Retinal dopamine D1 and D2 receptors: characterization by binding or pharmacological studies and physiological functions.

Cellular and Molecular Neurobiology, Vol. 10, No. 3, 1990

Review

Retinal Dopamine D 1 and D 2 Receptors: Characterization by Binding or Pharmacological Studies and Physiological Functions M. Schorderet 1'2'4 and J. Z. N o w a k a Received December 21, 1989; accepted March 23, 1990 KEY WORDS: retina; amacrine cells; horizontal cells; photoreceptors; dopamine; dopamine function(s); binding studies of dopamine receptors; dopamine synthesis and release; acetylcholine release; melatonin synthesis.

SUMMARY

1. In the retinal inner nuclear layer of the majority of species, a dopaminergic neuronal network has been visualized in either amacrine cells or the so-called interplexiform cells. 2. Binding studies of retinal dopamine receptors have revealed the existence of both D1- as well De-subtypes. The Dl-subtype was characterized by labeled SCH 23390 (Kd ranging from 0.175 to 1.6 nM and Bma x from 16 to 482 fmol/mg protein) and the D2-subtype by labelled spiroperidol (Kd ranging from 0.087 to 1.35 nM and Bma x from 12 to 1500 fmol/mg protein) and more selectively by iodosulpiride (Kd0.6nM and Bmax82fmol/mg protein) or methylspiperone (Kd 0.14 nM and Bma x 223 fmol/mg protein). 3. Retinal dopamine receptors have been also shown to be positively coupled with adenylate cyclase activity in most species, arguing for the existence of Dl-SUbtype, whereas in some others (lower vertebrates and rats), a negative coupling (De-subtype) has been also detected in peculiar pharmacological conditions implying various combinations of dopamine or a D2-agonist with a Dl-antagonist or a De-antagonist in the absence or presence of forskolin. 1 Department of Pharmacology, University Medical Center, 1211 Geneva 4, Switzerland. 2 School of Pharmacy, Place du Chfiteau, 1005 Lausanne, Switzerland. 3 Department of Biogenic Amines, Polish Academy of Sciences, P-225, 90-950 Lodz, Poland. 4 To whom correspondence should be addressed at Department of Pharmacology, University Medical Center, 1211 Geneva 4, Switzerland. 303

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4. A subpopulation of autoreceptors of D2-subtype (probably not coupled to adenylate cyclase) also seems to be involved in the modulation of retinal dopamine synthesis and/or release. 5. Light/darkness conditions can affect the sensitivity of retinal dopamine D1 and/or D2-receptors, as studied in binding or pharmacological experiments (cAMP levels, dopamine synthesis, metabolism and release). 6. Visual function(s) of retinal dopamine receptors were connected with the regulation of electrical activity and communication (through gap junctions) between horizontal cells mediated by D~ and D2 receptor stimulation. Movements of photoreceptor cells and migration of melanin granules in retinal pigment epithelial cells as well as synthesis of melatonin in photoreceptors were on the other hand mediated by the stimulation of D2-receptors. 7. Other physiological functions of dopamine D~-receptors respectively in rabbit and in embryonic avian retina would imply the modulation of acetylcholine release and the inhibiton of neuronal growth cones. INTRODUCTION

In addition to its neurotransmitter function in some highly specialized structures of the CNS (Carlsson and Lindquist, 1963), a large number of morphological, biochemical, and pharmacological studies has indicated that dopamine is playing a similar role in the retina of lower and higher vertebrates (Ehinger, 1983; Jensen and Daw, 1983; Kamp, 1985; Dowling, 1986; Nowak, 1987; 1988; Rogawski, 1987; Bodis-Wollner and Piccolino, 1988). In most, if not all, vertebrate species, the retinal dopamine is localized in a network of specialized cells, either amacrine or interplexiform cells, with their cell bodies being essentially visualized in the inner nuclear layer. From the pioneer work of Brown and Makman (1972), it has also been demonstrated that a dopamine-sensitive adenylate cyclase does exist in the retina of all species studied (see the reviews by Schorderet and Magistretti, 1983; Kamp, 1985), implying an unequivocal population of dopamine receptors of Dl-Subtype (Kebabian and Calne, 1979). The search for retinal D2 receptors, which are negatively coupled to adenylate cyclase, was unsuccessful at the beginning. However, the evidence has now been provided for their existence at least in some species (Qu et al., 1989; Nowak et al., 1990a). In addition, the biochemical studies of dopamine D1 and/or D2 receptors were corroborated with the various data obtained in binding and functional studies (Schorderet and Magistretti, 1983; Watling, 1983; Dearry and Burnside, 1986a; Dowling, 1986; Iuvone, 1986; Rogawski, 1987; Piccolino et al., 1989). Finally, the mechanisms for the synthesis, release, and uptake of dopamine--some of them being regulated by light--and their modulation by various pharmacological agents have also been consistently investigated under a variety of experimental conditions (Kramer, 1971; Dubocovich and Weiner, 1981, 1985; Iuvone, 1984; Ofori et al., 1986a,b; Nowak, 1987, 1988). The purpose of the present review is to examine the data collected up to now by various technical approaches on the existence, characterization, and role(s) of retinal dopamine receptors and to reconcile the results of biophysical, biochemi-

