title: Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse.
abstract: The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation.
authors.affiliation: BB Brodie Department of Neuroscience, University of Cagliari, Monserrato, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.forename: Antonio
authors.initials: A
authors.lastname: Luchicchi
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors; D003042:Cocaine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D013681:Tegmentum Mesencephali / Q000166:cytology*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D009292:Narcotic Antagonists; D009294:Narcotics; D018722:Nicotinic Agonists; D010880:Piperidines; D011720:Pyrazoles; D009270:Naloxone; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009538:Nicotine; D009020:Morphine; D003042:Cocaine; D000077285:Rimonabant