Genetic Vulnerability to Tobacco Addiction?
A single-nucleotide polymorphism within the α5 gene of the nicotinic receptor reduces α5 nAChR function and in humans is associated with a greater risk of nicotine dependence, heavier smoking, and increased rewarding effects from cigarettes. Subunit expression is high in the medial habenula, interpeduncular nucleus, and ventral tegmental area. The habenula projects to the interpeduncular nucleus, which is adjacent to dopaminergic cells in the ventral tegmental area. The blockade of α5 receptors blunts nicotine withdrawal, and α5 subunit knockout mice self-administer nicotine at high doses that otherwise limit intake in wildtype mice with normal α5 subunit expression. Thus, one hypothesis is that the α5 habenula-interpeduncular pathway mediates some of the aversive effects of nicotine and is involved in nicotine withdrawal symptoms.
Figure 7.26 Signaling pathways related to extracellular signal-regulated kinase (ERK) activation that may be involved in nicotine dependence and withdrawal. (A) Nicotine could affect ERK/CREB (cyclic adenosine monophosphate response element binding protein) signaling by direct activation of nicotinic receptors or indirectly via changes in tyrosine kinase receptor activation. Dashed lines indicate multi-step processes. (B) Summary of changes in response to chronic nicotine exposure and withdrawal in the amygdala, prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Each of these brain areas is connected by reciprocal connections to the ventral tegmental area. Changes in signaling within these pathways are likely to alter communication between brain areas involved in drug dependence. [Taken with permission from Brunzell DH, Russell DS, Picciotto MR. In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. Journal of Neurochemistry, 2003, (84), 1431–1441.]