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cal, and pharmacological experiments with those obtained in functional studies. Thus, this state-of-the-art report is aimed at the covering of the major trends of the research devoted to the retina in vitro in the frame of possible biological and/or visual implications of dopaminergic cells. BINDING STUDIES OF D O P A M I N E RECEPTORS IN M A M M A L I A N A N D N O N M A M M A L I A N RETINA

Since the first reports of specific dopamine receptors characterized by [3H]spiroperidol (Table I) or [3H]ADTN binding and displacement in retinal Table I.

Dopamine Receptors: Binding Characteristics in Nonmammalian and Mammalian Retina Species

Ka

Bmax

(nM)

(fmol/ mg protein)

Reference

[3H]Spiroperidol binding (D1 and D 2 subtype) Nonmammals Goldfish ( Carassius auratus )

Turtle Mammals Rat Rabbit Rabbit (light-adapted) Rabbit (dark-adapted) Calf Cow Human

0.23 0.21

37 12.43

Redburn et al., 1980b Piccolino et al., 1989

0.35 0.20 0.78 0.86 0.27 1.35 0.38 0.087

155 24 59 63 38 107 64 1500

Schaeffer, 1980 Makman et al., 1980b Nowak et al., 1990c Nowak et al., 1990c Makman et al., 1980b Magistretti and Schorderet, 1979 Watling, 1980 McGonigle et al., 1988

[3H]SCH 23390 or [125I]SCH 23982 binding (D 1 subtype) Nonmammals Chicken embryo Chicken embryos a Turtle Mammals Rat Rat Rat (light-adapted) Rat (dark-adapted) Rat (various ages) Rabbit Rabbit a Calf Calf

0.38 0.795 0.21

128 32.2 52.34

Makman and Dvorkin, 1986 Agui et al., 1988 Piccolino et al., 1989

0.52 0.20 0.40 0.40 0.45-0.60 0.175 0.33 1.6 1.1

244 236 119 125 16-258 482 1i2 304 150

Makman and Dvorkin, 1986 Gredal et al., 1987 Porceddu et al., 1987 Porceddu et al., 1987 De Montis et al., 1988 Hensler et al., 1987 Elena et al., 1989 Makman and Dvorkin, 1986 De Keyser et al., 1988

[125I]Iodosulpiride binding (D 2 subtype) Rabbit

0.6

82

Elena et al., 1989

[3H]Methylspiperone (D 2 subtype) Human retiuoblastoma (WERI 27) " as studied with [125I]SCH 23982.

0.14

223

Monsma et al., 1989

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crude membranes of rat, guinea pig, rabbit, calf, monkey, and carp (Magistretti and Schorderet, 1979; Wafting et al., 1979; Makman et al., 1980a,b; Schaeffer, 1980; Thai et at., 1980; Osborne, 1981) or in synaptosomal fractions of mammalian retina (Redburn and Kyles, 1980; Redburn et al., 1980a,b), the use of new ligands selective for either D1 or D2 receptors has allowed a more accurate detection and characterization of these subtypes of dopamine receptors [see also Creese et al. (1983) for an analysis of the first binding data obtained in retina]. In fact, the first results published by Magistretti and Schorderet (1979), Wafting et al. (1979), Redburn et al. (1980a,b), and Wafting and Iversen (1981), which came from experiments performed with radioactive spiroperidol (syn.: spiperone) or domperidone, have indicated that the dopamine receptors identified in bovine and carp retina represented mostly the D1 type [irrespective of the fact that the two ligands have a much higher affinity for D2 than for D1 receptors; see Seeman (1981) and Creese et al. (1983)]. Furthermore, all the sites labeled by [3H]spiroperidol and a subset of the sites labeled by [3H]ADTN in mammalian retina appeared to be guanine nucleotide sensitive, suggesting that they may be linked to the enzyme adenylate cyclase (Makman et al., 1980a,b). Yet an additional existence of retinal D2 receptors which were also investigated at the beginning by spiroperidol binding was suggested by Wafting (1980) and demonstrated later in rabbit (Dubocovich and Zahniser, 1982; Dubocovich et al., 1985) and turtle (Piccolino et al., 1989). Similar findings were published by McGonigle et al. (1988) for human retina, where both a large class and a small class of sites labeled by [aH]spiroperidol were characterized. In parallel, the use of new selective ligands for D2 receptors has helped to consolidate the evidence that the retina contains both subtypes (e.g., D 1 and D2) of dopamine receptors (Amlaiky and Caron, 1986; Monsma et al., 1989).

