Dopamine Release In Retina Research Articles

Studies on the interactions of retinal dopamine with choroidal thickness in the chicken

PurposeRecently, an increasing number of studies relied on the assumption that visually induced changes in choroidal thickness can serve as a proxy to predict future axial eye growth. The retinal signals controlling choroidal thickness are, however, not well defined. We have studied the potential roles of dopamine, released from the retina, in the choroidal response in the chicken.MethodsChanges in retinal dopamine release and choroidal thickness changes were induced by intravitreal injections of either atropine (250 µg or 360 nMol), atropine combined with a dopamine antagonist, spiperone (500 µMol), or spiperone alone and were tracked by optical coherence tomography (OCT). To visually stimulate dopamine release, other chicks were exposed to flicker light of 1, 10, or 400 Hz (duty cycle 0.2) and choroidal thickness was tracked. In all experiments, dopamine and 3,4-Dihydroxyphenylacetic acid (DOPAC) were measured in vitreous, retina, and choroid by high-performance liquid chromatography with electrochemical detection (HLPC-ED). The distribution of the rate-limiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), vascular endothelial growth factor (VEGF), and alpha2A adrenoreceptors (alpha2A-ADR) was studied in the choroid by immunofluorescence.ResultsThe choroid thickened strongly in atropine-injected eyes, less so in atropine + spiperone–injected eyes and became thinner over the day in spiperone alone-, vehicle-, or non-injected eyes. Flickering light at 20 lx, both 1 and 10 Hz, prevented diurnal choroidal thinning, compared to 400 Hz, and stimulated retinal dopamine release. Correlation analysis showed that the higher retinal dopamine levels or release, the thicker became the choroid. TH-, nNOS-, VEGF-, and alpha2A adrenoreceptor–positive nerve fibers were localized in the choroid around lacunae and in the walls of blood vessels with colocalization of TH and nNOS, and TH and VEGF.ConclusionsRetinal DOPAC and dopamine levels were positively correlated with choroidal thickness. TH-positive nerve fibers in the choroid were closely associated with peptides known to play a role in myopia development. Findings are in line with the hypothesis that dopamine is related to retinal signals controlling choroidal thickness.

Insights into the mechanism by which atropine inhibits myopia: evidence against cholinergic hyperactivity and modulation of dopamine release.

Background and PurposeThe ability of the muscarinic cholinergic antagonist atropine to inhibit myopia development in humans and animal models would suggest that cholinergic hyperactivity may underlie myopic growth. To test this, we investigated whether cholinergic agonists accelerate ocular growth rates in chickens. Furthermore, we investigated whether atropine alters ocular growth by downstream modulation of dopamine levels, a mechanism postulated to underlie its antimyopic effects.Experimental ApproachMuscarinic (muscarine and pilocarpine), nicotinic (nicotine) and non‐specific (oxotremorine and carbachol) cholinergic agonists were administered to chicks developing form‐deprivation myopia (FDM) or chicks that were otherwise untreated. Vitreal levels of dopamine and its primary metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) were examined using mass spectrometry MS in form‐deprived chicks treated with atropine (360, 15 or 0.15 nmol). Further, we investigated whether dopamine antagonists block atropine's antimyopic effects.Key ResultsUnexpectedly, administration of each cholinergic agonist inhibited FDM but did not affect normal ocular development. Atropine only affected dopamine and DOPAC levels at its highest dose. Dopamine antagonists did not alter the antimyopia effects of atropine.Conclusion and ImplicationsMuscarinic, nicotinic and non‐specific cholinergic agonists inhibited FDM development. This indicates that cholinergic hyperactivity does not underlie myopic growth and questions whether atropine inhibits myopia via cholinergic antagonism. This study also demonstrates that changes in retinal dopamine release are not required for atropine's antimyopic effects. Finally, nicotinic agonists may represent a novel and more targeted approach for the cholinergic control of myopia as they are unlikely to cause the anterior segment side effects associated with muscarinic treatment.

