Exercise during Abstinence Normalizes Ultrastructural Synaptic Plasticity Associated with Nicotine-Seeking following Extended Access Self-Administration.

: Nicotine-craving progressively increases, or incubates, over abstinence following extended access self-administration. While not yet examined for nicotine, the incubation of cocaine-seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine-seeking following extended access self-administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes. Given that in humans, tobacco/nicotine use begins during adolescence, we used an adolescent-onset model. Nicotine-seeking was assessed in male rats following extended access nicotine or saline self-administration (23-hr/day, 10 days) and 10 days of abstinence, conditions known to induce the incubation of nicotine-seeking, using a within-session extinction/cue-induced reinstatement procedure. A subset of rats had 2-hr/day access to a running wheel during abstinence. Ultrastructural alterations of synapses in the nucleus accumbens core and shell were examined using electron microscopy. Nicotine-seeking was elevated following extended access self-administration and abstinence (in sedentary group), and levels of seeking were associated with an increase in the density of asymmetric (excitatory) and symmetric (inhibitory) synapses onto dendrites in the core, as well as longer asymmetric synapses onto spines, a marker of synaptic potentiation, in both the core and shell. Exercise normalized each of these changes; however, in the shell, exercise and nicotine similarly increased the synapse length. Together, these findings indicate an association between nicotine-seeking and synaptic plasticity in the nucleus accumbens, particularly the core, and indicate that the efficacy of exercise to reduce nicotine-seeking may be mediated by reversing these adaptations.