Quantitative Changes in Gαolf Protein Levels, but not D1 Receptor, Alter Specifically Acute Responses to Psychostimulants

Abstract

Striatal dopamine D1 receptors (D1R) are coupled to adenylyl cyclase through Gaolf. Although this pathway is involved in important brain functions, the consequences of quantitative alterations of its components are not known. We explored the biochemical and behavioral responses to cocaine and D-amphetamine (D-amph) in mice with heterozygous mutations of genes encoding D1R and Gaolf (Drd1a + /À and Gnal + /À), which express decreased levels of the corresponding proteins in the striatum. Dopamine-stimulated cAMP production in vitro and phosphorylation of AMPA receptor GluR1 subunit in response to D-amph in vivo were decreased in Gnal + /À, but not Drd1a + /À mice. Acute locomotor responses to D1 agonist SKF81259, D-amph and cocaine were altered in Gnal + /À mice, and not in Drd1a + /À mice. This haploinsufficiency showed that Gaolf but not D1R protein levels are limiting for D1R-mediated biochemical and behavioral responses. Gnal + /À mice developed pronounced locomotor sensitization and conditioned locomotor responses after repeated injections of D-amph (2 mg/kg) or cocaine (20 mg/kg). They also developed normal D-amph-conditioned place preference. The D1R/cAMP pathway remained blunted in repeatedly treated Gnal + /À mice. In contrast, D-amph-induced ERK activation was normal in the striatum of these mice, possibly accounting for the normal development of long-lasting behavioral responses to psychostimulants. Our results clearly dissociate biochemical mechanisms involved in acute and delayed behavioral effects of psychostimulants. They identify striatal levels of Gaolf as a key factor for acute responses to psychostimulants and suggest that quantitative alterations of its expression may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine function.

Haloperidol Regulates the State of Phosphorylation of Ribosomal Protein S6 via Activation of PKA and Phosphorylation of DARPP-32

“…This observation was particularly interesting, as in these mice the levels of Ga olf are decreased by approximately 50% (cf. Figure 5a), which results in a large reduction of cAMP signaling (Corvol et al, 2007). Taken together, these results indicate that haloperidol increases rpS6 phosphorylation by removing the inhibitory tone normally exerted by D2Rs on A2AR-mediated cAMP production.…”

“…We found that blockade of A2ARs with 3 mg/kg of KW6002 reduced the effect of haloperidol on phospho-Ser235/236-rpS6 (Figure 4a and b). A similar decrease in haloperidol-induced rpS6 phosphorylation was observed in Gnal + /À mice carrying a Haloperidol regulation of ribosomal protein rpS6 E Valjent et al heterozygous mutation of the gene encoding for Ga olf , which reduces the levels of this protein in the striatum (Corvol et al, 2007) (Figure 5). This observation was particularly interesting, as in these mice the levels of Ga olf are decreased by approximately 50% (cf.…”

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum

“…Because this receptor utilizes the same G-protein ␣ olf ␤ 2 ␥ 7 heterotrimer (6), it will be interesting to explore whether poor coupling of the D 1 R is also observed in the striatum and whether the G olf represents the rate-limiting step in adenylyl cyclase activation. Supporting the latter possibility, our previous analyses of mutant Drda1a and Gnal mice have revealed that the G-protein rather than the receptor controls psychostimulant responses (60).…”

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

“…The connection to D1 signaling is complex, however, as comparisons between heterozygous Gα olf (representing the likely molecular situation in DYT25) and D1 dopamine receptor mice show several interesting differences at the molecular and behavioral level. For example, Gα olf heterozygous mice show a decreased behavioral response and cAMP increase to cocaine or D-amphetamine, whereas similar behavioral changes are not observed in D1 receptor heterozygous mice [106,111]. These and related differences (reviewed in detail in Herve [104]), and the role of Gα olf in A2A signaling and in cholinergic neurons, highlight the need for further studies identifying which of these roles (or combination of effects) is key for dystonia pathogenesis.…”

“…Gα olf null mice are hyperactive at baseline, implicating loss of Gα olf with a hyperkinetic state [108]. These mice show marked deficiencies in locomotor and molecular responses linked to D1 activation, including a blunted increase in movement to D1 agonists or acute cocaine, and reduced activation of cAMP, PKA, ERK or c-fos [109][110][111] following D1 treatment. This link to D1 signaling is particularly intriguing considering that D1 hypersensitivity is strongly implicated in L-dopa induced dyskinesias in Parkinson disease in connection with abnormal plasticity [112]-a pathogenic mechanism thought to be important in the pathogenesis of primary dystonia [113][114].…”