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  • In rats exposed to day

    2019-07-30

    In rats exposed to 1 day of nicotine withdrawal (24 h after the last nicotine administration) we expected a decrease of general locomotor activity and a decrease of global striatal dopamine release, which were assessed in a previous study following 14 days of nicotine exposure and 24 h of nicotine withdrawal (Fung et al., 1996). Interestingly, in the present study only the vertical locomotor activity and the ventral striatal dopamine release were decreased, while the horizontal locomotor activity and the dorsal striatal dopamine release remained increased following acute nicotine withdrawal. The explanation of this finding might be offered by the authors of this previous study, who showed a reduction of the maximum number of D2 3,3\',5\'-Triiodo-L-thyronine sites in the nucleus accumbens, but found no alteration of the density and binding affinity of dopamine receptors (D1 and D2) in the putamen and nucleus caudatus (Fung and Lau, 1988). Additionally, the dose and the schedule of the nicotine exposure may also contribute to the difference between the previous and present results. Thus, while tolerance is more likely to be induced by continuous infusion of nicotine (performed in the previous study), sensitization is frequently induced by intermittent injection of nicotine (performed in the present study) (Di Chiara, 2000, Di Chiara et al., 2004). Nonetheless, continuous exposure to nicotine at doses that result in tolerance to the nicotine-induced sensitization, induces itself a sensitization that is demasked as the tolerance wears off. Hereby tolerance and sensitization must be regarded as two distinct adaptive changes that usually require different conditions, but may also occur following the same dose and schedule of chronic nicotine exposure (Di Chiara, 2000, Di Chiara et al., 2004). Consequently, during acute nicotine withdrawal these competing phenomena could be manifested differently between the two subdivisions of the striatum and accordingly, the two aspects of locomotor activity (Di Chiara, 2000, Di Chiara et al., 2004). The discrepancies between the behavioral and neurochemical parameters observed following acute nicotine withdrawal is underlined by the differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways (Janhunen et al., 2005, Janhunen and Ahtee, 2007). On one hand, there are clear differences in the distribution and characteristics of various nAchR subtypes between the dorsal and ventral striatum (Exley et al., 2012, Exley et al., 2013, Janhunen et al., 2005, Janhunen and Ahtee, 2007). Acute nicotine exposure increases directly the striatal dopamine neurotransmission via presynaptic nAchRs that are α6β2 and/or α4β2 subunit-containing, depending on the brain region (Janhunen et al., 2005, Janhunen and Ahtee, 2007). The nAchR subtypes that regulate dopaminergic neurotransmission depend critically upon α5 subunits (non-α6 nAchRs) in the dorsal striatum and upon α6 subunits (α6 nAchRs) in the ventral striatum (Exley et al., 2012). Chronic nicotine exposure produces no change in the control of dopamine release by α6 relative to non-α6 nAchRs in the putamen and nucleus caudatus, but it induces a downregulation of the α6 nAchRs and an upregulation of non-α6 nAchRs in the nucleus accumbens (Exley et al., 2013). In addition, nicotine modulates the release of dopamine indirectly, through the release of glutamate and GABA following activation of post-synaptic α7 containing nAchRs (Exley et al., 2012, Exley et al., 2013, Janhunen et al., 2005, Janhunen and Ahtee, 2007). On the other hand, there are also differences in the regulation of dopamine release by different nicotinic agonists (Exley et al., 2012, Exley et al., 2013, Janhunen 3,3\ et al., 2005, Janhunen and Ahtee, 2007). For example, nicotine stimulates especially the mesolimbic dopaminergic pathway, in contrast, epibatidine, the most potent nAchR agonist known to date, stimulates preferentially the nigrostriatal pathway (Janhunen et al., 2005, Janhunen and Ahtee, 2007). The differing dose–response curves of the two nicotinic agonists regarding the dorsal and ventral striatal dopamine release suggest different abilities for downregulation and desensitization of the nAchRs found in these brain regions (Janhunen et al., 2005, Janhunen and Ahtee, 2007). This imbalance in the distribution and the function of nAchRs between the dorsal and ventral striatum might explain the dopamine dysregulation assessed during acute nicotine withdrawal.