Interplay of β2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion

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Abstract
Acetylcholine (ACh) is a known modulator of the activity of dopaminergic (DAergic) neurons through the stimulation of nicotinic ACh receptors (nAChRs). Yet, the subunit composition and specific location of nAChRs involved in DA-mediated locomotion remain to be established in vivo. Mice lacking the β2 subunit of nAChRs (β2KO) display striking hyperactivity in the open field, which suggests an imbalance in DA neurotransmission. Here, we performed the selective gene rescue of functional β2*-nAChRs in either the substantia nigra pars compacta (SNpc) or the ventral tegmental area (VTA) of β2KO mice. SNpc rescued mice displayed normalization of locomotor activity, both in familiar and unfamiliar environments, whereas restoration in the VTA only rescued exploratory behavior. These data demonstrate the dissociation between nigrostriatal and mesolimbic β2*-nAChRs in regulating unique locomotor functions. In addition, the site-directed knock-down of the β2 subunit in the SNpc by RNA interference caused hyperactivity in wild-type mice. These findings highlight the crucial interplay of nAChRs over the DA control of spontaneous locomotion.