Clozapine and other neuroleptic drugs antagonize the light-evoked suppression of melatonin biosynthesis in chick retina: involvement of the D4-like dopamine receptor

Abstract

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.

Pharmacological modifications in dopaminergic neurotransmission affect the quinpirole-evoked suppression of serotonin N-acetyltransferase activity in chick retina: an impact on dopamine D4-like receptors

“…Analysis of the dose-response curves for QNP revealed that in retinas of animals treated with these drugs the Dg-like DA receptors regulating NAT activity may become supersensitive. On the other hand, raclopride, a Dz/D3-DA receptor antagonist with very low affinity for the D 4 receptor (Lahti et al, 1993;Zawilska and Nowak, 1994a;Zawilska et al, 1994), given chronically to chicks failed to modify the sensitivity of the studied D4-DA receptors. Up-regulation of DA receptors controlling NAT activity of chick retina has been previously reported for tissues in which lesions of neuronal cells produced by kainic acid resulted, among other phenomena, in a dramatic decline in the retinal DA neurotransmission (Zawilska and Iuvone, 1992).…”

“…Data are expressed as means _+ SEM (for the number of tissue samples given in parenthesis) Quinpirole (/zg/kg, i.p. ) In experimental animals long-term administration of antipsychotic drugs is well known to lead to up-regulation of brain DA receptors of the D2 subclass, whereas chronic therapy with DA agonists results in down-regulation of these receptors (reviewed in Seeman, 1980 (Cohen et al, 1992;O'Malley et al, 1992;Matsumoto et al, 1995), and the demonstration of physiological functions of the D4-DA receptor in fish and avian retina (Zawilska and Nowak, 1994a,b;Zawilska et al, 1994;Hillman et al, 1995;Zawilska and Derbiszewska, 1995) suggest that the retina may provide a useful model with which to study the D4-DA receptor subtype. In the present study we have extended the analysis of the D4-1ike DA receptor regulating melatonin biosynthesis in chick retina by examining adaptive changes in its sensitivity after the prolonged pharmacological modification in the retinal DA-ergic transmission.…”

“…In the present study we have extended the analysis of the D4-1ike DA receptor regulating melatonin biosynthesis in chick retina by examining adaptive changes in its sensitivity after the prolonged pharmacological modification in the retinal DA-ergic transmission. Chronic treatment of chicks with sulpiride and clozapine, two antipsychotic drugs which have been previously shown to effectively block the D4-1ike DA receptors regulating melatonin biosynthesis in the retina (Zawilska and Nowak, 1994a,b;Zawilska et al, 1994), resulted in a significant enhancement in responsiveness of these receptors to the stimulatory action of quinpirole (QNP). Analysis of the dose-response curves for QNP revealed that in retinas of animals treated with these drugs the Dg-like DA receptors regulating NAT activity may become supersensitive.…”

“…Recently we have demonstrated that DA receptors that regulate, in an inhibitory manner, the activity of serotonin N-acetyltransferase (NAT; a penultimate and crucial regulatory enzyme in melatonin biosynthesis) and melatonin content of chick retina represent a D4-1ike subtype (Zawilska and Nowak, 1994a,b;Zawilska et al, 1994). The present study was undertaken to examine whether a long-term alteration in DA-ergic transmission can modify the response of these receptors to the action of an agonist -quinpirole (QNP).…”

Clotiapine in schizophrenia: a guide to its use

“…Like clozapine, clotiapine blocks 5HT 3 receptors, downregulates cortical 5HT 2 receptors, has high affinity for the 5HT 6 and 5HT 7 receptors, shows relatively weak affinity for the dopamine D 2 receptor and relatively high affinity for D 1 and D 4 receptors, and selectively blocks a subset of GABA A receptors [20,[23][24][25][26][27][28][29]. The order of affinity for CNS receptor types is 5HT 2 …”