D-2 Dopamine Receptor Activation Facilitates Endocannabinoid-Mediated Long-Term Synaptic Depression of GABAergic Synaptic Transmission in Midbrain Dopamine Neurons via cAMP-Protein Kinase A Signaling

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2009; 28(52):14018-30. DOI: 10.1523/JNEUROSCI.4035-08.2008
Source: PubMed

ABSTRACT Endocannabinoid (eCB) signaling mediates short-term and long-term synaptic depression (LTD) in many brain areas. In the ventral tegmental area (VTA) and striatum, D(2) dopamine receptors cooperate with group I metabotropic glutamate receptors (mGluRs) to induce eCB-mediated LTD of glutamatergic excitatory and GABAergic inhibitory (I-LTD) synaptic transmission. Because D(2) receptors and group I mGluR agonists are capable of inducing the release of eCBs, the predominant hypothesis is that the cooperation between these receptors to induce eCB-mediated synaptic depression results from the combined activation of type I cannabinoid (CB(1)) receptors by the eCBs. By determining the downstream effectors for D(2) receptor and group I mGluR activation in VTA dopamine neurons, we show that group I mGluR activation contributes to I-LTD induction by enhancing eCB release and CB(1) receptor activation. However, D(2) receptor activation does not enhance CB(1) receptor activation, but facilitates I-LTD induction via direct inhibition of cAMP-dependent protein kinase A (PKA) signaling. We further demonstrate that cAMP/PKA signaling pathway is the downstream effector for CB(1) receptors and is required for eCB-mediated I-LTD induction. Our results suggest that D(2) receptors and CB(1) receptors target the same downstream effector cAMP/PKA signaling pathway to induce I-LTD and D(2) receptor activation facilitates eCB-mediated I-LTD in dopamine neurons not by enhancing CB(1) receptor activation, but by enhancing its downstream effects.

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Available from: Bin Pan, Aug 18, 2015
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    • "On the other side, D2 receptors controlled anandamide production in the striatum. This may serve as an inhibitory feedback mechanism counteracting dopamine-induced facilitation of psychomotor activity (Giuffrida et al., 1999), as well as controlling Gi/o protein availability for CB1 receptors (González et al., 2009) and facilitating endocannabinoid-mediated long-term synaptic depression of GABAergic neurons (Kreitzer and Malenka, 2007), an effect also seen in the ventral tegmental area (Pan et al., 2008). A similar interaction of endocannabinoids with D1 receptors has been recently proposed (Martín et al., 2008) and this proposal has been extended to glutamatergic synapses in which dopamine and its receptors also promote endocannabinoid-mediated synaptic depression (see Lovinger and Mathur, 2012). "
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    • "Thus, the facilitation of eCB-LTD via dopamine may be one mechanism by which dopamine modulates neuronal activity within the PFC, and its subsequent behavior. At PFC? VTA synapses, dopamine D2 receptors cooperate with group I mGluRs to induce eCB-LTD of inhibitory inputs and facilitate LTP (Pan et al., 2008a,b). The mediator of these phenomena is most likely 2-AG, given that this eCB has been shown to act as a negative regulator of spike-timing-dependent LTP induction within the VTA, as opposed to inducing spike-timing-dependent LTP in this brain area (Kortleven et al., 2011). "
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    • "In fact, it has been shown that cocaine-induced AMPA receptor redistribution in VTA DA neurons (a form of excitatory drug-evoked synaptic plasticity) can be mimicked by optogenetic activation of VTA DA neurons and local DA release highlighting the importance of VTA DA neurons and DA signalling as the converging point at which addictive drugs act to reorganize the brain reward circuitry (Brown et al. 2010). DA signalling within the VTA also plays an important role in induction of GABAergic plasticity (Pan et al. 2008a; Dacher & Nugent, 2011; Dacher et al. 2013), so it is likely that selective activation of DA neurons by such in vivo manipulations produce parallel drug-induced GABAergic plasticity as appeared after exposures to morphine and cocaine (Liu et al. 2005; Dacher & Nugent, 2011). Because of the importance of GABAergic transmission and plasticity in VTA DA cell firing and the shaping of reward-and drug-related learning (Parker et al. 2011; Tan et al. 2012; van Zessen et al. 2012; Tolu et al. 2013; Graziane et al. 2013 "
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