Decreased Sensitivity to Light of the Photic Entrainment Pathway during Chronic Clorgyline and Lithium Treatments

Abstract

Certain antidepressant drugs (ADs) cause disturbances in sleep that could result from their capacity to alter the timing of circadian rhythms. Effects on the timing of rhythms could be due to the drugs' known capacity to alter the frequency of the intrinsic rhythm of the circadian pacemaker, or to a capacity to modify the pacemaker's response to external stimuli that serve as time cues (Zeitgebers) that regulate the timing (phase) of its rhythm. To examine the possibility that ADs alter the sensitivity of the system that mediates the phase-shifting effects of light, hamsters were treated chronically with the MAOI, clorgyline, and lithium. Each hamster was then exposed to a single 5-min light pulse (intensity range = 0.00137 to 137 microW/cm2) at circadian phases known to elicit phase advances (CT18) and phase delays (CT13.5) in the daily onset of wheel running. The half-saturation constant (sigma), photic sensitivity (1/sigma), and maximum phase-shifting response to light were estimated from the best-fit stimulus response curves. In addition, threshold sensitivity, the light intensity required to produce a threshold phase-shifting response, was determined. Clorgyline decreased the magnitude of light-induced phase advances at each of the light intensities tested. Clorgyline also decreased the magnitude of light-induced phase delays at low light intensities, but increased the magnitude of phase delays at higher light intensities. Clorgyline decreased the sensitivity of the photic phase-shifting system, as indicated both by the threshold sensitivities at CT13.5 and CT18, and by 1/sigma at CT13.5. Lithium decreased the threshold sensitivity at CT18, and 1/sigma at CT13.5. Lithium decreased the magnitude of phase delays, but not phase advances. Clorgyline's effects on the photic entrainment pathway may be mediated by its effects on serotonin, which has been shown to modulate the pacemaker's response to morning and evening light, and by tolerance to this effect of serotonin. The fact that both clorgyline and lithium decrease the photic sensitivity of the entrainment pathway suggests that other psychoactive drugs might also share this property. It is possible that the decreased sensitivity to light of the entrainment pathway affects the clinical response to these and other psychoactive medications.

Chronic Ethanol Intake Alters Circadian Phase Shifting and Free-Running Period in Mice

“…Similar attenuation of photic phase shifting has also been reported for other sedative-anxiolytic drugs (Duncan et al, 1998; Dwyer and Rosenwasser, 1998; Subramanian and Subbaraj, 1996). Nevertheless, mice and hamsters apparently differ in the circadian phase dependence of such effects.…”

“…The present results are consistent with previous studies showing that both chronic (Seggio et al, 2007) and acute (Ruby et al, 2009) ethanol exposure attenuates photic phase shifting in Syrian hamsters. Similar attenuation of photic phase shifting has also been reported for other sedative-anxiolytic drugs (Duncan et al, 1998;Dwyer and Rosenwasser, 1998;Subramanian and Subbaraj, 1996). Nevertheless, mice and hamsters apparently differ in the circadian phase dependence of such effects.…”

“…Thus, whereas Mistlberger and Nadeau (1992) originally reported period lengthening during voluntary ethanol intake in hamsters, our laboratory observed period shortening during voluntary ethanol intake in Wistar rats (Dwyer and Rosenwasser, 1998) and both lengthening and shortening of the free-running period in Long-Evans rats during forced ethanol intake (Rosenwasser et al, 2005a). Taken together, the results of these studies resemble the inconsistent effects on the free-running period seen during treatment with other anxiolytic and antidepressant drugs (Duncan et al, 1998;Rosenwasser, 1996;Subramanian and Subbaraj, 1996;Wollnik, 1992).…”

A New Concept for Melatonin Deficit On Pineal Calcification and Melatonin Excretion

“…There is overwhelming evidence that melatonin exerts its chronobiotic effects via the SCN (Cassone et al 1986). On the other hand, there are many hints pointing to the assumption that the SCN`s sensitivity for light and melatonin varies with time (Thompson et al 1990;Owen and Arendt 1992;Dubocovich et al 1996) as well as under the influence of various modulators (Medanic and Gillette 1992;Rea et al 1994;Duncan et al 1998). It also varies between states (McIntyre et al 1990), but moreover between individuals (Lewy et al 1985;McArthur et al 1996).…”

Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

“…We used 40-250 adult flies (typically 1-to 3-day-old males) per experimental condition and obtained similar results across experimental replicates (aggregate results are reported). Although there is some evidence that lithium may regulate light sensitivity (Seggie et al, 1989;Duncan et al, 1998), our initial focus was the analysis of its effect on the free-running clock (ie DD conditions). We observed that lithium induced a significant increase in the period of the free-running locomotor rhythms of the fly.…”