Endocannabinoid Signaling Mediates Cocaine-Induced Inhibitory Synaptic Plasticity in Midbrain Dopamine Neurons

Abstract

Drugs that increase GABA levels in the brain reduce cocaine seeking in rodents and humans, suggesting that GABAergic inhibition regulates cocaine-seeking behavior. We previously reported that repeated cocaine exposure in vivo facilitates long-term potentiation by reducing the strength of GABAergic inhibition in dopamine neurons of the ventral tegmental area (VTA). Selective blockade of cocaineinduced reduction of GABAergic inhibition in the VTA might diminish cocaine-induced aberrant synaptic plasticity and addictive behavior. Here, we investigated the mechanism for cocaine-induced reduction of GABAergic inhibition. We show that a pathophysiologically relevant concentration of cocaine enables a normally ineffective stimulus to induce long-term depression (LTD) of IPSCs (I-LTD) in VTA dopamine neurons of midbrain slices. Activation of D 2 dopamine receptors and group I metabotropic glutamate receptors and subsequent recruitment of endocannabinoid signaling are required for I-LTD induction. We further demonstrate that in vivo pretreatment with antagonists to these receptors blocks cocaine-induced reduction of GABAergic inhibition and that repeated cocaine exposure in vivo occludes the subsequent induction of I-LTD ex vivo. Together, these results suggest that repeated cocaine exposure reduces the strength of GABAergic inhibition in dopamine neurons by inducing I-LTD-like modification in vivo.

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

“…Indeed, either intracellular loading of DAG lipase inhibitors or G-protein inhibitor GDb-S into DA neurons proved to block endocannabinoid-mediated actions on discrete GABA receptors [48,49] by supporting the localization of 2-AG-synthesizing enzyme DAG lipase in the DA cell [33], which would release 2-AG following group I mGluR activation [48,50]. This is of particular interest when we consider that VTA DA neurons, by releasing endocannabinoids, can regulate their ongoing spontaneous activity through activation of CB1 receptors on these three diverse presynaptic inhibitory inputs [33].…”

“…Accordingly, 2-AG, released by DA neurons and through activation of CB1 receptors on VGLUT1-positive terminals, also negatively regulates spike time-dependent LTP induction, but not its expression [32]. Thus, it appears that under circumstances of strengthened excitatory plasticity, such as those induced by cocaine [56], 2-AG released by DA cells would mediate LTD and impair LTP at the same synapses to protect DA cells from aberrant excitation, and it would simultaneously silence inhibitory afferents [48].…”

Morphine-induced modulation of LTD at GABAergic synapses in the ventral tegmental area

“…Cocaine-induced inhibitory LTD is induced using bath application of cocaine paired with synaptic stimulation (Pan et al, 2008b). The cocaine-induced LTD protocol is complex because cocaine inhibits the uptake of DA, norepinephrine and serotonin and each of these neurotransmitters could play a role in induction of such LTD that might only be specific to cocaine.…”

Deficiency in Endocannabinoid Signaling in the Nucleus Accumbens Induced by Chronic Unpredictable Stress

“…Striatal slices containing the NAc (250 mm thick) were prepared as described in our previous studies (Pan et al, 2008a, b). The slices were immediately transferred and incubated in artificial cerebrospinal fluid (ACSF) containing 125 mM NaCl, 3 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 1.25 mM NaH 2 PO 4 , 26 mM NaHCO 3 , and 10 mM glucose.…”

“…Values of 2-3 DSE trials were averaged for each neuron, and the decay time constant (t) and magnitude of DSE were measured as described (Pan et al, 2009). The depression (%) of fEPSPs by agonists and antagonists, and the magnitude of LTD were determined as described (Pan et al, 2008a, b). Concentration-response curves were obtained using a sigmoidal dose-response equation: y ¼ (maximumÀ minimum)/(1 + (EC 50 /x) N ), in which E max is the maximal response, x is the concentration of the drug, EC 50 is the concentration of the drug eliciting half-maximal response, and N is the Hill slope of the concentration-response curve.…”