CHRNA4 and Cognitive impairment: Nicotine is delivered rapidly to the brain and acts at nicotinic acetylcholine receptors (nAChRs) to modulate the release of various neurotransmitters, including acetylcholine, dopamine, and serotonin, at the prefrontal cortex and hippocampus.33 Prolonged activation of nAChR by repeated nicotine exposure (eg, cigarette smoking) desensitizes and upregulates nAChR density,34 which unmasks cognitive impairment as the amount of nicotine exposure is reduced, resulting in a higher level of unbound nAChRs (eg, smoking reduction).