα olf β 2 γ 7 heterotrimer in several disease states associated with dysfunctional striatal signaling. SIGNIFICANCE STATEMENT Dysfunction or imbalance of cAMP signaling in the striatum has been linked to several neurologic and neuropsychiatric disorders, including Parkinson's disease, dystonia, schizophrenia, and drug addiction. By genetically targeting the γ 7 subunit in distinct striatal neuronal subpopulations in mice, we demonstrate that the formation and function of the Gα olf β 2 γ 7 heterotrimer, which represents the rate-limiting step for cAMP production in the striatum, is selectively disrupted. Furthermore, we reveal cell type-specific roles for Gα olf β 2 γ 7 -mediated cAMP production in the control of spontaneous locomotion as well as behavioral and molecular responses to psychostimulants. Our findings identify the γ 7 protein as a novel therapeutic target for disease states associated with dysfunctional striatal cAMP signaling., (Copyright © 2021 the authors.)