Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats

Behavioral sensitization to nicotine, which appears following repeated nicotine administration, has been suggested to take part in the development of smoking habit in humans. The mesolimbic dopaminergic system plays a role in this process and a hypersensitivity of postsynaptic neurons of the nucleus accumbens as been proposed as a mechanism, but changes in dopamine D(1) or D(2) receptors have not been demonstrated to date. A challenge administration of nicotine (0.5 mg/kg s.c.) produced a strong increase in locomotor activity in rats repeatedly pretreated with nicotine (0.5 mg/kg s.c.), but not saline, once a day for 5 days. This behavioral sensitization was accompanied by an increase in D(3) receptor binding and mRNA in the shell of nucleus accumbens. D(3) receptor expression was unchanged in the core of nucleus accumbens and dorsal striatum, as it was in the shell of nucleus accumbens after an acute administration of nicotine to naive rats. In contrast, no changes were noticed in D(1) and D(2) receptor expressions in any brain region examined after chronic or acute treatment with nicotine. In addition, nicotine challenge decreased preprodynorphin and preprotachykinin mRNA levels in naive rats, but only preprotachykinin mRNA levels in rats pretreated with nicotine. These biochemical changes resemble those occurring during behavioral sensitization to levodopa of dopamine-denervated rats, which had been causally related to the induction of D(3) receptor expression. We propose that a similar mechanism is responsible for behavioral sensitization to nicotine.