Deletion of Go2alpha abolishes cocaine-induced behavioral sensitization by disturbing the striatal dopamine system.
The alpha-subunits of the trimeric Go class of GTPases, comprising the splice variants Go1alpha and Go2alpha, are abundantly expressed in brain and reside on both plasma membrane and synaptic vesicles. Go2alpha is involved in the vesicular storage of monoamines but its physiological relevance is still obscure. We now show that genetic depletion of Go2alpha reduces motor activity induced by dopamine-enhancing drugs like cocaine, as repeated injections of cocaine fail to provoke behavioral sensitization in Go2alpha(-/-) mice. In Go2alpha(-/-) mice, D1 receptor signaling in the striatum is attenuated due to a reduced expression of Golf alpha and Gs alpha. Following cocaine treatment, Go2alpha(-/-) mice have lower D1 and higher D2 receptor amounts compared to wild-type mice. The lack of behavioral sensitization correlates with reduced dopamine levels in the striatum and decreased expression of tyrosine hydroxylase. One reason for the neurochemical changes may be a reduced uptake of monoamines by synaptic vesicles from Go2alpha(-/-) mice as a consequence of a lowered set point for filling. We conclude that Go2alpha optimizes vesicular filling which is instrumental for normal dopamine functioning and for the development of drug-induced behavioral sensitization.
Brunk
Irene
I
Institute for Integrative Neuroanatomy, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Blex
Christian
C
Sanchis-Segura
Carles
C
Sternberg
Jan
J
Perreau-Lenz
Stephanie
S
Bilbao
Ainhoa
A
Hörtnagl
Heide
H
Baron
Jens
J
Juranek
Judyta
J
Laube
Gregor
G
Birnbaumer
Lutz
L
Spanagel
Rainer
R
Ahnert-Hilger
Gudrun
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001692:Biological Transport; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003042:Cocaine; D004298:Dopamine