Nicotinic and dopamine D2 receptors mediate nicotine-induced changes in ventral tegmental area neurotensin system.

Neuropeptides have been implicated in the psychopathology of stimulants of abuse. Neurotensin is a neuropeptide associated with the regulation of the nigrostriatal and mesolimbic dopamine pathways. In addition, the ventral tegmental area, a midbrain region implicated in the rewarding effects of most, if not all, addictive drugs, appears to be a particularly critical target for nicotine action. Because neurotensin has been linked with both mesolimbic and mesocortical dopamine function, we examined the impact of nicotine treatment on central nervous neurotensin systems by measuring changes in neurotensin tissue content because it has been shown that such changes reflect alterations in release and activity of this peptide system. Male Sprague-Dawley rats received multiple administrations of (+/-) nicotine 4.0 mg/kg/day (0.8 mg/kg, i.p.; 5 x 2-h intervals) in the presence or absence of selective dopamine receptor antagonists (dopamine D(1); SCH 23390 or dopamine D(2); eticlopride) or two doses of the non-selective nicotinic acetylcholine receptor antagonist (mecamylamine; 3.0 and 6.0 mg/kg, s.c.). The nicotine treatment significantly decreased neurotensin-like immunoreactivity content in the ventral tegmental area, as well as related regions such as prefrontal cortex, substantia nigra, and anterior striatal region 12-18 h after drug treatment, but not the nucleus accumbens. The nicotine-mediated decrease in the neurotensin-like immunoreactivity of the ventral tegmental area was selectively blocked by a specific dopamine D(2), but not a dopamine D(1), receptor antagonist, while mecamylamine attenuated at the low (3.0 mg/kg) and completely blocked at high (6.0 mg/kg) dose this nicotine effect. These findings with previous studies, suggest that nicotine-mediated dopamine release activates D(2) receptors which in turn increases neurotensin release, turnover and acutely reduces tissue levels in the ventral tegmental area and other limbic and basal ganglia structures.