Acute ethanol impairs photic and nonphotic circadian phase resetting in the Syrian hamster

Abstract

Disrupted circadian rhythmicity is associated with ethanol (EtOH) abuse, yet little is known about how EtOH affects the mammalian circadian clock of the suprachiasmatic nucleus (SCN). Clock timing is regulated by photic and nonphotic inputs to the SCN involving glutamate release from the retinohypothalamic tract and serotonin (5-HT) from the midbrain raphe, respectively. Our recent in vitro studies in the SCN slice revealed that EtOH blocks photic phase-resetting action of glutamate and enhances the nonphotic phase-resetting action of the 5-HT1A,7 agonist, 8-OH-DPAT. To explore the basis of these effects in the whole animal, we used microdialysis to characterize the pharmacokinetics of intraperitoneal injection of EtOH in the hamster SCN extracellular fluid compartment and then studied the effects of such EtOH treatment on photic and serotonergic phase resetting of the circadian locomotor activity rhythm. Peak EtOH levels (approximately 50 mM) from a 2 g/kg injection occurred within 20-40 min with a half-life of approximately 3 h. EtOH treatment dose-dependently attenuated photic phase advances but had no effect on phase delays and, contrary to in vitro findings, markedly attenuated 8-OH-DPAT-induced phase advances. In a complementary experiment using reverse microdialysis to deliver a timed SCN perfusion of EtOH during a phase-advancing light pulse, the phase advances were blocked, similar to systemic EtOH treatment. These results are evidence that acute EtOH significantly affects photic and nonphotic phase-resetting responses critical to circadian clock regulation. Notably, EtOH inhibition of photic signaling is manifest through direct action in the SCN. Such actions could underlie the disruption of circadian rhythmicity associated with alcohol abuse.

Chronic ethanol attenuates circadian photic phase resetting and alters nocturnal activity patterns in the hamster

“…The clock depends upon photic input for synchrony with the external environment, and this signaling pathway represents a potentially vulnerable target for the disruptive chronobiological effects of alcohol abuse. Evidence supporting this idea comes from recent studies in hamsters and mice in which acute EtOH was shown to act directly in the SCN to strongly inhibit photic phase-resetting responses (48,55). Here, we extend this work to show that chronic EtOH consumption can disrupt phaseadvance shifting in hamsters presented with photic stimuli late in the dark phase, when levels of EtOH measured in the SCN are relatively low.…”

“…Glutamatergic activation of SCN N-methyl-D-aspartate (NMDA) receptors is essential for light-induced phase shifting to occur (1,10,38,39). In recent reports, we showed that acute EtOH can block such glutamate-induced phase shifts in the SCN in vitro (48) and impair photic phase shifts in vivo (55). These results are consistent with reports that EtOH decreases glutamate release (41,44) and inhibits NMDA-evoked ion currents (35).…”

“…This could have been insufficient to overcome a strong phase-resetting signal produced by bright light, but adequate to inhibit a weaker signal produced by the 25-lux exposure. The 5-mM concentration is considerably below the 50-mM EtOH concentration present in the SCN after an acute intraperitoneal 2.0 mg/kg EtOH injection, which blocked phase-advance shifts produced by a 270-lux pulse (55). Moreover, in the mouse SCN slice, the dose required to block glutamatergic (photic-like) phase-advances was 20 -50 mM (48).…”

“…5. An EtOHonly control group was not included, as EtOH itself has no phase-resetting action (55,58).…”

Acamprosate-responsive brain sites for suppression of ethanol intake and preference

“…The circadian phase of alcohol intake could be regulated by signaling from the SCN to the VTA (37) and/or by clock gene activity within the reward areas (47,63). In view of findings that 1) the SCN clock is directly disrupted by ethanol (4,5,45,49,50) and 2) the SCN and IGL possess transmitter systems sensitive to acamprosate, including ACh, glutamate, and glycine (29,41,58), these circadian regulatory areas represent potential substrates for acamprosate's modulation of ethanol intake. Results from the present study bear out this hypothesis, as acamprosate implants targeted to the SCN and IGL inhibited ethanol intake in WT mice to a similar degree as acamprosate implants in the VTA and PPT.…”