Effects of 7-Methylxanthine on Deprivation Myopia and Retinal Dopamine Release in Chickens

Introduction: Intake of 7-methylxanthine (7-MX), an adenosine receptor (AR) antagonist, has been shown to inhibit school myopia in children and deprivation myopia in rhesus monkeys, but the underlying mechanisms are not known. Also retinal dopamine seems to be involved in the control of eye growth, and in the brain, ARs and dopamine receptors interact widely by heteromerization. We have studied whether 7-MX can inhibit deprivation myopia also in chickens and whether inhibition may involve the retinal dopamine system. Methods: 7-MX was applied by either tube-feeding (100 µg/g body weight, twice a day) or intravitreal injection (12.5 µg, every other day). Forty-eight 2-week-old chicks wore unilateral diffusers and were randomly assigned to either the tube-feeding group (involving 7-MX, vehicle [xanthan gum], or no feeding, for 13 days) or the intravitreal injection group (involving 7-MX, vehicle, or DMSO, for 8 days). Refractions (REs), ocular biometry (AL, VCD), and scleral and choroidal thickness (ChT) were measured before and after treatment. Dopamine and dihydroxyphenylacetic acid (DOPAC) content were determined in retina and vitreous by HPLC at the end of the experiments. Results: No matter how 7-MX was applied, it did not inhibit deprivation myopia in chicks. No significant differences were observed in RE, VCD, AL, and scleral fibrous layer thickness. Feeding 7-MX produced more choroidal thinning in the open contralateral eye compared to control eyes in the vehicle-fed group (–40 ± 14 vs. –1 ± 7 µm, unpaired t test, p < 0.05). DOPAC and dopamine concentration in vitreous and DOPAC concentration in retina did not change with 7-MX. Vitreal dopamine content was significantly decreased in deprived eyes in the groups fed with the vehicle xanthan gum (paired t test, p < 0.01) but not in 7-MX-treated eyes, perhaps indicating a small effect of 7-MX on dopamine. Conclusions: In our study, 7-MX had no effect on DM in chicks and only minor effects on ChT and retinal dopamine. It remains unclear whether 7-MX inhibits myopia through a retinal mechanism or whether it acts directly on choroid and sclera. In the latter case, the finding that myopia is suppressed in mammals but not birds might be explained by differences in scleral structure.

Probing the Potency of Artificial Dynamic ON or OFF Stimuli to Inhibit Myopia Development.

To determine whether equiluminant artificial dynamic ON or OFF stimuli on a computer screen can induce bidirectional changes in choroidal thickness (ChTh) in both humans and chickens, and whether such changes are associated with bidirectional changes in retinal dopamine release in chickens. Experiment 1: Before and after ON or OFF stimulation for 1 hour, ChTh was measured with optical coherence tomography (OCT). Experiment 2: chicks (n = 14) were raised under ON or OFF stimulation for 3 hours. ChTh was determined by OCT. Experiment 3: chicks were raised for 7 days either under room light (500 lux, n = 11), dynamic ON stimulus (700 lux, n = 15), or dynamic OFF stimulus (700 lux, n = 7). In addition, negative lenses were attached to their right eyes. After experiments 2 and 3, retinal and vitreal dopamine (DA), and its metabolites, were measured by HPLC-electrochemical detection. Experiment 1: Dynamic ON stimuli caused thicker choroids (+5.3 ± 2.0 μm), whereas OFF stimuli caused choroidal thinning (-4.7 ± 0.5 μm) (right eye data only, P < 0.001). Experiment 2: After 3 hours, chickens developed thicker choroids with ON stimuli (+37.4 ± 12.4 μm) and thinner choroids with OFF stimuli (-11.3 ± 3.6 μm, difference P < 0.01). Vitreal DA, 3-methoxytyramine, and homovanillic acid levels were elevated after ON stimulation, compared with the OFF (P < 0.05). Experiment 3: After 7 days, chickens with lenses developed more myopia both with ON and OFF stimulation, compared with room light. ON stimulation increased vitreal DA compared with OFF. Artificial dynamic ON or OFF stimuli had similar effects on ChTh in humans and chickens, but more work will be necessary to determine whether such stimuli can be used as novel interventions of myopia.

