TY - JOUR
T1 - Quantitative changes in Gαolf protein levels, but not D1 receptor, alter specifically acute responses to psychostimulants
AU - Corvol, Jean Christophe
AU - Valjent, Emmanuel
AU - Pascoli, Vincent
AU - Robin, Aurélie
AU - Stipanovich, Alexandre
AU - Luedtke, Robert R.
AU - Belluscio, Leonardo
AU - Girault, Jean Antoine
AU - Hervé, Denis
N1 - Funding Information:
This work was supported by Inserm and by grants from Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie (MILDT) and Agence Nationale de la Recherche to JAG. J-CC was supported by a fellowship (Poste d’accueil) from Inserm.
PY - 2007/5/24
Y1 - 2007/5/24
N2 - Striatal dopamine D1 receptors (D1R) are coupled to adenylyl cyclase through Gαolf. 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 Gαolf (Drd1a+/- and Gnal+/-), 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+/-, but not Drd1a+/- mice. Acute locomotor responses to D1 agonist SKF81259, D-amph and cocaine were altered in Gnal+/- mice, and not in Drd1a+/- mice. This haploinsufficiency showed that Gαolf but not D1R protein levels are limiting for D1R-mediated biochemical and behavioral responses. Gnal+/- 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+/- 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 Gαolf 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.
AB - Striatal dopamine D1 receptors (D1R) are coupled to adenylyl cyclase through Gαolf. 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 Gαolf (Drd1a+/- and Gnal+/-), 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+/-, but not Drd1a+/- mice. Acute locomotor responses to D1 agonist SKF81259, D-amph and cocaine were altered in Gnal+/- mice, and not in Drd1a+/- mice. This haploinsufficiency showed that Gαolf but not D1R protein levels are limiting for D1R-mediated biochemical and behavioral responses. Gnal+/- 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+/- 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 Gαolf 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.
KW - Addiction
KW - Dopamine D1a receptor
KW - Drd1a
KW - G protein
KW - Gnal
KW - Psychostimulants
UR - http://www.scopus.com/inward/record.url?scp=34247325227&partnerID=8YFLogxK
U2 - 10.1038/sj.npp.1301230
DO - 10.1038/sj.npp.1301230
M3 - Article
C2 - 17063155
AN - SCOPUS:34247325227
SN - 0893-133X
VL - 32
SP - 1109
EP - 1121
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 5
ER -