The subtype of dopamine receptor mediating the suppressive effect of light on melatonin biosynthesis in chick retina was characterized pharmacologically. Acute exposure of animals to light during the dark phase of the light-dark cycle dramatically decreased melatonin levels and activity of serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthetic pathway). Various antagonists of dopamine receptors were tested for their ability to block this action of light on the retinal melatonin formation. Intraocular (i. oc.) pretreatment of chicks with neuroleptic drugs--blockers of the D2-family of dopamine receptors, i.e., clotiapine, clozapine (an atypical neuroleptic with high affinity for a D4-subtype dopamine receptor), haloperidol, spiroperidol, sulpiride, and YM-09151-2, significantly antagonized the light-evoked suppression of the nighttime NAT activity of the chick retina in a dose-dependent manner. In contrast, remoxipride (a D2-selective dopamine antagonist), raclopride and (+)-UH-232 (D2/D3-dopamine receptor antagonists), as well as SCH 23390, a blocker of the D1-family of dopamine receptors, were ineffective. Clozapine, haloperidol, spiroperidol and sulpiride also potently antagonized the suppressive action of light on melatonin content of the chick retina. It is suggested that the dopamine receptor mediating the inhibitory effect of light stimulation on the nighttime melatonin biosynthesis in the retina of chick represents a D4-like subtype.

Dopamine plays an important role in regulation of melatonin biosynthesis in retinas of several vertebrate species. In the avian retina, the dopamine receptor that controls melatonin production represents a D4-like subtype. Stimulation of this receptor by quinpirole (QNP) results in a dose-dependent decline of the nighttime activity of serotonin N-acetyltransferase (NAT, a key regulatory enzyme in melatonin biosynthesis) and melatonin level of the retina. The present study was undertaken to determine whether the ability of QNP to suppress nocturnal NAT activity of chick retina was affected by prolonged adaptation of animals to light and darkness. In the retina of chicks kept under a light:dark (LD) illumination cycle, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels measured at the end of the light phase were significantly higher than those found in the middle of the dark phase. In animals maintained under continuous light (LL) or darkness (DD) dopamine and DOPAC contents of the retina measured at these two time points were similar and resembled levels found during, respectively, the light and dark phase in the retina of chicks kept under LD illumination cycle. Adaptation of chicks to LL and DD resulted in an attenuated and enhanced, respectively, response of the retinal NAT activity to the suppressive action of QNP. When compared to the LD group, a parallel shift to the right (LL group) or left (DD group) of the dose-response curve for QNP was observed, and the ED50 values for this dopamine receptor agonist were 3.4-times higher (LL) or 2.8-lower (DD) than those calculated for the control LD animals. It is suggested that prolonged exposure to light or darkness, by altering the level of the retinal dopaminergic neurotransmission, may modify the reactivity of the D4-like dopamine receptors regulating NAT activity of the chick retina.

Stimulation of a D4-like dopamine (DA) receptors inhibits a cAMP-dependent increase in serotonin N-acetyltransferase activity and melatonin biosynthesis in the chick retina. In order to gain more insight into the molecular mechanisms underlying this suppressive action of DA, the effects of selective stimulation of the D2-family of DA receptors (including the D4-subtype) on cAMP formation were examined in chick retina using two experimental approaches: measurements of adenylyl cyclase activity in retinal homogenates, and cAMP accumulation in eye cup preparation prelabeled with [3H]adenine. The DA-sensitive adenylyl cyclase system is well expressed in chick retina. DA increased both basal and forskolin-stimulated adenylyl cyclase activity. This effect of DA was antagonized by SCH 23390 (a blocker of D1-family of DA receptors) and not affected by sulpiride (a D20-family blocker). Incubation of retinal homogenates with quinpirole (a predominant agonist of D3/D4 DA receptor subtypes) did not produce any major changes in adenylyl cyclase activity. On the other hand, activation of D4-like DA receptor subtype by quinpirole decreased forskolin-stimulated cAMP formation in intact chick retina maintained in "eye-cup" preparations. It is suggested that D4-like DA receptors regulating melatonin biosynthesis in chick retina may be indirectly linked to the cAMP generating system.

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Dopamine (DA) plays an important role in the regulation of melatonin biosynthesis in retinas of several vertebrate species. In the retina of chick, the DA receptor controlling melatonin production represents a D4-like subtype. Stimulation of this receptor by quinpirole (QNP) results in a dose-dependent decline of the nighttime activity of serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthesis) and melatonin level of chick retina. The present study was undertaken to determine whether long-term treatment with antipsychotic drugs (clozapine-30 mg/kg, i.m.; sulpiride-100 mg/kg, i.m.; and raclopride-10 mg/kg, i.p., once daily for 21 days) and L-DOPA (80 mg/kg, i.p., once daily for 7 days) affects the response of the melatonin generating system of chick retina to the suppressive effect of QNP. Chronic administration to chicks of clozapine and sulpiride, but not raclopride, resulted in a markedly increased response of retinal NAT activity to the action of QNP. ED50 values for QNP were 3-times (clozapine) and 4-times (sulpiride) lower than those in the respective vehicle-treated control groups. On the other hand, QNP was significantly less potent in retinas of birds treated with L-DOPA than in control animals; the ED50 value for QNP was 3-times higher in birds injected with L-DOPA than in the vehicle-treated group. These results indicate that long-term treatment with clozapine, sulpiride and L-DOPA may modify the reactivity of D4-like DA receptors regulating NAT activity of chick retina. A possibility of modifications of circadian and electrophysiological processes within the eye following prolonged administration of DA-ergic drugs is discussed.