Color vision predicts processing modes of goal activation during action cascading

One of the most important functions of cognitive control is action cascading: the ability to cope with multiple response options when confronted with various task goals. A recent study implicates a key role for dopamine (DA) in this process, suggesting higher D1 efficiency shifts the action cascading strategy toward a more serial processing mode, whereas higher D2 efficiency promotes a shift in the opposite direction by inducing a more parallel processing mode (Stock, Arning, Epplen, & Beste, 2014). Given that DA is found in high concentration in the retina and modulation of retinal DA release displays characteristics of D2-receptors (Peters, Schweibold, Przuntek, & Müller, 2000), color vision discrimination might serve as an index of D2 efficiency. We used color discrimination, assessed with the Lanthony Desaturated Panel D-15 test, to predict individual differences (N = 85) in a stop-change paradigm that provides a well-established measure of action cascading. In this task it is possible to calculate an individual slope value for each participant that estimates the degree of overlap in task goal activation. When the stopping process of a previous task goal has not finished at the time the change process toward a new task goal is initiated (parallel processing), the slope value becomes steeper. In case of less overlap (more serial processing), the slope value becomes flatter. As expected, participants showing better color vision were more prone to activate goals in a parallel manner as indicated by a steeper slope. Our findings suggest that color vision might represent a predictor of D2 efficiency and the predisposed processing mode of goal activation during action cascading.

Changes in dopamine and ZENK during suppression of myopia in chicks by intense illuminance

High ambient illuminances have been found to slow the development of deprivation myopia in several animal models. Almost complete inhibition of myopia was observed in chickens when intermittent episodes of high illuminance were alternated with standard office illuminance (50% duty cycle, alternate periods of 1 min 15,000 lux and 1 min 500 lux, continued for 10 h per day), or when illuminances were increased to 40,000 lux. Since the mechanisms by which bright light suppresses myopia are poorly understood, we have studied the roles of two well-established signaling molecules in myopia, dopamine and ZENK, in the chicken. In line with previous studies, we found that retinal dopamine release (as reflected by vitreal DOPAC content) was severely reduced during development of deprivation myopia. We found that illuminance of 15,000 lux, provided by quartz-halogen lamps, partially rescued the drop in retinal dopamine release. The finding is in line with the assumption that dopamine is involved in the light-induced inhibition of myopia. No differences in vitreal DOPAC were found when bright light was provided continuously or with 1:1 min alternating exposure with 500 lux. As previously described by others, wearing diffusers suppressed the expression of ZENK protein in glucagonergic amacrine cells (GACs) but neither continuous nor 1:1 min alternating bright to normal light could rescue the suppression of ZENK in GACs. While it is well known that light increases global retinal ZENK mRNA and protein levels, the changes of ZENK protein induced specifically in GACs by diffuser wear appear independent of light levels.

Ambient illuminance, retinal dopamine release and refractive development in chicks

Form deprivation and low illuminance of ambient light are known to induce myopia in chicks. Low concentrations of retinal dopamine, a light-driven neurohormone, was previously shown to be associated with form deprivation myopia. In the present study we examined the dependence of retinal dopamine release in chicks on illuminance during light–dark cycles and in continuous light, and the role of retinal dopamine release in illuminance dependent refractive development. Newly hatched chicks (n = 166) were divided into two experimental groups, a dopamine (n = 88) and a refraction group (n = 78). Both groups were further divided into six illumination groups for exposure of chicks to illuminances of 50, 500 or 10,000 lux of incandescent illumination (referred to throughout as low, medium, and high illuminance, respectively), either under a light–dark cycle with lights on between 7 AM and 7 PM or under continuous illumination. For the dopamine experiment, chicks were euthanized and vitreous was extracted on day 14 post-hatching at 7, 8 AM and 1 PM. Vitreal dihydroxyphenylacetic acid (DOPAC) and dopamine concentrations were quantified by high-performance liquid chromatography coupled to electrochemical detection. For the refraction experiment, chicks underwent refraction, keratometry and A-scan ultrasonography on days 30, 60 and 90 post-hatching, and each of those measurements was correlated with vitreal DOPAC concentration measured at 1 PM (representing the index of retinal dopamine release). The results showed that under light–dark cycles, vitreal DOPAC concentration was strongly correlated with log illuminance, and was significantly correlated with the developing refraction, corneal radius of curvature, and axial length values. On day 90, low vitreal DOPAC concentrations were associated with myopia (−2.41 ± 1.23 D), flat cornea, deep anterior and vitreous chambers, and thin lens. Under continuous light, vitreal DOPAC concentrations measured at 1 PM in the low, medium, and high illuminance groups did not differ from the concentrations measured at 8 AM. On day 90, low DOPAC concentrations were associated with emmetropia (+0.63 ± 3.61), steep cornea, and shallow vitreous chamber. We concluded that ambient light over a log illuminance range of 1.69–4 is linearly related to vitreal DOPAC concentration. Under both light–dark cycles and continuous light, the intensity of ambient light regulates the release of retinal dopamine. Refractive development is associated with illuminance dependent dopamine release.

