Journal
NEUROPSYCHOPHARMACOLOGY
Volume 34, Issue 7, Pages 1829-1842Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2009.5
Keywords
VTA; LTP; PKA; PKG; GABA; nitric oxide
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Funding
- NIH [DA11289, DA021973, DA024527]
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Drugs of abuse usurp the mechanisms underlying synaptic plasticity in areas of the brain, a process that may contribute to the development of addiction. We previously reported that GABAergic synapses onto dopaminergic neurons in the ventral tegmental area (VTA) exhibit long-term potentiation (LTPGABA) blocked by in vivo exposure to morphine. The presynaptically maintained LTP requires the retrogradely released nitric oxide (NO) to activate a presynaptic cGMP signaling cascade. Previous work reported that inhibitory GABA(A) receptor synapses in the VTA are also potentiated by cAMP. Here, we explored the interactions between cGMP-dependent (PKG) and cAMP-dependent (PKA) protein kinases in the regulation of these GABAergic synapses and LTPGABA. Activation of PKG was required for NO-cGMP signaling and was also essential for the induction of synaptically elicited LTPGABA, but not for its maintenance. Synapses containing GABA(A) receptors were potentiated by NO-cGMP signaling, whereas synapses containing GABA(B) receptors on the same cells were not potentiated. Moreover, although the cAMP-PKA system potentiated GABA(A) synapses, synaptically induced LTPGABA was independent of PKA activation. Surprisingly, however, raising cGMP levels saturated potentiation of these synapses, precluding further potentiation by cAMP and suggesting a convergent end point for both signaling pathways in the regulation of GABAergic release. We further found that persistent GABAergic synaptic modifications observed with in vivo morphine did not involve the presynaptic cAMP-PKA cascade. Taken together, our data suggest a synapse-specific role for NO-cGMP-PKG signaling pathway in opioid-induced plasticity of VTA GABA(A) synapses. Neuropsychopharmacology (2009) 34, 1829-1842; doi:10.1038/npp.2009.5; published online 4 February 2009
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