title: Noradrenergic inputs from locus coeruleus to posterior ventral tegmental area are essential to support ethanol reinforcement.
abstract: Although dysregulation of the dopaminergic mesolimbic system is generally considered central to addiction, the involvement of other circuits is increasingly being appreciated. An interaction between locus coeruleus (LC) noradrenergic neurons and the posterior ventral tegmental area (pVTA) dopaminergic system, in the processing of drug-triggered reward, has been suggested, but not demonstrated in behaving animals. Herein, we try to tease out the precise role of noradrenergic neurons in the LC-VTA circuit in mediating reward and reinforcement behavior associated with ethanol. In the standard two-lever (active/inactive) operant paradigm, the rats were trained to self-administer ethanol in pVTA and subjected to pharmacological intervention. Intra-pVTA administration of phenylephrine (alpha-1 adrenoceptor agonist) increased ethanol self-administration, while prazosin and disulfiram (agents that reduce noradrenergic tone) produced opposite effects. While degeneration [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, DSP-4, intraperitoneal route] or silencing (lidocaine or muscimol, both via intra-LC route) of the LC noradrenergic neurons decreased, phenylephrine via the intra-LC route reinstated ethanol self-administration. Furthermore, lidocaine reduced ethanol self-administration, but the effect was fully attenuated by noradrenaline given directly in the pVTA. This suggests that the feedback signals from LC to pVTA are necessary to sustain the ethanol self-infusion activity. Ethanol self-administration significantly increased tyrosine hydroxylase immunoreactivity in pVTA and LC; the response was blocked by DSP-4 pre-treatment. While dopamine D1, but not D2, receptors were localized on noradrenergic LC neurons, pre-treatment with SCH-23390 (intra-LC) dampened the lever press activity. We suggest that two-way communications between VTA and LC regions is essential for ethanol-triggered reinforcement behavior.
authors.affiliation: Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, India.
authors.forename: Gajanan P
authors.initials: GP
authors.lastname: Shelkar
authors.affiliation: School of Biological Sciences, National Institute of Science Education and Research (NISER), Institute of Physics Campus, Sachivalaya Marg, PO Sainik School, Bhubaneswar, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: School of Biological Sciences, National Institute of Science Education and Research (NISER), Institute of Physics Campus, Sachivalaya Marg, PO Sainik School, Bhubaneswar, India.
authors.forename: Praful S
authors.initials: PS
authors.lastname: Singru
authors.affiliation: Indian Institute of Science Education and Research (IISER), India.
authors.forename: Nishikant K
authors.initials: NK
authors.lastname: Subhedar
authors.affiliation: Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, India.
authors.forename: Dadasaheb M
authors.initials: DM
authors.lastname: Kokare
mesh_terms: D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D059331:Adrenergic Neurons / Q000187:drug effects*; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant; D004221:Disulfiram / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D065086:Acetaldehyde Dehydrogenase Inhibitors; D018663:Adrenergic Agents; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000779:Anesthetics, Local; D001552:Benzazepines; D001596:Benzylamines; D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D058785:GABA-A Receptor Agonists; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D010656:Phenylephrine; D009118:Muscimol; D000431:Ethanol; D008012:Lidocaine; D014446:Tyrosine 3-Monooxygenase; C012102:DSP 4; D004221:Disulfiram; D011224:Prazosin
keywords: dopamine D1 receptors; ethanol reinforcement; locus coeruleus; posterior ventral tegmental area; α1-Adrenergic receptors