If a rat is given a single daily meal, over time it develops a pattern of locomotor activity that anticipates the meal, even under conditions that provide no time cues. This anticipatory activity has been attributed to a meal-entrained circadian rhythm. Administration of some abused drugs has been shown to have entraining effects that resemble those of meals. For example, rats given injections of methamphetamine (MA) every 24 h also develop increased locomotor activity 1-3 hr before injections, even under conditions that provide no time cues. Rats provided with meals, or given MA or cocaine injections on a schedule beyond the typical range of circadian entrainment (S31 h), do not develop anticipatory activity, but do show a transient increase in locomotion that follows the meal or drug injection by 24-28 h. Meals also entrain a number of physiological rhythms, including release of corticosterone, enzyme activity in the intestines, pancreas and liver, mitotic activity in the intestinal epithelium, and insulin release. Together, these changes function to promote and prepare for the results of feeding behavior. The purpose of this research is to determine if drug-related circadian rhythms play a similar role in drug taking. Research on this topic is important because drug-entrained circadian rhythms could prime and prepare organisms for daily episodes of drug taking, enhancing search behavior, intake, and tolerance. Such rhythms could also contribute to drug-motivation and relapse in an abstinent person otherwise actively avoiding priming cues such as people, places or objects associated with past drug use. If this is the case, treatment strategies that consider circadian effects in designing pharmacological and behavioral interventions should have improved success. In the experiments proposed here, the potential role of drug-related circadian rhythms in drug abuse will be explored in three aims.
Aim1 tests the hypothesis that circadian entrainment is typical of and limited to drugs of abuse, by screening 4 abused drugs (methamphetamine, fentanyl, nicotine and ethanol) and 2 control drugs (haloperidol, p-hydroxyamphetamine) for their ability to entrain locomotor activity.
Aim 2 addresses whether circadian anticipatory activity is related to drug seeking and intake.
Aim 3 tests whether drug intake and reinforcement are increased when drugs are available on a circadian schedule, compared to a non-circadian schedule. Taken together, these experiments will establish whether circadian entrainment is a common property of abused drugs, and its importance in the regulation of drug-seeking and taking. ? ?
| Gillman, Andrea G; Kosobud, Ann E K; Timberlake, William (2010) Effects of multiple daily nicotine administrations on pre- and post-nicotine circadian activity episodes in rats. Behav Neurosci 124:520-31 |
| Gillman, Andrea G; Leffel 2nd, Joseph K; Kosobud, Ann E K et al. (2009) Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-h intervals. Behav Brain Res 205:102-14 |
| Gillman, Andrea G; Kosobud, Ann E K; Timberlake, William (2008) Pre- and post-nicotine circadian activity rhythms can be differentiated by a paired environmental cue. Physiol Behav 93:337-50 |