Dopamine Dt Receptors In addition to the early conclusion drawn from binding studies performed with spiroperidol, new ligands were provided to establish definitely the existence of retinal D1 receptors by this technique. Most authors have used [3H]SCH 23390, a substituted benzazepine endowed with a selective dopamine D1 antagonist activity (Kebabian et al., 1986; Niznik, 1987). With the aid of this compound, it has been possible to demonstrate the existence of D1 receptors in the retina of several nonmammalian and mammalian species including turtle (Piccolino et al., 1989), chick embryo (Makman and Dvorkin, 1986), adult hen (Nowak et al., unpublished), rat (Makman and Dvorkin, 1986; Gredal et al., 1987; Porceddu et al., 1987; De Montis et al., 1988), rabbit (Hensler et al., 1987; Nowak et al., unpublished), and calf (Makman and Dvorkin, 1986; De Keyser et aL, 1988). Agui et al. (1988) as well as Elena et aL (1989) have applied a SCH23390 analogue, namely, an iodinated SCH23982, to reveal D 1 receptors in chick embryo retina and in rabbit retina, respectively. The binding characteristics (e.g., Kd and Bmax) of these and other studies (cited in the next section) are summarized in Table I. An autoradiographic study was also performed by Elena et al. (1989) with the same ligand. The D1 receptors were found in the inner and outer plexiform layers as well as in the inner nuclear layer. Thus, there is now

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sufficient experimental evidence arguing for the existence of dopamine D1 receptors in mammalian and nonmammalian retina. Most, if not all, of these receptors (Makman et al., 1980a,b; Ventura et al., 1989) seem to be positively coupled to adenylate cyclase [see Dopamine Receptors Positively Coupled to Adenylate Cyclase (D1 Receptors)]. Dopamine D 2

Receptors

In contrast to numerous reports dealing with the binding studies of dopamine D1 receptors, there is a paucity of data based on a similar technique and dealing with the characterization of the retinal D2 receptors. The first indirect evidence was provided by Watling (1980), who showed that lisuride, a synthetic ergolene whose affinity for D2 receptors is approximately eight times higher than for D1 receptors (Seeman and Niznik, 1988), was the most potent displacer (IC50 = 2.7 nM) of [3H]spiroperidol binding in bovine retina. Various ergot alcaloids, including lisuride, metergoline, and bromocriptine, were also tested under similar experimental conditions and found to be very potent displacing agents [IC50 from 10 to 20nM (Schorderet et al., 1980)]. On the basis of other comparable displacement experiments of [3H]spiroperidol binding performed in rabbit retinal and striatal homogenates, Dubocovich et al. (1985) concluded that the number of D2 receptors in the ocular tissue was two- to threefold lower than that found in the striatum (the respective Bmax values being 268 vs 608 fmol/mg protein). An even lower density of [3H]spiroperidol specific binding sites in the rabbit retina (Bmax = 59 fmol/mg protein) was recently reported by Nowak et al. (1990a). Yet in the human retina the density of [3H]spiroperidol-labeled sites (Bmax= 1650 fmol/mg protein) appears to be much higher than in the rabbit retina (McGonigle et al., 1988), indicating that the amount of the retinal D2 receptors may differ among vertebrates. Using spiroperidol and N-propyl-norapomorphine as ligands for binding and autoradiographic studies in bovine retina, Brann and Young (1986) have localized the binding in the membranes of rod photoreceptors and characterized the labeled sites as D2 receptors. This localization favors the suggestion that dopamine may also regulate some biochemical processes occurring in photoreceptors of higher vertebrates through the stimulation of D2 receptors, in analogy with some events demonstrated in lower vertebrates such as frog and hen (see Putative or Proven Physiological Functions Linked to the Stimulation of Dopamine Receptors in Mammalian and Nonmammalian Retina). However, another autoradiographic study of dopamine receptors (performed with tritiated spiroperidol) which was carried out in rat, monkey, and human retina revealed the spiroperidol-labeled receptors in four layers, i.e., outer nuclear, outer plexiform, inner nuclear, and inner plexiform, but not in photoreceptors (Zarbin et al., 1986). Finally, a more selective autoradiographic analysis of binding sites was recently performed in rabbit and rat retina by Elena et al. (1989). The D2 receptors, specifically labeled with [125I]iodosulpiride, were found in the two plexiform layers only. The use of other new selective radioactive agents such as methylspiperone and N-(p-aminophenethyl)-spiperone (NAPS) has recently allowed Monsma et

