Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2^*and α6(Nonα4)β2^*nAChR Expression and Function

Abstract

Nicotine treatment has long been associated with alterations in ␣4␤2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of longterm nicotine treatment on the ␣6␤2* nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal ␣6␤2* nAChR function and expression. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, ␣6␤2* nAChR blockade with ␣-conotoxin MII (␣-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate ␣6␤2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, ␣6␤2* nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the ␣6␤2* nAChR subtypes altered with long-term nicotine treatment, we used the novel ␣-CtxMII analog E11A in combination with ␣4 nAChR knockout mice. 125 I-␣-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the ␣6␣4␤2* subtype but increased the ␣6(non␣4)␤2* nAChR population. These data indicate that ␣6␤2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the ␣6(non␣4)␤2* nAChR subtype and suggest that the ␣6␣4␤2* nAChR and/or ␣4␤2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions.

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

“…Purely ␣6 or mixed ␣4␣6 receptors may have different pharmacological and physiological, and perhaps also cell biology, properties. The mixed ␣4␣6␤2 receptor has higher affinity for nicotinic agonists than the ␣6␤2 receptor , and chronic nicotine (Perez et al, 2008) has opposite effects on the expression of these subtypes in the striatum. These findings may possibly explain the recent evidence of a dominance of purely ␣6*-sensitive responses in the nAc, whereas ␣4 responses dominate in the CPu (Exley et al, 2008).…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…The results of a recent experiment has added further complexity. It was found that the decrease in overall conotoxinMII binding observed after oral nicotine administration is due to two opposite effects on different α6* subtypes: a decrease in the α4α6β2* subtype and an increase in the α6(nonα4)β2* subtype [118].…”

“…Accordingly, α4-/-mice chronically treated with oral nicotine show increased αconotoxinMII binding in striatum [118].…”

“…Ex vivo, studies have shown that α6β2* receptors mediate 30-50% of 3 H-dopamine release in the CPu and nAc [71], and voltammetry studies indicate that they are responsible for most of the dopamine release in the nAc obtained with the burst stimulation of striatal slices [74]. Chronic oral nicotine treatment, which up-regulates the α6(non-α4)β2 subtype but leads to the loss of α4α6β2, abolishes α6* mediated effects on burst firing, thus suggesting that is the former subtype that primarily modulates this type of α6β2*-mediated dopamine release [118].…”

The Nicotine Metabolite, Cotinine, Alters the Assembly and Trafficking of a Subset of Nicotinic Acetylcholine Receptors

“…The lack of cotinine-induced up-regulation of ␣6␤2␤3 is potentially related to its action on only a portion of this receptor population. This effect could also partially explain discrepancies between groups that detect upregulation (7,55,56) or down-regulation (57) in varying brain regions based on concentrations of nicotine or cotinine present. These studies show that nicotine's primary metabolite, cotinine, has a similar effect on the trafficking and assembly of nAChRs as seen with nicotine.…”