Chronic pre-treatment with nicotine enhances nicotine-evoked striatal dopamine release and α6 and β3 nicotinic acetylcholine receptor subunit mRNA in the substantia nigra pars compacta of the rat

Whilst local intrastriatal infusion of nicotine consistently elicits striatal dopamine release, systemic administration often fails to do so. Since chronic nicotine administration is known to result in desensitisation-induced upregulation of nicotinic acetylcholine receptors (nAChRs), the present study investigated whether chronic pre-treatment could enhance the response to systemic nicotine and, if so, whether increases in specific nAChR subunit mRNA levels in the substantia nigra pars compacta (SNc) may underlie this effect. In vivo microdialysis studies in male Sprague–Dawley rats revealed that following 4 days pre-treatment with nicotine (0.8 mg kg−1 s.c.), local intrastriatal nicotine infusion (3 mM) elicited significantly higher dopamine efflux compared to vehicle pre-treated controls (peak release: 1273 ± 199% basal versus 731 ± 113% basal), whereas systemic nicotine challenge (0.8 mg kg−1 s.c.) elicited no response. In contrast, following 8 days pre-treatment with nicotine (0.8 mg kg−1 s.c.), systemic nicotine challenge (0.8 mg kg−1 s.c.) now produced significantly higher dopamine efflux than that of vehicle pre-treated controls (147 ± 30% basal versus 91 ± 5% basal). Eight days pre-treatment with nicotine also significantly elevated the levels of α6 (∼55%) and β3 (∼43%) nAChR subunit mRNA in the SNc, suggesting that up-regulation of these nAChR subunit genes in the nigrostriatal tract may contribute to the enhanced nicotine-evoked striatal dopamine release.