Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype

Abstract

Introduction: Nicotine is a major psychoactive ingredient in tobacco yet very few individuals quit smoking with the aid of nicotine replacement therapy. Targeted therapies with more selective action at nicotinic acetylcholine receptors (nAChRs) that contain a β2 subunit (β2*nAChRs; *denotes assembly with other subunits) have enjoyed significantly greater success, but exhibit potential for unwanted cardiac, gastrointestinal, and emotive side effects.

Discussion: This literature review focuses on the preclinical evidence that suggests that subclasses of β2*nAChRs that assemble with the α6 subunit may provide an effective target for tobacco cessation. α6β2*nAChRs have a highly selective pattern of neuroanatomical expression in catecholaminergic nuclei including the ventral tegmental area and its projection regions. α6β2*nAChRs promote dopamine (DA) neuron activity and DA release in the mesolimbic dopamine system, a brain circuitry that is well-studied for its contributions to addiction behavior. A combination of genetic and pharmacological studies indicates that activation of α6β2*nAChRs is necessary and sufficient for nicotine psychostimulant effects and nicotine self-administration. α6β2*nAChRs support maintenance of nicotine use, support the conditioned reinforcing effects of drug-associated cues, and regulate nicotine withdrawal.

Conclusions: These data suggest that α6β2*nAChRs represent a critical pool of high affinity β2*nAChRs that regulates nicotine dependence phenotype and suggest that inhibition of these receptors may provide an effective strategy for tobacco cessation therapy.

Figure 1.

The putative composition of mesolimblic α6β2* nicotinic acetylcholine receptors (nAChRs). nAChRs are pentameric in structure, made up of a combination of five subunits that assemble around an ion pore. The ACh binding site is believed to be at the interface of the α6/α4 and β2 subunits. The accessory subunit, β3, is highly expressed in α6β2*nAChRs. Agonist binding results in opening of the ion pore and activation of the receptor. Following activation, the bound nAChRs desensitize and become impermeable to cation penetration through the ion pore. The α4α6β2*nAChRs have a higher affinity for agonist binding and are slower to desensitize.

Figure 2.

A neuroanatomical summary of α6β2*nicotinic acetylcholine receptor (nAChR) contributions to behaviors associated with nicotine and tobacco addiction. A preponderance of the evidence suggests that activation of α6β2*nAChRs in the ventral tegmental area (VTA) and on dopamine (DA) terminals in the dorsal and ventral striatum (aka NAc core and shell) supports nicotine-stimulated DA release. Antagonism of α6β2*nAChRs in the NAc shell or VTA greatly attenuates nicotine self-administration. α6β2*nAChRs in the NAc shell regulate motivation to self-administer nicotine. Mesolimbic rescue of α4, α6, or β2 subunits on a null mutant background is sufficient to rescue self-administration phenotype, suggesting that α4α6β2*nAChRs regulate this behavior. IntraVTA infusion of α-conotoxin MII also blocks the rewarding effects of cues paired with a drug reinforcer. Studies in transgenic mice with highly sensitive α4 or α6 subunit containing nAChRs show that nicotine-associated stimulation of VTA DA neurons is at the α4α6β2*nAChRs and the α6-sensitive mice bred on an α4 knockout background show that α4α6β2*nAChRs regulate the locomotor stimulating effects of nicotine, likely at the level of the VTA and perhaps within the nigrostriatal circuitry that includes projections to the dorsal striatum. Affective but not somatic withdrawal is attenuated by injection of an α6β2*nAChR antagonist into the lateral ventricle; the locus of this effect is not clear. Several studies show that antagonism of α6β2*nAChRs and α4β2*nAChR does not have the same effect as selective antagonism of α6β2*nAChRs, perhaps due to expression of α4β2*nAChRs on gamma-aminobutyric acid terminals in mesolimblic DA areas. These studies suggest that α6β2*nAChRs may be an effective target for tobacco cessation. Increasing evidence suggests that α4α6β2β3nAChRs represent a critical pool of high affinity β2*nAChRs that support nicotine addiction behavior.