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.

Download full-text


Available from: Bin Pan, Jul 02, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Persistent changes in excitatory and inhibitory synaptic strengths to the ventral tegmental area (VTA) dopamine (DA) neurons in response to addictive drugs may underlie the transition from casual to compulsive drug use. While enormous amount of work has been done in the area of glutamatergic plasticity of the VTA, little is known regarding the learning rules governing GABAergic plasticity in the VTA. Spike-timing-dependent plasticity, STDP, has attracted considerable attention primarily due to its potential roles in processing and storage of information in the brain and there is emerging evidence for the existence of STDP at inhibitory synapses. We therefore used whole-cell recordings in rat midbrain slices to investigate whether near coincident pre- and postsynaptic firing induces a lasting change in synaptic efficacy of VTA GABAergic synapses. We found that a Hebbian form of STDP including LTP and LTD can be induced at GABAergic synapses onto VTA DA neurons and relies on the precise temporal order of pre-and postsynaptic spiking. Importantly, GABAergic STDP is heterosynaptic (NMDR-dependent): triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells. GABAergic STDP is postsynaptic and has an associative component since pre- or postsynaptic spiking per se did not induce STDP. STDP of GABAergic synapses in the VTA provides physiologically relevant forms of inhibitory plasticity that may underlie natural reinforcement of reward-related behaviors. Moreover, this form of inhibitory plasticity may mediate some of the reinforcing, aversive and addictive properties of drugs of abuse.
    The Journal of Physiology 07/2013; 591(19):4699-4710. DOI:10.1113/jphysiol.2013.257873 · 4.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antagonism of group I metabotropic glutamate receptors (mGluR 1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses, and mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome. It remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB(1) receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.Neuropsychopharmacology accepted article preview online, 24 January 2013; doi:10.1038/npp.2013.29.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(7). DOI:10.1038/npp.2013.29 · 7.83 Impact Factor