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 (ED50) of 5 pg per day, or a peak concentration in the vitreous humor of 108 pM, compared to an ED50 of 2.5 ng for subconjunctival injections as reported by Stone et al. (1989, 1990). [3H]-spiperone, a D2-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 ED50 dose. In contrast, the maximum spiperone concentrations in the retinal pigment epithelium (RPE) were 30 pM and 410 pM, respectively, after intravitreal or subconjunctival ED50 doses. Spiperone concentrations in sclera after ED50 doses to the two sites differed by 4 x 104 (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 D1-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 D2-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.

Dopamine D1 Receptors Contribute Critically to the Apomorphine-Induced Inhibition of Form-Deprivation Myopia in Mice

“…Consistent with the findings that retinal dopamine was reduced during the development of FDM in most of the species studied, local administration of dopamine, levodopa (a dopamine precursor), or the nonselective dopamine agonist apomorphine (APO) can inhibit FDM development in animal models, including chickens, 6,17,18 rabbits, 19 monkeys, 20 and guinea pigs. 8,21 Although the stability of retinal dopamine during FDM development in mice is different from the decreased levels in other species, [12][13][14] daily systemic APO injection in mice nevertheless offers protection against FDM development by at least 75%, in agreement with other species.…”

“…Based on previous results of combined pharmacologic intervention, D2R activation may have a major role in the APO-mediated inhibition of axial eye growth. 6,17 The inhibitory effect of APO on FDM in chickens was abolished by coadministration of the dopamine antagonist haloperidol, which shows somewhat greater affinity for D2Rs compared with D1Rs. 6 Furthermore, Rohrer et al 17 showed that in chickens the APO-induced protection against FDM was almost completely abolished by the D2R antagonist spiperone but not by the D1R antagonist SCH 23390.…”

Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation

“…It is thought that the central RPE becomes senescent due to hyperplastic senile changes first proposed by Duke-Elder and Perkins (87), whereas the peripheral RPE retains repair capacity due to its competency to reenter the cell cycle (70). Although the molecular bases for the proliferative capacity of peripheral RPE are unresolved, they may arise from emmetropization, a coordinated process of development and growth of various tissues of the eye by mechanisms not yet elucidated (70,88). Interestingly, a recent study showed that down-regulation of Ran GTPase promotes cellular senescence possibly by decreasing competency of nucleocytoplasmic transport driven by Ran GTPase (89 ::RPE-cre::Ranbp2 Ϫ/Ϫ , whereas the secondary effects on deficits of the dark-adapted ERG of rod photoreceptors appeared first in this transgenic line.…”

Myopia, Light and Circadian Rhythms

“…For example, in form-deprivation in chicks, the protective effects of the non-specific dopaminergic agonist apomorphine were blocked by the D 2 specific antagonist spiperone, but not by the D 1 specific antagonist SCH-23390 (Rohrer, Spira et al 1993). …”

“…T h e r o l e o f d o p a m i n e i n t h e c o n t r o l o f o c u l a r g r o w t h i s f u r t h e r s u p p o r t e d b y t h e demonstration that ocular administration of dopamine agonists can inhibit the axial growth and myopic refractions produced by form-deprivation in chicks (Rohrer, Spira et al 1993;Nickla, Totonelly et al 2010) and primates (Iuvone, Tigges et al 1991). Also, extraocular administration of the dopamine precursor levodopa by intraperitoneal injection in guinea pigs raises retinal dopamine content and reduces the development of myopia during formdeprivation (Mao, Liu et al 2010).…”