Neurobiological Effects

Binge/Intoxication Stage

Nicotine as a Nicotinic Acetylcholine Receptor Agonist

The initial molecular site of action for the physiological effects of nicotine is the nicotinic acetylcholine receptor (nAChR). nAChRs are cationic ligand-gated ion channels that are expressed throughout the central nervous system. Neuronal nAChRs can be presynaptic or postsynaptic and activate other neurons by increasing the influx of calcium, so producing neurotransmitter release. The influx of calcium on postsynaptic neurons can also trigger many cellular signal transduction processes, including the activation of protein kinase and calmodulin-dependent kinase. nAChRs are pentameric structures with at least two ligand-binding sites at the interface between subunits (Figure 7.13). A wide variety of nAChR subtypes with different pharmacological and electrophysiological properties exists. The genes that encode nAChR subunits have been identified and cloned in mammals (α1-α10 and β1-β9), and several subunits have been found in the central nervous system (α2-α7 and β2-β4). These subunits co-assemble to form functional pentameric receptors. Three distinct families of nAChRs are represented in the body and brain. The α1, β1, γ, δ, and ε subunits represent the muscle acetylcholine receptor family. The α2–6 and β2–4 subunits represent one central nervous system family. A third family can form homopentameric acetylcholine receptors composed of α7–10 subunits. All high-affinity binding sites for nicotine include the β2 subunit, a critical subunit for the reinforcing effects of nicotine.

Figure 7.12 The boundary model of tobacco use. The upper boundary (A) marks a zone that represents the weighted sum of all of the aversive biological consequences of smoking cigarettes. The intermediate zone (B) represents the relative range of indifference to the pharmacological properties of the drug. The lower boundary (C) marks a zone that represents the weighted sum of all of the biologically based pressures to smoke. The zones represent different rates of smoking sustained by an individual, varying from high psychosocial pressure to smoke (light blue) to very low psychosocial pressure (purple). [Modified with permission from Kozlowski LT, Herman CP. The interaction of psychosocial and biological determinants of tobacco use: more on the boundary model. Journal of Applied Social Psychology, 1984, (14), 244–256.]

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