Molecular Mechanism of Action
The most widely expressed subtypes of nAChRs in the brain contain the α4, α7, and β2 subunits. Various nAChR α and β subunit combinations, notably the α4β2 subtype, are present throughout the mesocorticolimbic dopamine pathway, including the ventral tegmental area, prefrontal cortex, amygdala, septal area, and nucleus accumbens. The α4 subunit is critical for the relatively slow electrical currents associated with the slow desensitization component of nAChRs and the release of dopamine produced by systemic nicotine. Knockout of the α4 and β2 subtypes blocks the reinforcing effects of nicotine, as does knockout of the α7 subtype.
In summary, intravenous nicotine self-administration is blocked by dopamine receptor antagonists and lesions of the midbrain dopamine system. Nicotine increases dopamine release in the nucleus accumbens and acutely activates the mesocorticolimbic dopamine system through three possible actions:
1) Direct action on dopamine neurons,
2) Acting through presynaptic activation of glutamate release, and
3) Acting through the activation of GABA interneurons that desensitize more rapidly.
The combined activation of glutamate and deactivation of GABA presumably prolongs the dopaminergic response in the ventral tegmental area. Glutamate (NMDA) receptor antagonists block nicotine self-administration and nicotine-induced dopamine release. GABA receptor agonists have similar effects. Thus, glutamate and GABA appear to modulate nicotine reward. Opioid peptides may also be involved in the reinforcing effects of nicotine, independent of dopamine activation.
Withdrawal/Negative Affect Stage
As described above, animals will regularly self-administer nicotine intravenously, supporting the hypothesis that nicotine is the active ingredient for producing the rewarding effects of tobacco. Adult rats will self-administer nicotine in continuous access situations (24 h/day) to the point of dependence and will show an escalation in drug intake with intermittent access (Figure 7.23). This suggests that intermittent daily use with concomitant daily withdrawal from nicotine contributes to the excessive nicotine intake associated with compulsive use and addiction.