Exley_2013_Eur.J.Neurosci_38_3036

Nicotine directly regulates striatal dopamine (DA) neurotransmission via presynaptic nicotinic acetylcholine receptors (nAChRs) that are alpha6beta2 and/or alpha4beta2 subunit-containing, depending on region. Chronic nicotine exposure in smokers upregulates striatal nAChR density, with some reports suggesting differential impact on alpha6- or alpha4-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 alpha6-subunit-containing (*) relative to non-alpha6* 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 mug/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 alpha6-nAChRs (alpha6alpha4beta2beta3), and an emergence in function of non-alpha6* nAChRs. In CPu, there was no change in the control of DA release by its alpha6 nAChRs (alpha6beta2beta3) relative to non-alpha6. 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 alpha6alpha4beta2beta3 nAChRs. This imbalance in function of alpha6:non-alpha6 nAChRs might contribute to DA dysregulation in nicotine addiction.