REGULATION OF MELATONIN AND DOPAMINE BIOSYNTHESIS IN CHICK RETINA - THE ROLE OF GABA

Melatonin biosynthesis in chick retina occurs as a circadian rhythm. B iosynthesis of the neurohormone is highest at night in darkness, and i s suppressed by light. The role of gamma-aminobutyric acid (GABA) in t he nocturnal regulation of melatonin synthesis was examined. Systemic or intravitreal administration of muscimol, a GABA-A receptor agonist, to light-exposed chicks at the beginning of the dark phase of the lig ht/dark cycle increased retinal melatonin levels and the activity of s erotonin N-acetyltransferase (NAT), a key regulatory enzyme of the mel atonin biosynthetic pathway. Baclofen, a GABA-B receptor agonist, also increased NAT activity of light-exposed retinas, but muscimol was app roximately 40-fold more potent than baclofen. Effects of both muscimol and baclofen on NAT activity were inhibited by GABA-A antagonists, bi cuculline and picrotoxin, and the effect of baclofen was unaffected by the GABA-B selective antagonist, CGP 35348. Thus, activation of GABA- A receptors appears to be associated with increased melatonin biosynth esis. The GABA-uptake inhibitor, nipecotic acid, and the GABA-transami nase inhibitor, aminooxyacetic acid, also increased NAT activity of li ght-exposed retinas. The high levels of NAT activity associated with e xposure to darkness were unaffected by either muscimol or baclofen, bu t picrotoxin and bicuculline significantly inhibited retinal NAT activ ity in darkness. The rate of dopamine synthesis, estimated from in sit u tyrosine hydroxylase activity, was higher in light-exposed retinas t han in darkness. Muscimol inhibited dopamine synthesis in light, and p icrotoxin stimulated dopamine synthesis in darkness. The stimulation o f melatonin synthesis by muscimol in light-exposed retinas appears to be related to inhibition of retinal dopamine neurons. The increase of NAT activity elicited by muscimol in light-exposed retinas was inhibit ed by administration of the dopamine receptor agonists apomorphine and quinpirole. Blocking dopamine receptors with spiperone or inhibiting dopamine biosynthesis with alpha-methyl-p-tyrosine also increased NAT activity in light, and the effects of the dopamine antagonists and mus cimol were not additive. The decrease of NAT activity elicited by GABA antagonists in darkness was inhibited by spiperone. Thus, GABA may in directly regulate retinal melatonin biosynthesis, by inhibiting dopami nergic activity in retina.