Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-h intervals

Abstract

Administration of several drugs of abuse on a 24-hour schedule has been shown to entrain both predrug (anticipatory) and post-drug (evoked) circadian activity episodes that persist for several days when the drug is withheld. The present tested the entrainment effects of fentanyl, an opioid agonist with a noted abuse liability, and haloperidol, an antipsychotic dopamine antagonist without apparent abuse liability. Adult female Sprague-Dawley rats housed under constant light in cages with attached running wheels received repeated low, medium, or high doses of either fentanyl or haloperidol on a 24-hour administration schedule followed by a 31-hour schedule (Experiment 1) or solely on a 31-hour schedule (Experiment 2). The results showed that all three doses of fentanyl entrained both predrug and post-drug episodes of wheel running when administered every 24░hours, and the combined pre-and post-fentanyl activity episodes persist for at least 3 days when the drug is withheld during test days. On the 31-hour schedule, fentanyl produced an ``ensuing" activity episode approximately 24░hours post-administration, but failed to produce an anticipatory episode 29-31░hours postadministration. In contrast, haloperidol injections failed to produce both pre-drug episodes on the 24-hour schedule and circadian ensuing episodes on the 31-hour schedule, and post-haloperidol suppression of activity appeared to mask the freerunning activity rhythm. Taken together, these results provide additional evidence that drugs of abuse share a common ability to entrain circadian activity episodes.

Haloperidol alters circadian clock gene product expression in the mouse brain

“…The results of Honma and Honma ' s study (1995) of SCN lesioned rats showing that haloperidol can alter behavioural circadian rhythms mediated outside of the SCN is in broad agreement with our results, indicting that haloperidol elicits circadian effects by, in part at least, acting outside of the SCN. Further, the lack of effect on SCN clock gene product expression is in line with the observation that halopediol does not entrain rat behavioural circadian rhythms (Gillman et al 2009). Other factors, such as the time between treatment and sampling for acutely treated animals (e.g., is 6 h suffi cient time to see alterations in levels of PER1 protein?…”

Naloxone’s Effect on Activity-Induced Phase Shifts of Circadian Rhythms

“…The study looking at fentanyl-induced phase advances (Vansteensel et al, 2005) did not report activity levels of the animals, but the actograms shown in that report do not appear to show increased activity in the mid subjective day acutely linked to the injection. Nevertheless, fentanyl is known to increase activity levels for 2-3 hr after injection, at least in rats (Gillman et al, 2009).…”

Effects of multiple daily nicotine administrations on pre- and post-nicotine circadian activity episodes in rats.

“…Drug users generally administer a drug on a daily basis for an extended period of time before they develop substance dependence (American Psychiatric Association, 2000). In recent years, considerable evidence has emerged that long-term administration of drugs of abuse engages the endogenous circadian systems that control the timing of daily behavioral and physiological events (Abarca, Albrecht, & Spanagel, 2002; Gillman, Kosobud, & Timberlake, 2008; Gillman, Leffel, Kosobud, & Timberlake, 2009; Kosobud et al, 2007; Kosobud, Pecoraro, Rebec, & Timberlake, 1998; McClung et al, 2005; Pecoraro, Kosobud, Rebec, & Timberlake, 2000; Spanagel et al, 2005; White, Feldon, Heidbreder, & White, 2000). Drug effects on these circadian timing systems likely contribute to the development and maintenance of drug-taking behaviors and drug-induced neural plasticity as well as the expression of withdrawal symptoms and craving.…”

“…Long-term daily intraperitoneal or subcutaneous administration of nicotine (Gillman et al, 2008), fentanyl (Gillman et al, 2009), methamphetamine (Kosobud et al, 1998), and cocaine (White et al, 2000) has been shown to induce two distinct circadian episodes of activity that are independent of the free-running SCN-driven rest-activity cycle. The first episode is known as the pre-drug (PRE) episode and emerges 1–2 hours prior to the daily administration time in the absence of any predictive environmental cues.…”

“…The post-drug episode appears to reflect a combination of both the acute locomotor effects of the drug as well as a circadian-synchronized effect that may initiate physiological compensatory mechanisms to counteract the acute effects of the drugs or may simply serve to initiate the timing of the pre-drug episode. Both the pre- and the post-drug episodes persist (i.e., continue to be expressed) for two or more days when the drug is withheld (Gillman et al, 2008; Gillman et al, 2009; Kosobud et al, 2007; Kosobud et al, 1998; White et al, 2000), providing compelling evidence that the episodes are entrained to the daily drug administration time. Together, these results indicate that administration of nicotine and other drugs of abuse creates drug-oriented circadian activity episodes that could contribute both to the evoked effects of the drugs and to the timing of drug-seeking and drug-use behaviors.…”