SENSITIVITY TO NICOTINE AND BRAIN NICOTINIC RECEPTORS ARE ALTERED BY CHRONIC NICOTINE AND MECAMYLAMINE INFUSION

DBA/2 mice were chronically infused with saline (control), 4 mg/kg/hr of nicotine, 4 mg/kg/hr of mecamylamine or nicotine + mecamylamine for 7 days. The binding of L-[H-3]nicotine was significantly increased in seven of eight brain regions dissected from mice 5 hr after cessation of drug treatment. Similarly, [H-3]nicotine binding was increased in six of eight regions by chronic mecamylamine treatment. Treatment with both drugs led to increases in [H-3]nicotine binding that were at lea st the sum of the those observed with either drug alone. These increas es were partially reversed 48 hr after cessation of treatment. No sign ificant effects of nicotine or mecamylamine treatment on alpha-[I-125] bungarotoxin binding were observed 5 hr after treatment was stopped wh en assayed using a single ligand concentration. However, saturation an alyses of the cerebral cortex detected small increases from control af ter treatment with nicotine or both drugs. No effects of chronic treat ment on alpha-[I-125]bungarotoxin binding were evident 48 hr after tre atment was stopped. Mice treated with nicotine, mecamylamine or both d rugs tested 5 hr after withdrawal were less sensitive to acute injecti on with nicotine than were saline-infused mice. However, the effects o f mecamylamine may have been influenced by continued presence of this drug at the time of testing. Mice tested 48 hr after cessation of trea tment were more sensitive to nicotine than those tested after 5 hr, bu t some tolerance to the effects of nicotine persisted in the nicotine- treated mice. The results indicate that either chronic nicotine (agoni st) or mecamylamine (antagonist) treatment results in increases in nic otinic receptors measured by high affinity [H-3]nicotine binding, and that the increases observed when both drugs are administered are even greater. Mice treated with nicotine were tolerant to the effects of ni cotine both 5 and 48 hr after withdrawal. However, the ability of chro nic mecamylamine treatment to induce tolerance to nicotine, or block t olerance induced by chronic nicotine, remains unclear.