Selective down-regulation of [125i]Y0-α-conotoxin MII binding in rat mesostriatal dopamine pathway following continuous infusion of nicotine

• Published in: Neuroscience Vol. 137; no. 2; pp. 565 - 572
• Main Authors: MUGNAINI, M, GARZOTTI, M, SARTORI, I, PILLA, M, REPETO, P, HEIDBREDER, C. A, TESSARI, M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 2006
• Subjects: Animals; Binding Sites - drug effects; Binding Sites - physiology; Binding, Competitive - drug effects; Binding, Competitive - physiology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Conotoxins - metabolism; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - physiology; Fundamental and applied biological sciences. Psychology; Iodine Radioisotopes; Male; Mesencephalon - drug effects; Mesencephalon - metabolism; Neural Pathways - drug effects; Neural Pathways - metabolism; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Pyridines - metabolism; Radioligand Assay; Rats; Rats, Wistar; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - metabolism; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - physiopathology; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Tobacco Use Disorder - metabolism; Tobacco Use Disorder - physiopathology; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; Vertebrates: nervous system and sense organs; Dopamine; α-Conotoxin; Rat; Rodentia; chronic treatment; withdrawal; Catecholamine; up-regulation; Vertebrata; Chronic; Mammalia; Treatment; Animal; Neurotransmitter; Nicotine; α-conotoxin MII
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2005.09.008

Prolonged exposure to nicotine, as occurs in smokers, results in up-regulation of all the neuronal nicotinic acetylcholine receptor subtypes studied so far, the only differences residing in the extent and time course of the up-regulation. alpha6beta2*-Nicotinic acetylcholine receptors are selectively enriched in the mesostriatal dopaminergic system and may play a crucial role in nicotine dependence. Here we show that chronic nicotine treatment (3mg/kg/day for two weeks, via s.c. osmotic minipumps) caused a significant decrease (36% on average) in the binding of [(125)I]Y(0)-alpha-conotoxin MII (a selective ligand for alpha6beta2*-nicotinic acetylcholine receptors in this system) to all the five regions of the rat dopaminergic pathway analyzed in this study. After one week of withdrawal, binding was still lower than control in striatal terminal regions (namely the caudate putamen and the accumbens shell and core). In somatodendritic regions (the ventral tegmental area and the substantia nigra) the decrease was significant at the end of the treatment and recovered within one day of withdrawal. This effect was not due to displacement of [(125)I]Y(0)-alpha-conotoxin MII binding by residual nicotine. In fact the binding was not changed by 565 ng/g nicotine (obtained with a single injection of nicotine), a concentration much higher than that found in the brain of rats chronically treated with nicotine (240 ng/g). In addition, consistent with previous studies reporting an up-regulation of other subtypes of nicotinic acetylcholine receptors, we found that nicotine exposure significantly increased (40% on average) the binding of [(125)I]epibatidine (a non-selective agonist at most neuronal heteromeric nicotinic acetylcholine receptors) in three up to five regions containing only alpha-conotoxin MII-insensitive [(125)I]epibatidine binding sites, namely the primary motor, somatosensory and auditory cortices. In conclusion, this work is the first to demonstrate that alpha6beta2*-nicotinic acetylcholine receptors, unique within the nicotinic acetylcholine receptor family, are down-regulated following chronic nicotine treatment in rat dopaminergic mesostriatal pathway, a finding that may shed new light in the complex mechanisms of nicotine dependence.