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al. (1989) to identify D2 receptors (by saturation and competition studies) in

human retinoblastoma cell line (WERI27) (Table I). Moreover, dopamine inhibition of [3H]methylspiperone labeling revealed the existence of both highand low-affinity agonist binding sites, which were converted to a homogeneous low-affinity state by the addition of 5'-guanylylimidodiphosphate (GppNHp). These results suggest that the D2 recognition sites of this retinoblastoma cell line can exhibit a functional coupling with the Gi protein, thus mediating inhibitory interactions between receptors and adenylate cyclase. A similar interaction has recently been demonstrated in the retina of rat (Qu et al., 1989; Nowak et al., 1990a) and hen (Nowak et al., 1990b) but not in that of rabbit (Nowak et al., 1990c). It should be noted that Makman et al. (1982) have earlier proposed that D2 receptors in the retina (and also in the striatum) of rat and calf may exist in two distinguishable yet interconvertible conformational states, with different properties depending on the presence or absence of guanine nucleotides and sodium ions. Interestingly, no cell cultures among 27 of various origins (neuroblastoma or retinoblastoma clonal cell lines) were found to express simultaneously both D1and D2-receptor subtypes, as measured by binding experiments (Monsma et al., 1989), and this is in contrast with some recent biochemical studies performed on the whole rat and hen retina (see the following section). N-(p-Azidophenethyl)-spiperone (N3-NAPS), the azide derivative of NAPS, has been also used to identify D2-receptor binding sites by photoaffinity labeling in bovine and rabbit retinal preparations (Amlaiky and Caron, 1986). It is a hope that additional binding studies will be carried out with these or other new selective ligands for D2 receptors [for example, [3H]raclopride (see Lidow et al., 1989)] in crude homogenates or subceUular fractions of mammalian and nonmammalian retina, in order better to correlate the binding data with findings obtained in other experimental approaches (see next sections). PHARMACOLOGICAL STUDIES OF DOPAMINE RECEPTORS IN MAMMALIAN AND NONMAMMALIAN RETINA

The seminal paper of Brown and Makman (1972), who have demonstrated for the first time the existence of a dopamine-sensitive adenylate cyclase in rat and bovine retina, has prompted a large number of investigators to study dopamine receptors by this pharmacological technique. This early work was focused on dopamine receptors positively linked to the enzyme adenylate cyclase, or D1 subtype of receptors according to the classification of Kebabian and Calne (1979). Using isolated intact retinas or homogenized tissue of different animal species, a variety of drugs acting as dopamine agonists (endowed with intrinsic activity) or as dopamine antagonists (lacking intrinsic activity while inhibiting the positive effects of dopamine or other dopamine agonists) has been tested by several groups in order to characterize extensively the receptors mediating the dopamine-evoked activation of the cAMP,generating system (see the reviews by Schorderet and Magistretti, 1983; Kamp, 1985). More recently, some experiments were also undertaken in mammalian and nonmammalian retina (Qu et al., 1989; Nowak et al., 1990a) in order possibly

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to detect the dopamine receptors negatively coupled with adenylate cyclase (classified as D2 subtype). Although such attempts were initially confronted with some methodological difficulties to unmask the existence of retinal D2 receptors by measuring a decrease in cAMP accumulation or adenylate cyclase activity (Schorderet, 1989), other biochemical and physiological studies related to defining the retinal functions connected with Da- and/or D2-receptor involvement (see Putative or Proven Physiological Functions Linked to the Stimulation of Dopamine Receptors in Mammalian and Nonmammalian Retina) led to the proposal that the D2 subtype of receptors does exist in vertebrate retina as well (Dearry and Burnside, 1986a,b; Rogawski, 1987; Besharse et al., 1988; Piccolino et al., 1989). This assumption was finally supported by recent data obtained in retinas of different species such as frog (Iuvone, 1986), hen (Nowak et al., 1990b), and rat (Qu et al., 1989; Nowak et al., 1990a). However, in contrast to the unequivocal characterization of Da receptors in retinas of most, if not all, animal species studied so far, the revealing of D2 receptors seems to remain a difficult task being possibly linked to some methodological problems and/or to species specificity (Schorderet, 1989; Nowak et al., 1990c).

