title: Striatal dopamine transmission is reduced after chronic nicotine with a decrease in α6-nicotinic receptor control in nucleus accumbens.
abstract: Nicotine directly regulates striatal dopamine (DA) neurotransmission via presynaptic nicotinic acetylcholine receptors (nAChRs) that are α6β2 and/or α4β2 subunit-containing, depending on region. Chronic nicotine exposure in smokers upregulates striatal nAChR density, with some reports suggesting differential impact on α6- or α4-containing nAChRs. Here, we explored whether chronic nicotine exposure modifies striatal DA transmission, whether the effects of acute nicotine on DA release probability persist and whether there are modifications to the regulation of DA release by α6-subunit-containing (*) relative to non-α6* nAChRs in nucleus accumbens (NAc) and in caudate-putamen (CPu). We detected electrically evoked DA release at carbon-fiber microelectrodes in striatal slices from mice exposed for 4-8 weeks to nicotine (200 μg/mL in saccharin-sweetened drinking water) or a control saccharin solution. Chronic nicotine exposure subtly reduced striatal DA release evoked by single electrical pulses, and in NAc enhanced the range of DA release evoked by different frequencies. Effects of acute nicotine (500 nm) on DA release probability and its sensitivity to activity were apparent. However, in NAc there was downregulation of the functional dominance of α6-nAChRs (α6α4β2β3), and an emergence in function of non-α6* nAChRs. In CPu, there was no change in the control of DA release by its α6 nAChRs (α6β2β3) relative to non-α6. These data suggest that chronic nicotine subtly modifies the regulation of DA transmission, which, in NAc, is through downregulation of function of a susceptible population of α6α4β2β3 nAChRs. This imbalance in function of α6:non-α6 nAChRs might contribute to DA dysregulation in nicotine addiction.
authors.affiliation: Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building, Oxford OX1 3PT, UK. richard.exley@dpag.ox.ac.uk
authors.forename: Richard
authors.initials: R
authors.lastname: Exley
authors.affiliation: Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building, Oxford, OX1 3PT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Clements
authors.affiliation: University Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Henrike
authors.initials: H
authors.lastname: Hartung
authors.affiliation: Departments of Biology and Psychiatry, University of Utah, Salt Lake City, UT, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: School of Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Franklin
authors.affiliation: School of Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Bermudez
authors.affiliation: Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building, Oxford, OX1 3PT, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D008297:Male; D008810:Mice, Inbred C57BL; D008839:Microelectrodes; D017072:Neostriatum / Q000187:drug effects* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6; D009538:Nicotine; D004298:Dopamine
keywords: addiction; mouse; reward; voltammetry; α-conotoxin-MII