Enhanced Endocannabinoid-Mediated Modulation of Rostromedial Tegmental Nucleus Drive onto Dopamine Neurons in Sardinian Alcohol-Preferring Rats

Abstract

The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake.

Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain

“…In agreement with our previous study, we found that a subpopulation of RMTg neurons is sensitive to painful stimuli (Lecca et al, 2012). Reduced RMTg-evoked inhibition of DA neurons is associated with their enhanced spontaneous discharge and with vulnerability to drug and alcohol abuse (Lecca et al, 2012;Melis et al, 2013Melis et al, , 2014. Although chronic peripheral neuropathy did not induce changes in firing activity of RMTg neurons, we observed a shortened RMTg-evoked inhibition of DA cells, which is suggestive of a reduced GABA release onto DA cells and, in turn, of their disinhibition, although we cannot exclude that electrical stimulation might excite passing fibers from other regions.…”

“…Firing rate and burst firing of VTA DA neurons is controlled by inhibitory and excitatory afferents (Marinelli et al, 2006;Morikawa and Paladini, 2011). Among inhibitory inputs to DA cells, the RMTg plays an important role, as it densely innervates VTA DA cells with GABAergic afferents (Barrot et al, 2012;Lecca et al, 2011;Lecca et al, 2012;Melis et al, 2014). This nucleus receives a dense excitatory innervation from the lateral habenula and, therefore, is involved in neural circuits mediating aversion (Balcita-Pedicino et al, 2011;Jhou et al, 2009aJhou et al, , 2009b.…”

Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli

“…The GABAergic tail of the ventral tegmental area (tVTA) (Kaufling et al, 2009(Kaufling et al, , 2010aPerroti et al, 2005), or rostromedial tegmental nucleus (RMTg) (Jhou et al, 2009a(Jhou et al, , 2009b, is a mesopontine structure, which exerts a major inhibitory control over dopamine cells of the VTA and substantia nigra pars compacta (SNc) (Bourdy and Barrot, 2012;Matsui et al, 2014;Sánchez-Catalán et al, 2014). The tVTA has been implicated in motor functions (Bourdy et al, 2014;Lavezzi et al, 2015), responses to drugs of abuse (Jalabert et al, 2011;Jhou et al, 2012Jhou et al, , 2013Kaufling et al, 2010b;Lavezzi et al, 2012;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Matsui et al, 2014;Melis et al, 2014;Rotllant et al, 2010), and reward prediction error (Hong et al, 2011). In addition, stimulation of the habenulo-tVTA pathway favors avoidance behaviors (Stamatakis and Stuber, 2012).…”

Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

“…Extensive previous work has shown that activation of G q/11 -coupled receptors in dopamine neurons stimulates 2-AG formation and retrograde modulation of synaptic transmission (Kortleven et al, 2012; Melis et al, 2004a; 2004b; 2014; Pan et al, 2008; Riegel and Lupica, 2004; Tung et al, 2016; Wang et al, 2015). In our experiments, activating mGluR, orexin, or neurotensin receptors rapidly inhibited I A by 20–35% and mimicked the magnitude of effects of 100 nM-1 μM exogenous 2-AG.…”

“…Midbrain dopamine neurons are well-suited for this purpose, because immunohistochemistry suggests that they lack expression of CB 1 receptors (Herkenham et al, 1991; Mátyás et al, 2008) and an abundance of evidence shows that they synthesize (Mátyás et al, 2008) and release 2-AG, which acts in a retrograde manner to strongly regulate both glutamatergic (Kortleven et al, 2012; Labouèbe et al, 2013; Melis et al, 2004a; 2004b) and GABAergic (Melis et al, 2014; Pan et al, 2008; Riegel and Lupica, 2004; Tung et al, 2016; Wang et al, 2015) inputs. To isolate direct effects on intrinsic excitability from synaptically-mediated effects, we used a preparation of acutely dissociated midbrain dopamine neurons, which retain their distinctive electrophysiological properties, including regular pacemaking (Hainsworth et al, 1991; Puopolo et al, 2007).…”