Differential Responses of Circadian Activity Onset and Offset Following GABA-ergic and Opioid Receptor Activation

Abstract

The circadian pacemaker in the mammalian suprachiasmatic nuclei is responsive to photic and nonphotic stimuli. In the present study, the authors have investigated the response of activity onset and offset to application of nonphotic stimuli: the benzodiazepine midazolam and the opioid receptor agonist fentanyl. In correspondence with previous studies, both stimuli induced phase advances of the activity onset when given in the mid- to late subjective day. In contrast, activity offset did not phase advance following these injections. Injections during the early subjective day induced small phase delays of the activity onset, while large phase delays occurred in activity offset. Phase shifts, induced at both circadian time zones, were paralleled by an increase in the length of daily activity (alpha). The increase in a remained present during several days after the injection. The different kinetics in phase shifting of the activity onset and offset indicate complexity in phase-shifting behavior of the circadian pacemaker in response to nonphotic stimuli. Moreover, the data show responsiveness of the circadian system to GABA-ergic and opioid receptor activation, not only during the mid- to late subjective day but also during the early subjective day. The data implicate that the early subjective day is an interesting phase for analysis of molecular and biochemical processes involved in nonphotic phase shifting.

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

“…A role for GABA-active drugs in non-photic phase shifts was first suggested by the finding that systemic injection of short acting BDZs (i.e., triazolam, midazolam, brotizolam) as well as the GABA A agonist muscimol produced phase shifts similar to those resulting from injection of NPY-like neuropeptides into the SCN (Turek and Losee-Olsen, 1986; Wee and Turek, 1989; Yokota et al, 2000; Ebihara et al, 1988; Vansteensel et al, 2003a). Interestingly, the induction of phase shifts by triazolam also results from its ability to induce locomotor activity.…”

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

“…Like other opiates, fentanyl interacts with μ opioid receptors, acutely activates the mesolimbic dopamine system, and produces a robust activation of locomotor activity [26, 28]. Chronobiological studies in hamsters have revealed that fentanyl also modifies the ability of the SCN to react to photic stimuli and can induce behavioral phase shifts in the rest-activity cycle when administered during the subjective day [76, 77]. …”

The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei

“…midazolam), neuropeptide Y (NPY), opioids (e.g. fentanyl) and serotonin (5‐HT) agonists (Albers & Ferris, 1984; Mrosovsky, 1988, 1996; Wee & Turek, 1989; Tominaga et al ., 1992; Marchant & Mistlberger, 1995; Meijer et al ., 2000; Vansteensel et al ., 2003). Several nonphotic stimuli have been reported to result in suppression of Per1 and Per2 expression, which has led to the proposition that these genes play an important role in phase resetting also during the day (Horikawa et al ., 2000; Yokota et al ., 2000; Fukuhara et al ., 2001; Maywood & Mrosovsky, 2001; Maywood et al ., 2002).…”