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.