There is a limited number of subunits (α4, α5, α6, β2, and β3) densely localized on pre-synaptic DAergic axon terminals in the striatum (Grady et al., 2007), where β2-containing nAChRs can directly influence local DA release based on the neuronal activity firing rate (see Figure 2) (Zoli et al., 2002; Rice and Cragg, 2004). In the proposed model, ACh released from tonically active striatal cholinergic interneurons normally acts on these receptors to gate the probability of DA release and enhance the contrast between tonic and phasic firing patterns. In a manner similar to those in the VTA, these β2-nAChRs will rapidly desensitize following agonist application. Initial nicotine administration causes a reduction of dopamine release from tonically active neurons; however, a reward-related burst of action potentials will result in even greater transmitter release due to loss of the normal modulatory control of endogenous Ach (Zhou et al., 2001; Rice and Cragg, 2004; Salminen et al., 2004; Zhang and Sulzer, 2004).
