Journal
NEUROPSYCHOPHARMACOLOGY
Volume 38, Issue 5, Pages 854-862Publisher
SPRINGERNATURE
DOI: 10.1038/npp.2012.251
Keywords
DREADD; striatopallidal; amphetamine; G-alpha-s; striatum; Gs
Categories
Funding
- NIH [1F31MH091921, RO1MH61887, U19MH82441]
- NIMH Psychoactive Drug Screening Program
- Michael Hooker Chair in Pharmacology
- NICHD [P30 HD03110, 5R37-MH-073853, 1F32-DA030026]
- NIH
- Forest Laboratories
- NeuroSearch
- F Hoffmann La Roche
- Lundbeck USA
- Merck
- Omeros
- [R01NS064577]
- [K02NS054840]
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Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to G alpha(olf) and induce cAMP accumulation in cultured neurons and HEK-T cells. The rM3Ds was then selectively and stably expressed in striatopallidal neurons by creating a transgenic mouse in which an adenosine2A (adora2a) receptor-containing bacterial artificial chromosome was employed to drive rM3Ds expression. In the adora2A-rM3Ds mouse, activation of rM3Ds by clozapine-N-oxide (CNO) induces DARPP-32 phosphorylation, consistent with the known consequence of activation of endogenous striatal G alpha(s)-coupled GPCRs. We then tested whether CNO administration would produce behavioral responses associated with striatopallidal G(s) signaling and in this regard CNO dose-dependently decreases spontaneous locomotor activity and inhibits novelty induced locomotor activity. Last, we show that CNO prevented behavioral sensitization to amphetamine and increased AMPAR/NMDAR ratios in transgene-expressing neurons of the nucleus accumbens shell. These studies demonstrate the utility of adora2a-rM3Ds transgenic mice for the selective and noninvasive modulation of G alpha(s) signaling in specific neuronal populations in vivo. This unique tool provides a new resource for elucidating the roles of striatopallidal MSN G alpha(s) signaling in other neurobehavioral contexts. Neuropsychopharmacology (2013) 38, 859-862; doi:10.1038/npp.2012.251; published online 16 January 2013
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