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In order to explore the potential clinical utility of CCK-B antagonists for the treatment of nicotine withdrawal symptoms, the auditory startle reflex was examined in rats undergoing withdrawal from the chronic administration of nicotine. Rats were exposed to nicotine continuously for 12 days (6 mg kg-1 day-1) via osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal for several days. Acute treatment with the CCK-B antagonist LY288513, at doses that have no effect on startle responses in naive rats, blocked the nicotine withdrawal-induced increase in the acoustic startle reflex. These results indicate that CCK-B antagonists may be an efficacious treatment for some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.

In order to explore the neurophysiology of nicotine withdrawal, we examined the activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine cells in rats undergoing withdrawal from chronic exposure to nicotine. Animals were exposed to nicotine (6 mg kg-1 day-1 base) via s.c. implanted osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal. Rats were anesthetized on various days of the procedure and single-unit recordings were made from A9 and A10 dopamine cells. Chronic administration of nicotine led to a decreased firing rate of A10, but not A9, dopamine cells. Upon withdrawal from the chronic exposure to nicotine, the firing rates of A10 dopamine cells returned to control levels, while the firing rate of A9 dopamine cells significantly increased above control levels. This increased dopamine neuronal activity may play a role in some behavioural symptoms of nicotine withdrawal.