Dopamine Receptors Positively Coupled to Adenylate Cyclase (D~ Receptors) A positive coupling between recognition sites for dopamine or dopamine agonists (e.g. epinine, aporphines, aminotetralines) and adenylate cyclase has been found in retinas of an invertebrate [Octopus bimaculatus (Makman et al., 1975)] as well as of nonmammalian (including avians and fishes) and many mammalian (including monkeys) vertebrates (see the reviews by Schorderet and Magistretti, 1983; Kamp, 1985). In most cases, the studies of D1 receptors can be done either with isolated intact retinas or with retinal homogenates and they were recently reconducted in rat, rabbit, hen, and turtle with new types of selective D1 agonists, e.g., SKF 38393 (Qu et al., 1989; Schorderet, 1989; Piccolino et al., 1989; Nowak et al., 1990a,b,c). Markstein and his colleagues (Markstein et al., 1987; Fl/ickiger et al., 1988; Seiler et al., 1989) have used the calf retina homogenate as a model neural tissue to screen potential D1 agonists of diverse chemical structures including the novel 8/3-ergolene CK204-933, or the 8tramino-ergoline CQP201-403 and a series of monohydroxy-l,2,3,4,4a,5,10, 10a-octahydrobenz[g] quinolines. The latter screenings were essentially based on the method described by Kebabian et al. (1972) for the dopamine-sensitive adenylate cyclase of the rat caudate nucleus and slightly modified for calf retinal homogenates (Markstein et al., 1987). In these and other studies performed on retinas of hen, rat, rabbit, and calf, the pharmacological characterization of dopamine D1 receptors was also improved by the availability of a new selective D1 antagonist of the benzazepine family such as SCH 23390, which appeared to be a potent and selective blocker of the dopamine-induced accumulation of cAMP (Vanderheyden et al., 1986; De Keyser et al., 1988; Qu et al., 1989; Schorderet 1989; Nowark et al., 1990a,b,c). Up to now, similar experiments were not undertaken with the human retina. Among nonmammalian vertebrates, the retinas of teleost fish, specifically

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that of the carp (Cyprinus carpio) and of the turtle (Pseudemys scripta elegans) appear to be very well suitable for pharmacological and functional studies of dopamine-sensitive adenylate cyclase [Dowling and Watling, 1981; Watling and Dowling, 1981; Watling, 1983; Piccolino et al., 1989 (see also Putative or Proven Physiological Functions Linked to the Stimulation of Dopamine Receptors in Mammalian and Nonmammalian Retina)]. A purified preparation of the horizontal cells, implying enzymatic dissociation and subsequent isolation of the fractions by Ficoll gradients, was prepared by Van Buskirk and Dowling (1981) and used for detailed pharmacological and electrophysiological studies. Other attempts to isolate partly the retinal dopamine-sensitive adenylate cyclase had been done previously in the rabbit retina by Clement-Cormier and Redburn (1978), who have concentrated the enzyme in a Pz fraction, in which dopamine uptake and release also occur. Hopefully, more studies should be done now by means of various neurochemical techniques (immunocytochemical localization, affinity chromatography, cell sorting) in order to obtain an enriched preparation of a dopamine-sensitive adenylate cyclase of the best degree of purity.

Dopamine Receptors Negatively Coupled to Adenylate Cyclase (D2 Receptors) Although this topic was controversial during the last decade, due also to the difficult interpretation of some results obtained in binding studies (see Binding Studies of Dopamine Receptors in Mammalian and Nonmammalian Retina), new recent experimental evidence is in favor of the existence of D2 receptors, at least in lower vertebrates and some mammalian species. Qu et al. (1989) and Nowak et al. (1990a) have indeed shown that the rat retina contains D2 receptors, by introducing in their experimental protocol additional pharmacological agents such as forskolin and/or selective D2 agonists or antagonists. Forskolin, a diterpene extracted from the roots of Coleus forskohlii, is able to stimulate the activity of adenylate cyclase in a receptorqndependent way and is widely used to elevate intracellular cAMP in various target cells (Seamon and Daly, 1986). In the forskolin-exposed retina, the existence of D2 receptors negatively coupled to adenylate cyclase can then be unmasked by applying dopamine in the presence of a selective D1 antagonist such as SCH23390 (Qu et al., 1989; Nowak et al., 1990a,b) or a selective D2 agonist alone such as bromocriptine (Qu et al., 1989) or LY 171555 (syn.: quinpirole) (Nowak et al., 1990a,b). Thus, the diterpene was used as a pharmacological tool to elevate cAMP substantially (or maximally) before testing dopamine and dopamine-related drugs. Another trial was aimed at the possible detection of a dose-dependent decrease in basal cAMP levels induced by bromocriptine or LY 171555, as successfully achieved by Qu et al. (1989). These and other facts based on additional experiments performed in the presence of selective D2 antagonists, e.g., S-sulpiride, have clearly established that D2 receptors exist in the retina of rat (Qu et al., 1989; Nowak et al., 1990a). Similar results were found in retinas of some nonmammalian species, i.e., frog (Iuvone, 1986) and hen (Nowak et al., 1990b). In contrast, under similar experimental conditions, attempts to reveal the presence of D2 receptors negatively coupled to adenylate cyclase in rabbit retina were not successful (Schorderet, 1989; Nowak et al., 1990c), although the