Retinal pathways involved in the control of eye growth and myopia

AbstractPurpose To integrate information from studies on gene expression in animal mpdels and from genetic studies on human myopia to define the pathways which are involved in the development of myopiaMethods A literature search of studies on gene expression in animal models of myopia and human genetic studies was carried out using the Medline databaseResults Human genetic studies identify two clusters of mutations which are involved in human high myopia. One involves genes which affect photoreceptor and ON‐bipolar cell function in the outer retina. These mutations are associated with congenital stationary night blindness. A second cluster involves genes involved in extracellular matrix structure and function, which may be important in the sclera, which changes markedly during the development of myopia. ON‐bipolar cells play a major role in the control of dopamine release in the retina. Other evidence supports a role for dopamine in the control of eye growth, which suggests a plausible pathway linking the genes involved in the outer retina to control of eye growth. However, the down‐stream effects of changes in dpoamine release are not well‐characterised studies. However, animal studies have suggested that changes in the expression of the early intermediate gene ZENK and changes in glucagon release within the retina may play a roleConclusion Huamn genetic studies and studies of changes in gene expression in animal models of myopia provide a consistent but still incomplete picture of the pathways involved in the control of eye growth. Further studies on these pathways are of particular importance given that they implicate retinal dopamine release , which links them to the epidemiological evidence that bright light‐ induced dopamine release can prevent the development of myopia in humans

Dopaminergic amacrine cells express opioid receptors in the mouse retina

The presence of opioid receptors has been confirmed by a variety of techniques in vertebrate retinas including those of mammals; however, in most reports, the location of these receptors has been limited to retinal regions rather than specific cell types. Concurrently, our knowledge of the physiological functions of opioid signaling in the retina is based on only a handful of studies. To date, the best-documented opioid effect is the modulation of retinal dopamine release, which has been shown in a variety of vertebrate species. Nonetheless, it is not known if opioids can affect dopaminergic amacrine cells (DACs) directly, via opioid receptors expressed by DACs. This study, using immunohistochemical methods, sought to determine whether (1) μ- and δ-opioid receptors (MORs and DORs, respectively) are present in the mouse retina, and if present, (2) are they expressed by DACs. We found that MOR and DOR immunolabeling were associated with multiple cell types in the inner retina, suggesting that opioids might influence visual information processing at multiple sites within the mammalian retinal circuitry. Specifically, colabeling studies with the DAC molecular marker anti-tyrosine hydroxylase antibody showed that both MOR and DOR immunolabeling localize to DACs. These findings predict that opioids can affect DACs in the mouse retina directly, via MOR and DOR signaling, and might modulate dopamine release as reported in other mammalian and nonmammalian retinas.

Functional MT&lt;SUB&gt;1&lt;/SUB&gt; and MT&lt;SUB&gt;2&lt;/SUB&gt; Melatonin Receptors in Mammals

Melatonin, dubbed the hormone of darkness, is known to regulate a wide variety of physiological processes in mammals. This review describes well-defined functional responses mediated through activation of high-affinity MT1 and MT2 G protein-coupled receptors viewed as potential targets for drug discovery. MT1 melatonin receptors modulate neuronal firing, arterial vasocon-striction, cell proliferation in cancer cells, and reproductive and metabolic functions. Activation of MT2 melatonin receptors phase shift circadian rhythms of neuronal firing in the suprachiasmatic nucleus, inhibit dopamine release in retina, induce vasodilation and inhibition of leukocyte rolling in arterial beds, and enhance immune responses. The melatonin-mediated responses elicited by activation of MT1 and MT2 native melatonin receptors are dependent on circadian time, duration and mode of exposure to endogenous or exogenous melatonin, and functional receptor sensitivity. Together, these studies underscore the importance of carefully linking each melatonin receptor type to specific functional responses in target tissues to facilitate the design and development of novel therapeutic agent.

An in vivo microdialysis study of light/dark-modulation of vitreal dopamine release in zebrafish.

Dopamine (DA) is an important neuromodulator in the visual system. The release of DA in the retina largely depends on environmental lighting conditions. Most previous studies have assessed the effect of illumination on retinal DA or its metabolites using homogenates or in vitro preparations. This study was designed to investigate the effect of transitions between lighting conditions--from dark to steady or flickering light and vice versa--on retinal DA release in zebrafish using in vivo microdialysis. The transition from dark to flickering light increased DA release, whereas the transition from flickering light to dark decreased it. This latter effect depended on time of day within the light period, e.g., it was strongest in the late afternoon. When using steady light, none of these effects were seen. Our study also demonstrates that in vivo microdialysis can successfully be applied to the investigation of retinal DA release in zebrafish.

