The initial few minutes of nicotine exposure will enhance DA release in the NAc by activating α4β2* nAChRs on dopamine neuronal soma (Pidoplichko et al., 1997; Mansvelder and McGehee, 2000); however, β2*-containing receptors rapidly desensitize. Simultaneously, nicotine acts on α4β2* nAChRs located on GABAergic neurons to induce a transient inhibition of DA activity. These nicotinic receptors will also subsequently desensitize in the presence of nicotine with a net result being a reduction in the inhibitory control of GABA on dopaminergic transmission (Mansvelder and McGehee, 2002). On the same time scale, nicotine binds to α7 nAChRs present on glutamatergic terminals in the VTA, whose activation increases glutamate release onto NMDA-type glutamate receptors located on dopaminergic cell bodies and increases the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) (Mansvelder and McGehee, 2000; Schilstrom et al., 2000; Marchi et al., 2002; Pidoplichko et al., 2004). Hence, the cumulative result of nicotine acting on nAChRs in the VTA is enhanced excitatory input onto DA neurons which triggers reward-related high frequency burst firing resulting in increased accumbal DA outflow (Corrigall et al., 1994; Nisell et al., 1994; Schilstrom et al., 2000; Pidoplichko et al., 2004).