311

existence of the retinal receptors of the D2 subtype has been demonstrated in the same species by other in vitro pharmacological approaches (see the following section, D2 Autoreceptors) as well as in some other vertebrates by functional tests (see Putative or Proven Physiological Functions Linked to the Stimulation of Dopamine Receptors in Mammalian and Nonmammalian Retina). The reason for this discrepancy is not known at the present time. A possible explanation would be that in the retina of rabbit (and in some other species but rat, hen, and possibly frog), a stimulation of D2 receptors that is not expressed by adenylate cyclase inhibition implies different mechanism(s) of transduction, as shown in other brain areas for presynaptic (Memo et al., 1986; Bowyer and Weiner, 1989) and postsynaptic (Stoof et al., 1986) D2 receptors. Further work is now needed to clarify this important question. DA Receptors Linked to DA Release and/or Synthesis (D 2 Autoreceptors) The early work of Dubocovich and Weiner (1981) has shown a modulation by dopamine and various dopamine-related drugs of the calcium-dependent [3H]dopamine release evoked by electrical stimulation in the [3H]aminepreloaded rabbit retina in vitro. These authors have suggested that the receptors involved might be of the D2 subtype, as confirmed later by the test of additional agents (Dubocovich and Weiner, 1982; 1985; Nowak, 1987). Interestingly, a subsequent comparison of the pharmacological characteristics of the receptors mediating dopamine release with those positively linked to the cAMP-generating system (D1 type) indicated that the two populations varied, as found by their different affinities for both dopamine agonists and antagonists (Dubocovich and Weiner, 1985). The electrically or high K+-evoked calcium-dependent [3H]dopamine release is similar, if not identical, to the release of exogenous ([3H]amine) or endogenous dopamine from vertebrate retina provoked by light stimulation (Bauer et al., 1980; Brainard and Morgan, 1987; Nowak, 1987; 1988; Godley and Wurtman, 1988; Nowak and Zurawska, 1989a). To our knowledge there are no published reports describing the modulatory effect of D2 agonists or D2 antagonists on the light-evoked dopamine release in the retina; nevertheless, we would like to suggest that the D2 receptor-mediated regulation of the stimulated calciumdependent dopamine release from the CNS tissues (including the light-evoked dopamine release in the vertebrate retina) is a general phenomenon. This suggestion is based (1) on the mentioned similarities between the dopamine releasing effect of light and membrane depolarizing stimuli and (2) on the fact that such D2 receptor-mediated regulation does exist in the case of dopamine release evoked by electric current and high K + in the incubation medium. Thus, the retina of the rabbit (and perhaps of other species) is a neural preparation which contains a population of pharmacologically distinguishable D2 receptors responsible for the modulation of dopamine release. This type of receptors is presumably located at presynaptic sites and it has been previously defined as autoreceptors (Carlsson, 1975). These receptors do not seem to be connected with adenylate cyclase inhibition [see Dopamine Receptors Negatively Coupled to Adenylate Cyclase (D2 Receptors); see also Bowyer and Weiner (1989)].

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A different methodological approach was recently exploited by Ofori et al. (1986a,b). Taken into account some possible artifacts due to the use of exogenous labeled dopamine for a preloading of synaptic stores (Herdon et al., 1985), a LCEC technique was set up for investigating not only the release (see above) but also the synthesis o f dopamine in rabbit retina in vitro. Thus, all experiments devoted to the study of these two experimental paradigms were aimed at the measurement of endogenous D A , already present or formed during a 40-min incubation in the presence of its immediate precursor, L-dopa (Ofori et al., 1986a). On the other hand, a net dissociation between de n o v o synthesis and release of dopamine can be pharmacologically achieved by the measurement of both L-dopa accumulation (for dopamine synthesis, in the presence of an aromatic amino acid decarboxylase inhibitor) and dopamine content (for release, the monoamine oxidase being blocked by pargyline) measured in the tissue as well as in the incubation medium (Ofori et aI., 1986b; Ofori and Schorderet, 1988). Under these experimental conditions, high potassium (in the presence or absence of extracellular calcium) was found to trigger both the synthesis and the release of dopamine, although Ca 2÷ modulated the two events in an opposite way. This cation partially reduced the K÷-induced dopamine synthesis and maximally enhanced dopamine release (Ofori et al., 1986b; Ofori and Schorderet, 1988). Interestingly, two agents which should, to some extent, interact with presynaptic autoreceptors (D E subtype), namely, 3-PPP and LY 171555, were also potent inhibitors of tyrosine hydroxylase activity. The first agent has been shown to be a selective dopamine-autoreceptor agonist (Hjorth et al., 1981) and, as such, could modulate the biosynthesis of dopamine (Chesselet, 1984; Feenstra et al., 1983; Haubrich and Pflueger, 1982). The second agent is currently considered as a selective DE agonist (Niznik, 1987). The effects of both agents were very similar; therefore, it can be postulated that a population of DE receptors in vertebrate retina does exist and that they are located presynapticaUy since their stimulation resulted in a decreased synthesis of the neurotransmitter. It remains to be elucidated, however, whether the D 2 autoreceptors linked to an inhibition of dopamine synthesis and the D 2 autoreceptors involved in the modulation of the stimulated calcium-dependent dopamine release are similar entities or separate units, although they constitute in the latter case a pharmacologically identical population of receptor subtype. Paradoxically, 3-PPP (and not LY 171555) provoked a release of dopamine in the absence of any pharmacological stimulus, although its effect was observed only at supramaximal concentrations (Ofori et al., 1986b; Ofori and Schorderet, 1988). LIGHT-DEPENDENT CHANGES IN REACTIVITY OF D O P A M I N E RECEPTORS IN VERTEBRATE RETINA

