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Inhibition of GABA Transaminase Enhances Light-Induced Circadian Phase Delays but Not Advances

Department of Psychology, University of Toronto, 100 St. George Street, Toronto, Ontario M5S 1A1, Canada

Martin R. Ralph

Department of Psychology, University of Toronto, 100 St. George Street, Toronto, Ontario M5S 1A1, Canada

The CNS neurotransmitter GABA is distributed extensively throughout the suprachiasmatic nucleus, the site of circadian pacemaker cells in mammals. Pharmacological agents that act at GABA_A receptors alter specific circadian responses to light and may induce phase shifts of circadian rhythms. In the present study, the role of endogenously released GABA in rhythm regulation was investigated using vigabatrin (-vinyl GABA), an agent that has been shown to increase chronically or acutely the CNS levels of this neurotransmitter by inhibiting GABA transaminase. In Experiment 1, hamsters in constant darkness (DD) received a saline or a vigabatrin injection 1 hr before a 15-min, 700-lux light pulse. Vigabatrin increased photic phase delays but did not affect advances. In Experiment 2, vigabatrin delivered chronically via osmotic minipump treatment did not affect locomotor activity period in DD. However, after 14 days of infusion, photic phase delays (but not advances) were greatly increased in the vigabatrin group. In Experiment 3, in constant light (LL), chronic vigabatrin-treated animals showed an increased period that returned to pretreatment values after the 14-day drug infusion.

The results are consistent with the phase-dependent effects of other agents that alter GABA neurotransmission. The data support the general hypothesis that GABA modulates the circadian responses to light in a phase-dependent manner, and may participate in entrainment to light-dark cycles by influencing the relative responsiveness to light in the early and late subjective night.

Key Words: GABA • -aminobutyric acid • -vinyl GABA • vigabatrin • circadian rhythms • suprachiasmatic nucleus • phase shift • entrainment

Journal of Biological Rhythms, Vol. 9, No. 3-4, 251-261 (1994)
DOI: 10.1177/074873049400900306


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