title: 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.
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy, myriam@unica.it.
authors.forename: Miriam
authors.identifier: http://orcid.org/0000-0001-9631-8651
authors.initials: M
authors.lastname: Melis
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sagheddu
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: De Felice
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casti
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Madeddu
authors.affiliation: Department of Life and Environment Science, University of Cagliari, 09126 Cagliari, Italy.
authors.forename: Saturnino
authors.identifier: http://orcid.org/0000-0003-2561-0174
authors.initials: S
authors.lastname: Spiga
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, 09126 Cagliari Italy.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Sciences, Indiana University of Bloomington, Bloomington, Indiana 47405.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mackie
authors.affiliation: INSERM, U862 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, 33077 Bordeaux, France, and University of Bordeaux, NeuroCentre Magendie U862, 33077 Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, 09126 Cagliari Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Castelli
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy, Neuroscience Institute, National Research Council of Italy, Section of Cagliari, 09126 Cagliari Italy.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0002-4622-3205
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017849:Animals, Inbred Strains; D001095:Arachidonic Acids / Q000378:metabolism / Q000502:physiology*; D016739:Behavior, Addictive / Q000139:chemically induced / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D045042:Pedunculopontine Tegmental Nucleus / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate
keywords: alcoholism; cannabinoid; dopamine; rostromedial tegmental nucleus; synaptic plasticity; ventral tegmental area