Alpha-5 nicotinic acetylcholine receptor

Studies have shown that removing the α5 nAChR subunits from mice (α5 nAChR null) will make them less sensitive to acute effects of nicotine.[12] The mice showed decreased locomotion in an open field test and fewer nicotine-induced seizures.[11] Other studies have shown that α5 nAChR null mice display fewer signs of dependency and reduced anxiety-like behaviors.[11] Because the knockout mice show less aversion to increased nicotine intake, they tend to self-administer at much higher doses than wildtype mice. However, reintroduction of the alpha 5 subunit in the medial habenula in knockout mice restored normal levels of nicotine self-administration. This demonstrates that the expression of the alpha5 subunit in the medial habenula is sufficient to reinstate nicotine aversion.[13] In contrast, the targeted knockdown of α5 subunits in the habenulo-interpeduncular pathway in wildtype mice did not change the stimulatory effects observed in knockout mice demonstrating that the subunit is not necessary for nicotine aversion, and that other areas of the brain can compensate for this behavior.[12]

In a conditioned place preference study (CPP), researchers trained mice to associate nicotine administration with one chamber and saline administration in an adjacent chamber. At low doses of nicotine, alpha5 knockout mice and wildtype mice both showed preference for the nicotine chamber. However, at high doses of nicotine, only the α5 knockout mice preferred the nicotine chamber[13] demonstrating that the alpha5 knockout mice still experienced the rewarding aspects of nicotine, but not the normal aversive behaviors with nicotine overdose.

Studies from Tuesta et al. 2011 have shown that the dose-response curve is similar when comparing knockout mice to wildtype mice however the knockout mice consumed greater amounts of nicotine which resulted in the descending portion of the dose-response curve to descend declined slower in the knockout mice. There has been shown an increased response to nicotine in the ascending portion of the curve demonstrating the greater rewarding properties.[12]

Nicotine is commonly consumed by people for its rewarding properties resulting in dependence, addiction and withdrawal.[14] Human studies have shown that people with a single nucleotide polymorphism (SNP) within the α5 nAChR encoding gene (CHRNA5, rs16969968) correlates with an increased risk of nicotine dependency and pleasure along with more heavy smoking.[11][15][16][17] This particular SNP results in an aspartic acid to asparagine substitution at amino acid residue 398 (D398N).[12] The rs16969968 within CHRNA5 causes a reduction in the receptor function that is involved in producing withdrawal symptoms. Individuals with this SNP are commonly found in those of European descent; there is about a 30% greater risk of nicotine dependence in individuals carry a single copy of the variant and about a 50% greater risk in individuals with two copies.[12] Other studies have shown that people with this SNP develop nicotine dependence at a younger age.[12] Researchers conclude that fewer aversive effects of nicotine would promote the rewarding effects or hedonic drive that would transition people from nicotine abuse to dependency.[11][18] Additionally, SNP variants within rs16969968 in CHRNA5 have been associated with smoking-related behaviors such has a higher prevalence of smokers vs nonsmokers.[19]

Researchers speculate that layer VI pyramidal neurons in the prefrontal cortex are important for holding attention in cognitively demanding tasks. These neurons send feedback projections to the thalamus and are highly responsive to acetylcholine. In vivo studies have shown that the presence of alpha5 subunits of nAChRs on layer VI pyramidal neurons in the PFC are important for visual attention.[21] In slice electrophysiology experiments, researchers have shown that alpha5 subunits enhance currents in the PFC of an adult mouse. In vivo, researchers use a five-choice serial reaction task. The animals are randomly given 1 of 5 light stimulus, and they need to encode and recall the location of the stimulus in order to receive a reward. Transgenic mice without the gene that encodes alpha5 subunits showed impaired performance on the five-choice serial reaction task. This indicates that the alpha5 null mice have attentional deficits.[5] Interestingly, the deletion of alpha5 subunits in mice results in an upregulation of muscarinic acetylcholine receptors as an excitatory compensation response to circuitry dysfunction. Because of the cognitive enhancing effects of alpha5 nAChR agonists, it is a common target for neurodegenerative disorders with cognitive deficits along with ADHD.[22]

Due to technical limitations of invasive procedures, there are far fewer studies in about the role of the alpha5 nAChR subunit and cognition. Studies have performed microdialysis in subjects as they formed attention tasks and found significantly increased acetylcholine efflux.[5]