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: 6.34). 01/2009; 28(52):14018-30. DOI: 10.1523/JNEUROSCI.4035-08.2008
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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, Sep 29, 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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    ABSTRACT: Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission at the basal ganglia. However, this influence is generally indirect and exerted through the modulation of GABA and glutamate inputs received by nigrostriatal dopaminergic neurons, which lack of CB1 receptors although may produce endocannabinoids. Additional evidence suggest that CB2 receptors may be located in nigrostriatal dopaminergic neurons, as well as that certain eicosanoid-related cannabinoids may directly activate TRPV1 receptors, which have been found in nigrostriatal dopaminergic neurons, thus allowing in both cases a direct regulation of dopamine transmission by specific cannabinoids. In addition, CB1 receptors form heteromers with dopaminergic receptors which represent another way to make possible a direct interaction between both systems, in this case at the postsynaptic level. Through these direct mechanisms or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with dopamine transmission in the basal ganglia and this likely has an important influence on dopamine-related functions in these structures (i.e. control of movement) and, particularly, on different pathologies affecting these processes, in particular, Parkinson's disease, but also dyskinesia, dystonia and other pathological conditions. The present review will address the current literature supporting these cannabinoid-dopamine interactions at the basal ganglia, with emphasis in aspects dealing with the physiopathological consequences of these interactions. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13215 · 4.84 Impact Factor
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    • "It has been suggested that cannabinoids elicit their pharmacological effects in part through activation of dopaminergic neurons in the brain and more specifically the mesostriatal dopaminergic system with cell bodies located within the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) (French et al., 1997; Rodríguez De Fonseca et al., 2001; Pan et al., 2008; Morera-Herreras et al., 2008) by enhancing dopamine release in their respective dopamine terminal fields, the nucleus accumbens (NAc) (Tanda et al., 1997) and striatum (Taylor et al., 1988). "
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    ABSTRACT: The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the non-selective cannabinoid receptor 1 (CB1R) agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters (DAT) and GABAA receptors in mesostriatal dopaminergic regions of the rat. Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3 or 1 mg/kg, i.p.) for 20 consecutive days. Locomotor activity was measured on days 1, 10 and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments. Acutely, 0.3 and 1 mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next two measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra (SN) and ventral tegmental area (VTA) and increased D1 receptor mRNA and binding in nucleus accumbens (NAc). Furthermore, both DAT binding and mRNA levels were decreased in SN. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and in SN. Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region- , dose- and neurotransmitter-selective manner. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 12/2014; 18(6). DOI:10.1093/ijnp/pyu097 · 4.01 Impact Factor
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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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    ABSTRACT: Synaptic neuromodulation acts across different functional domains to regulate cognitive processing and behavior. Recent challenges are related to elucidating the molecular and cellular mechanisms through which neuromodulatory pathways act on multiple time scales to signal state-dependent contingencies at the synaptic level or to stabilise synaptic connections during behavior. Here, we present a framework with the synaptic neuromodulators endocannabinoids (eCBs) as key players in dynamic synaptic changes. Modulation of various molecular components of the eCB pathway yields interconnected functional activation states of eCB signaling (prior, tonic, and persistent), which may contribute to metaplastic control of synaptic and behavioral functions in health and disease. The emerging picture supports aberrant metaplasticity as a contributor to cognitive dysfunction associated with several pathological states in which eCB signaling, or other neuromodulatory pathways, are deregulated.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12501 · 3.18 Impact Factor
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