Histamine H(1) antagonist treatment with pyrilamine reduces nicotine self-administration in rats.

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT(2) and histamine H(1) receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT(2) antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H(1) receptor interaction with nicotine self-administration. Young adult female Sprague-Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of pyrilamine, a histamine H(1) antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20mg/kg) or chronic infusion via osmotic minipumps (50mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H(1) antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H(1) receptor blockade as key for the effectiveness of pyrilamine. H(1) antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.

IV nicotine self-administration in rats using the consummatory operant licking response.

Nicotine self-administered by tobacco smoking or chewing is very addictive in humans. Rat models have been developed in which nicotine is self-administered IV by the rats pressing a lever. However the reinforcing value of nicotine is much less in these models than the addictiveness of human tobacco use would indicate. The IV nicotine self-administration operant lever press model does not fully capture important aspects of tobacco use in humans. Conditioned oral consumption actions of smoking or chewing tobacco may play important roles in tobacco addiction. Neural circuitry underlying essential food consummatory responses may facilitate consummatory aspects of tobacco intake. To capture this motor consummatory aspect of tobacco addiction in the rat model of nicotine self-administration, we have developed a method of using a licking response instead of a lever press to self-administer IV nicotine. Sprague-Dawley rats were trained to lick one of two waterspouts for IV nicotine (0.03mg/kg/infusion). With the licking response rats self-administered stable nicotine levels throughout 24 sessions (45min each) of testing. The number of total licks/session significantly increased in a linear fashion over that period. The number of licks/infusion was substantial, rising steadily with training to an average of over 100 licks/infusion. Including the consummatory motor act with nicotine self-administration could help better model the compulsive aspects of tobacco addiction in humans.

Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats.

Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha4beta2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha4beta2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.