Pre- and post-nicotine circadian activity episodes are differentially affected by pharmacological treatments for drug addiction

Nicotine and other drugs of abuse can act as zeitgebers and entrain persisting circadian activity episodes when administered on a 24-hour schedule. There are two types of drug-induced circadian activity episodes: a pre-drug anticipatory episode characterized by a rise in activity beginning 1-2 hours prior to the drug administration time that is not linked to any predictive environmental cue, and a post-drug evoked episode that lasts for approximately the duration of the drug's physiological half-life. The present research examined how pharmacological treatments prescribed for nicotine and other substance addictions affected pre- and post-nicotine activity episodes in adult female Sprague-Dawley rats housed in wheel boxes under constant light and rate-limited feeding. For 16 consecutive days, the rats were administered a subcutaneous "zeitgeber" injection of either nicotine or saline on a 24-hour schedule to establish pre- and post-administration activity episodes. The rats were then were administered one of nine treatment conditions in place of the zeitgeber injection for two consecutive days. The treatment conditions were No Treatment, Saline Treatment, Varenicline, Mecamylamine, Acamprosate, Topiramate, Naltrexone, SB-334867, and Bupropion. The treatment phase was followed by a 4-day baseline in which no injections were administered and the rats were not disturbed. The treatment conditions had different effects on pre- and post-drug activity episodes as well as nicotine- and saline-induced episodes. All treatments reduced post-nicotine episodes, whereas post-saline episodes were increased by some treatments and decreased by others. All treatments increased pre-saline activity levels except the No Treatment condition and Mecamylamine (a nicotinic acetylcholine receptor antagonist), which reduced pre-saline activity. In contrast, pre-nicotine episodes were significantly reduced only by the No Treatment condition and by treatment with either the ?- and kappa-opioid antagonist naltrexone or the orexin-1 antagonist SB-334867. These results indicate that distinct neural mechanisms mediate both pre- and post-drug circadian activity episodes as well as nicotine- and saline-induced circadian effects. These results also argue that a number of pharmacological treatments currently prescribed for nicotine addiction may exacerbate pre-nicotine anticipatory episodes, while treatment with naltrexone or SB-334867 may help to alleviate the occurrence of these episodes.