The ability of dopamine, as well as nonselective (e.g., apomorphine) or selective (e.g., SKF 38393) D1 agonists, to stimulate adenylate cyclase activity (or cAMP accumulation) is stronger in the dark-adapted than in the light-adapted retinas of cows (Gnegy et al., 1984), rats (Spano et al., 1976; Porceddu et al., 1987), rabbits (Nowak et al., 1990c), or adult hens (Sek and Nowak, unpublished)

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and in chicken embryo retina cells in culture (De Mello et al., 1982). This dark-dependent phenomenon has been described as a Dl-receptor supersensitivity. It is thought to be an adaptive postsynaptic response to decreased synthesis and release of dopamine from the retinal dopaminergic cells with a concomitant diminution of available neurotransmitter at the receptor sites. On the contrary, the same sites were most probably occupied by endogenous dopamine in the light-adapted retinas, since it is well documented that light activates the amine synthesis, release, and metabolism (Kramer, 1971; Bauer et al., 1980; Morgan, 1982; Sovilla and Schorderet, 1982; Cohen et al., 1983; Parkinson and Rando, 1983; Iuvone, 1984; Brainard and Morgan, 1987; Godley and Wurtman, 1988; Boatright et al., 1989; Nowak and Zurawska, 1989a). In harmony with the "cAMP" data are the results of binding experiments, in which the density of D1 receptors labeled with [3H]SCH 23390 was significantly higher in retinas of dark-adapted rats, rabbits, and adult hens compared to light-adapted animals (Porceddu et al., 1987; Sek and Nowak, unpublished). There are also some indications that D2 receptors may also undergo adaptive alteration to changes in environmental lighting. Thus De Mello et al. (1982) reported that the amount of specific binding sites labeled with [3H]spiroperidol (a preferential D2 receptor ligand; see Binding Studies of Dopamine Receptors in Mammalian and Nonmammalian Retina) was higher in chicken embryo retinas cultured for 5 days in darkness than in similar cultures kept under constant illumination. An identical observation was done in retinas of rabbits, that were housed for 7 days in darkness (Dubocovich et al., 1985). Interestingly, Nowak et al. (1990c), working on retinas isolated from rabbits adapted either to light or to darkness for 4 hr, have recently reported very similar Kd and Bmax values for specific [3H]spiroperidol binding in both experimental groups. Yet the response of the cAMP-generating system to dopamine, apomorphine, and SKF 38393 of the dark-adapted retinas was significantly stronger than that of the light-adapted tissues. The cited results suggest that the supersensitivity of the retinal D2 receptors may also occur, but only after a rather long period of dark adaptation. It remains to be established why there is a time-related variability between D1 and D2 receptors in the development of receptor supersensitivity in retinas adapted to darkness. One possible explanation for this discrepancy may lie in a different location of both types of dopamine receptors, since D1 receptors are present in either horizontal or amacrine cells, or both, and D2 (postsynaptic) receptors--mainly in photoreceptors; this may in turn be connected with dissimilar physiological processes in which these receptor populations are involved (see the next section).

