Apomorphine blocks form-deprivation myopia in chickens by a dopamine D2-receptor mechanism acting in retina or pigmented epithelium

Abstract

Studies of form-deprivation myopia (FDM) in animal models have shown that postnatal ocular growth is regulated by the quality of patterned images on the retina. One of the major challenges in myopia research is to identify the biochemical mechanisms which translate retinal visual responses into signals that regulate scleral growth. Dopamine (DA) has been implicated in this process, since retinal DA levels decline in FDM and subconjunctival injections of apomorphine (Apo, a nonspecific DA agonist) prevent FDM in a dose-dependent way (Stone et al., 1989). To gain insight into where and how DA ligands act to regulate ocular elongation, we compared the action and distribution of DA receptor ligands injected intravitreally vs.subconjunctivally in young chicks. Ocular length was measured by A-scan ultrasound. We found that daily intravitreal injections of Apo block FDM at a 50% effective dose (ED 50) of 5 pg per day, or a peak concentration in the vitreous humor of 108 pM, compared to an ED 50 of 2.5 ng for subconjunctival injections as reported by Stone et al.(1989, 1990). [3 H]-spiperone, a D 2-receptor antagonist, reached average maximum retinal concentrations of 160 pM and 260 pM, during the first hour after intravitreal and subconjunctival administration, respectively, at the ED 50dose. In contrast, the maximum spiperone concentrations in the retinal pigment epithelium (RPE) were 30 pM and 410 pM, respectively, after intravitreal or subconjunctival ED 50doses. Spiperone concentrations in sclera after ED 50doses to the two sites differed by 4 x 10 4(0.4 pM vs.1.7 nM, respectively). The FDM-preventing action of Apo was blocked completely by simultaneous administration of spiperone but not by SCH 23390 (a D 1-receptor antagonist) in 100-fold molar excess. These results show that apomorphine acts to prevent FDM at an intraocular site, presumably in retina and/or pigment epithelium, but not sclera, whether administered intravitreally or subconjunctivally. A dose yielding a concentration of 100–260 pM, delivered ≤1 h per day, produces half-maximal inhibition. This action is mediated by D 2-receptors, for which the dissociation constant for apomorphine is ≤1 nM. The retinal pigment epithelium may act as a trophic relay station, responding to a retinal messenger which may be DA and secreting scleral growth-regulator(s) from its basal surface.