Exposure to nicotine produces an increase in dopamine D2(High) receptors: a possible mechanism for dopamine hypersensitivity.

Dopamine D2 receptors exist in both low- and high-affinity states (D2(High)), the latter being the functionally relevant state. Cocaine self-administration produces an increase in D2(High), a phenomenon that could explain why cocaine administration results in hypersensitivity to dopamine, even though drug addicts were found to have a decreased number of striatal dopamine D2 receptors. As nicotine acts through the same mesocortical dopaminergic signaling pathways as other stimulant drugs, which are known to increase the levels of D2(High), we hypothesized that nicotine exposure could produce an increase in D2(High) levels. We determined D2(High) levels in rats after nicotine administration (1.5 mg/kg/day; 14 days), in rats voluntarily self-administering nicotine using an intravenous self-administration (IVSA) protocol (mean dose 0.5 mg/kg/day; 14 days), as well as after a prolonged withdrawal. An increase in the levels of D2(High) was found in rats who had nicotine administered at a uniform dose, as well as in rats who self-administered nicotine via IVSA, but these changes appear to normalize over time, as indicated by lower D2(High) levels in rats after a prolonged withdrawal period. We suggest that nicotine-induced elevation in D2(High) levels could be participating in hypersensitivity to dopamine following nicotine exposure.