Pineal control of the dopamine D2-receptor gene and dopamine release in the retina of the chicken and their possible relation to growth rhythms of the eye.

Retinal dopamine (DA) and the DA D2-receptor have been implicated in the development of "deprivation myopia", induced by frosted eye occluders. We have studied the changes in D2-mediated dopaminergic transmission in the retina, their possible relations to eye growth rhythms and myopia, and their control by the pineal gland. (1) We found that the sensitivity of eye growth to retinal image degradation varied over the day. Intermittent periods of normal vision inhibited deprivation myopia more if they occurred in the evening than in the morning. (2) Diurnal growth rhythms in both eyes interacted even though it was previously shown that both deprivation myopia and the accompanying changes in retinal DA release can be monocularly induced. (3) The D2-receptor mRNA concentration in the retina showed no systemic diurnal changes and was not affected by deprivation myopia, but was increased after 2 days in darkness. Since DA release varies over the day, the gain of dopaminergic transmission may also vary, which could explain the observation described in (1) above. (4) Depletion of retinal DA by intravitreal application of reserpine, which lowers DA content severely, had little effect on D2-receptor mRNA concentration. (5) Selective illumination of the pineal gland reduced the D2-receptor mRNA content in the retina to a similar level to full illumination, indicating that the pineal gland controls the D2-receptor mRNA content in the retina. The pineal also controlled DA release in the retina. These results show that the pineal has a surprisingly large influence on both the retinal DA receptor gene transcription and DA release. It can probably control the gain of dopaminergic transmission in the retina and deprivation myopia and mediate the interactions of the growth rhythms in both eyes.

Vitreal dihydroxyphenylacetic acid (DOPAC) as an index of retinal dopamine release.

Dopamine is generally accepted as a major neurotransmitter associated with light-adaptive processes in the retina. However, little is known about its precise release pattern in vivo, largely due to the lack of an unambiguous method for the determination of dopamine release. We have found that vitreal levels of dihydroxyphenylacetic acid (DOPAC) reflect the rate of dopamine release in chickens. Blocking re-uptake with nomifensine significantly lowered vitreal DOPAC and retinal dopamine, confirming the retinal origin and reliance of vitreal DOPAC on intact re-uptake mechanisms. Further, inhibition of monoamine oxidase with pargyline reduced vitreal as well as retinal DOPAC levels, confirming that the DOPAC detected is generated by monoamine oxidase. Finally, we found that DOPAC diffused freely into and out of isolated vitreous bodies and we found the vitreous to be metabolically inert with respect to DOPAC, supporting the idea that vitreal levels of DOPAC are consequential to the retinal metabolism of dopamine. Exposure to light, which is known to increase retinal dopamine release, readily increased vitreal DOPAC levels. The accumulation of DOPAC in the vitreous over 6 h light fitted a mathematical model of DOPAC accumulation based on zero-order influx (proportional to dopamine release rates) and diffusion driven, first-order efflux.

Regulation of endogenous dopamine release in amphibian retina by gamma-aminobutyric acid and glycine.

Endogenous dopamine release in the retina of the African clawed frog (Xenopus laevis) increases in light and decreases in darkness. The roles of the inhibitory amino acid transmitters gamma-aminobutyric acid (GABA) and glycine in regulating this light/dark difference in dopamine release were explored in the present study. Exogenous GABA, the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, and the GABA-C receptor agonist cis-aminocrotonic acid (CACA) suppressed light-evoked dopamine overflow from eyecups. The effects of GABA-A and -B receptor agonists were selectively reversed by their respective receptor-specific antagonists, whereas the effect of CACA was reversed by the competitive GABA-A receptor antagonist bicuculline. The benzodiazepine diazepam enhanced the effect of muscimol on light-evoked dopamine release. Both GABA-A and -B receptor antagonists stimulated dopamine release in light or darkness. Bicuculline was more potent in light than in darkness. These data suggest that retinal dopaminergic neurons are inhibited by GABA-A and -B receptor activation in both light and darkness but that GABA-mediated inhibitory tone may be greater in darkness than in light. Exogenous glycine inhibited light-stimulated dopamine release in a concentration-dependent and strychnine-sensitive manner. However, strychnine alone did not increase dopamine release in light or darkness, nor did it augment bicuculline-stimulated release in darkness. Additionally, both strychnine and 7-chlorokynurenate, an antagonist of the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate subtype of glutamate receptor, suppressed light-evoked dopamine release. Thus, the role of endogenous glycine in the regulation of dopamine release remains unclear.

