The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders?
In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.
Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. logues@wyeth.com
Sheree F
SF
Logue
Steven M
SM
Grauer
Janet
J
Paulsen
Radka
R
Graf
Noel
N
Taylor
M Amy
MA
Sung
Lynn
L
Zhang
Zoë
Z
Hughes
Virginia L
VL
Pulito
Feng
F
Liu
Sharon
S
Rosenzweig-Lipson
Nicholas J
NJ
Brandon
Karen L
KL
Marquis
Brian
B
Bates
Mark
M
Pausch
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001058:Apomorphine; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D018967:Risperidone / Q000494:pharmacology
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C485998:Gpr88 protein, mouse; C497930:Ppp1r1b protein, rat; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D006220:Haloperidol; D018967:Risperidone; D001058:Apomorphine; D004298:Dopamine