Heteromeric Nicotinic Acetylcholine–Dopamine Autoreceptor Complexes Modulate Striatal Dopamine Release

Abstract

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D(2) autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D(2) autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-alpha(7) nACh receptor antagonist dihydro-beta-erythroidine or the D(2-3) receptor agonist quinpirole. Local perfusion of the D(2-3) receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-beta-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D(2) autoreceptor modulating the efficacy of non-alpha(7) nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between beta(2) subunits of non-alpha(7) nicotinic acetylcholine receptors and D(2) autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-alpha(7) nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.

Nicotine and methamphetamine share discriminative stimulus effects

“…The question then arises of what is the mechanism by which a nicotinic agonist and a dopamine releaser can interact. Because both locomotor activity and self-administration are known to be related to mesolimbic and nigrostriatal dopamine systems, it is possible that co-administration of these compounds modulates levels of DA release, particularly as nicotine is well known to modulate dopamine release (Quarta et al, 2006;Wonnacott et al, 2005) There have indeed been reports that nicotine and methamphetamine modulate each other's ability to alter dopamine levels. Chronic treatment with nicotine increased release of dopamine in striatal slices (e.g., Takaki, 1995).…”

“…Methamphetamine produced smaller increases in dopamine levels in rats sensitized to nicotine, but basal levels of dopamine were higher to begin with (Miyata et al, 1996). Not only is there an interaction between presynaptic D2 and nicotinic acetylcholine receptors on their modulation of dopamine release, there is evidence that β2 subunits of the nicotinic acetylcholine receptors physically interact with the D2 receptors, creating a heteromeric receptor complex (Quarta et al, 2006). Taken together, these studies indicate that nicotine and methamphetamine can each modulate the other's behavioral effects and that there are known interactions between central dopamine and nicotinic acetylcholine receptors that could plausibly serve as mediators of interactions of the behavioral effects of methamphetamine and nicotine.…”

“…The most obvious possibility is that nicotinic acetylcholine receptors are located on dopaminergic neurons in the ventral tegmental area which are important in regulating neuronal activity of these dopaminergic neurons (Mameli-Engvall et al, 2006;Ungless and Cragg, 2006). Administration of nicotine modulates dopamine release (Quarta et al, 2006;Wonnacott et al, 2005), and is known to alter behaviors controlled by these dopaminergic pathways including locomotor behavior (Kuribara, 1999;Suemaru et al, 1993) and self-administration of abused compounds, including both nicotine and methamphetamine (Glick et al, 2002;Hiranita et al, 2004;Hiranita et al, 2006;Rauhut et al, 2003). The failure of mecamylamine to block the cross-substitution of methamphetamine in nicotine-trained rats may be related to the finding that perfusion of mecamylamine into the nucleus accumbens did not alter dopamine levels in the ventral tegmental area or the nucleus accumbens (Rahman and McBride, 2002).…”

“…The failure of mecamylamine to block the cross-substitution of methamphetamine in nicotine-trained rats may be related to the finding that perfusion of mecamylamine into the nucleus accumbens did not alter dopamine levels in the ventral tegmental area or the nucleus accumbens (Rahman and McBride, 2002). In addition, there is now evidence that β2 subunits of nicotinic acetylcholine receptors create a heteromeric receptor complex with dopamine D2 receptors (Quarta et al, 2006). This hetereomeric autoreceptor decreases dopamine release, but as yet, the functional significance of this autoreceptor to dopamine-related behaviors has not been investigated.…”

“…There are known interactions between central nicotinic acetylcholine receptors and dopamine receptors in the central nervous system e.g. (e.g., Quarta et al, 2006;Wonnacott et al, 2005), which provide possible mechanisms for the co-abuse of methamphetamine and nicotine. Because of this, it is of interest to characterize the nature of the interaction of these two compounds.…”