Chromogranin A inhibits retinal dopamine release

Chromogranin A (CGA), a peripherally active prohormone, is a soluble component in the secretory granules of many endocrine tissues and is cosecreted with their peptide or amine hormones. Using an antibody prepared against purified rat adrenal CGA, immunostaining was localized to the inner and outer plexiform layers of the rat retina and to selected ganglion cells. Exogenous CGA (purified from human adrenals) when applied to perfused rat retina potently inhibited the potassium-induced release of endogenous dopamine (DA). This action was dose-dependent, with an IC 50 of 3 nM; at 100 nM CGA retinal DA release was completely abolished.

A simple perfusion system for measuring endogenous retinal dopamine release

A simple superperfusion apparatus for measuring endogenous dopamine (DA) release from rat retina is described. DA release is stimulated by increasing levels of potassium (K) in the superfusion medium and this K-stimulated release is calcium dependent. Exposure of dark-adapted retinae to light also increases endogenous DA release. This system should prove useful in determining what factors may control endogenous DA release in the retina.

Release of endogenous dopamine from the superfused rabbit retina in vitro: effect of light stimulation

Light exposure activates dopamine (DA)-releasing neurons in the retina. Previous studies have employed indirect means (i.e. accumulation of DA metabolites in vivo 4,11, or [ 3H]DA release from preloaded retina in vitro 2) to estimate light-stimulated retinal DA release. We describe a new technique, based on superfusion of retinal pieces in vitro, which allows direct measurement of endogenous DA release. Dark-adapted pieces of retina from male albino rabbits were individually superfused in vitro with a physiologic buffer containing nomifensine (30 μM) (a DA reuptake blocker), and exposed to steady white light (300 μW/cm 2) for 15 min. Retinal DA release into the superfusate was significantly greater (60%) during photic stimulation than during dark-exposure.

Dopaminergic regulation of cone retinomotor movement in isolated teleost retinas: II. Modulation by gamma-aminobutyric acid and serotonin.

In the accompanying paper we reported that 3,4-dihydroxyphenylethylamine (dopamine) induced light-adaptive retinomotor movements in teleost photoreceptors and that this effect was mediated by D2 dopamine receptors located on the photoreceptors themselves. In this study, we investigated the effects on cone retinomotor movement of three agents that have been reported by others to modulate retinal dopamine release: gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT, serotonin), and melatonin. We report here that the GABA antagonists bicuculline and picrotoxin induced light-adaptive cone contraction in dark-adapted green sunfish retinas cultured in constant darkness; thus they mimic the effect of light or exogenously applied dopamine. Since their effects were blocked by either the D2 dopamine antagonist sulpiride or by Co2+, it seems likely that these agents act by enhancing retinal dopamine release. The GABA agonist muscimol produced effects opposite to those of GABA antagonists. Muscimol inhibited light-induced cone contraction in previously dark-adapted retinas and induced dark-adaptive cone elongation in light-adapted retinas. These results suggest that in green sunfish retinas, as has been reported for other retinas, GABA inhibits dopamine release. 5-HT induced light-adaptive cone contraction in dark-adapted retinas; thus 5-HT also mimics the effect of light or exogenously applied dopamine. The effect of 5-HT was blocked by sulpiride, Co2+, or the 5-HT antagonist mianserin. These results suggest that 5-HT induces cone contraction by stimulating dopamine release. Melatonin neither inhibited dopamine-induced cone contraction in retinas cultured in the dark nor induced cone elongation in retinas cultured in the light. Our results suggest that both GABA and 5-HT (but not melatonin) affect cone retinomotor movements in green sunfish by modulating dopamine release: GABA by inhibiting and 5-HT by stimulating dopamine release. We report in the companion paper that dopamine induced contraction in isolated cone fragments. Together these observations strongly suggest that dopamine serves as the final extracellular messenger directly inducing light-adaptive cone retinomotor movement, and that GABA and 5-HT affect these movements by modulating dopamine release.