Mesocorticolimbic circuitry that is normally critical for reinforcing successful behaviors also participates in the addiction process [9
]. The dopaminergic centers of the midbrain and their targets have received much attention because of their roles in arousal, motivation, cognition, motor function, and processes associated with reinforcing behaviors that lead to reward. One of the important dopaminergic pathways originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures, including the prefrontal cortex, and areas such as the olfactory tubercle, the amygdala, the septal region, and the striatum, which includes a particularly important target, the nucleus accumbens.
The accumulation of evidence implicates these mesocorticolimbic circuits in addiction [7
]. Many addictive drugs, including nicotine, elevate dopamine (DA) in the nucleus accumbens, and that elevation correlates with the reinforcement of drug use, particularly during the acquisition phase [7
]. Blocking dopamine release in the nucleus accumbens with antagonists or lesions reduces nicotine self-administration in rats, which is interpreted to mean that inhibited dopamine release attenuates the rewarding effects of nicotine [8
]. Nicotine administration activates dopamine neuron firing as has been shown using rodent brain slices [39
] and using in vivo recordings from freely-moving rodents [40
]. Thus, the concentration of nicotine obtained from tobacco can activate nAChRs on midbrain dopamine neurons and influence associated excitatory and inhibitor circuitry and, thereby, increase dopamine neuron firing.
The midbrain DA area receives afferent cholinergic innervation from the nearby pedunculopontine tegmentum (PPT) and the laterodorsal tegmentum (LDT), which are a loose collection of cholinergic neurons interspersed with GABAergic and glutamatergic neurons [42
]. The midbrain DA area expresses diverse nAChR subtypes [25
], and particularly nAChRs containing the β2 subunit, usually in combination with α4 and/or α6 subunits, mediate nicotine-induced dopamine signals [44
]. Activation of nAChRs directly depolarizes DA neurons [39
] and, consequently, increases their firing [40
]. In addition, nicotine influences excitatory and inhibitory circuitry and local synaptic plasticity, which have longer lasting influences over midbrain activity [40
]. In this manner, nicotine supercedes the actions of normal environmental events that act upon the midbrain circuitry. The drug acts directly upon this circuitry, as if a reward-related sensory input has been received.
DA neurons fire in different modes [52
], commonly firing at low tonic frequencies interspersed with higher frequency phasic bursts that can be induced by unpredicted reward or unanticipated cues that have been conditioned to a known reward [55
]. Disrupting phasic bursts diminishes the ability to learn cues about reward and impairs the processing of reward [56
]. Nicotine administration increases the firing of DA neurons and increases the number and length of phasic bursts [40
], which particularly boosts DA concentrations in the nucleus accumbens [40
]. This action by nicotine requires β2-containing nAChRs. In mice lacking the β2 nAChR subunit (β2 −/−), nicotine does not produce burst firing from DA neurons [46
] and does not support self-administration [44
]. In β2 null mice, when β2 is reexpressed in the ventral tegmental area, nicotine self-administration is reinstated [48
]. In addition, nicotine self-administration also is influenced by the α4 and the α6 nAChR subunits, and those two subunits cannot completely substitute for each other even though they are abundantly expressed in VTA neurons [59
]. The results are consistent with the expression of α4β2 and α4α6β2 nAChRs in the VTA [48
] and consistent with the importance of these receptors in the VTA for the reinforcing properties of nicotine.