PUTATIVE OR PROVEN PHYSIOLOGICAL FUNCTIONS LINKED TO THE STIMULATION OF DOPAMINE RECEPTORS IN MAMMALIAN A N D NONMAMMALIAN RETINA

In parallel with biochemical and pharmacological studies aimed at the characterization of dopamine receptors in vertebrate retina, series of physiologi-

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cal attempts were applied to establish the role(s) of retinal dopamine and, consequently, those of its receptors. In analogy with weU-known dopamine function in some areas of the brain (Seeman, 1981; Bischoff, 1986), this catecholamine is actually considered as a retinal neurotransmitter or neuromodulator (for reviews, see Ehinger, 1983; Dowling, 1986; Nowak, 1988; Daw et al., 1989). Recent experimental work coming from different laboratories indicates that it may be involved in the regulation of (1) electrical activity and communication (through gap junctions) between horizontal cells, (2) movements of photoreceptor cells and migration of melanin granules in retinal pigment epithelial cells, and (3) synthesis of melatonin in photoreceptor cells. There are also some other indications suggesting that dopamine may regulate cholinergic neurotransmission in rat and rabbit retina (Yeh et al., 1984; Hensler and Dubocovich, 1986; Hensler et al., 1987). Moreover, it was implicated as a growth regulator in the developing retina (Lankford et al., 1988).

Regulation of the Horizontal Cells' Activity: Involvement of D1 and Dz Receptors There is now a substantial evidence documenting that horizontal cells communicate each other by means of electrical synapses in retinas of some vertebrates. This tight electrical coupling between neighboring horizontal cells, which enables a rapid spreading of electrically coded information from cell to cell, contributes to an extended receptive field size (corresponding to the large spatial summation area) of these cells. This phenomenon has been consistently detected in electrophysiological experiments (see Teranishi et al., 1984; Dowling, 1986; Piccolino, 1986; Piccolino and Demontis, 1988). Using the fluorescent dye Lucifer yellow, it has been shown in the retina of carp and white perch (Teranishi et al., 1984; Tornqvist et al., 1988) as well as of turtle (Piccolino and Demontis, 1988) that, upon injection into a horizontal cell, the dye normally diffuses to several adjacent horizontal cells via gap junctions. Exogenously applied dopamine markedly restricts the area of the dye penetration, most probably through its direct action (i.e., not involving any intermediary neurons) on horizontal cell coupling. In line with these findings are the results of electrophysiological measurements performed on both isolated intact retinas (Teranishi et al., 1984; Mangel and Dowling, 1985; Piccolino and Demontis, 1988; Witkovsky et al., 1988a) and cultured horizontal cells (Lasater and Dowling, 1985; Yang et al., 1988), which showed that the amine decreases the conductance of the electrical junctions between horizontal cells. These dopamineinduced effects were mimicked by stable, nonhydrolyzable cAMP analogues and by a selective D1 agonist such as SKF 38393. Moreover, they were blocked by a selective D1 antagonist such as SCH 23390 (and not by the selective D 2 antagonists raclopride and remoxipride). Thus, it has been concluded that the D1 subtype of receptors (positively linked to adenylate cyclase) was involved in this dopamine action. According to recent data of Witkovsky et al. (1988a,b), dopamine seems to be also capable of modifying the photoreceptor-derived input to the horizontal

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cells. In elegant electrophysiological experiments performed on eye-cups of the frog X e n o p u s laevis, dopamine has been shown to emphasize the light-driven cone input and to reduce the rod input. Its action was mimicked by either selective D1 or D2 agonists, such as SKF 38393 and LY 171555, respectively. Yet the selective D1 antagonist SCH 23390 blocked exclusively the effect of SKF 38393 (and not that of LY 171555), and spiroperidol--a rather selective De antagonist--prevented the action of LY 171555 and did not modulate the SKF 38393 effect. In addition, the dopamine-induced modulations of the light-evoked response of the horizontal cells were not blocked by either a D 1 or D2 antagonist alone, but they were inhibited only by the combination of SCH23390 and spiroperidol. Witkovsky et al. (1988a,b) have postulated that the D2 receptormediated changes in horizontal cell electrical activity (evoked by dopamine) resulted from the activation of the neurotransmitter receptors located on cone photoreceptors. Thus, the stimulation of these De receptors indirectly affects the horizontal cell activity, most probably by increasing the release of a cone transmitter. The D1 receptors, whose stimulation alters the light-evoked responses, would be present on horizontal cells. Piccolino and co-workers, on the basis of the results obtained with the selective D2-receptor agonist LY 171555, which increased the coupling between the horizontal cells of turtle retina, have also recently suggested a possible additional involvement of the Dz subtype of receptors in the control of this phenomenon (Piccolino and Demontis, 1988; see also Piccolino et al., 1989). Although the authors did not discuss the mechanism of action of LY 171555, it would be not unexpected [by comparing these data with those of Witkovsky et al. (1988a,b)] that the drug might exert its effect by interacting with Dz receptors situated in photoreceptor membrane. As mentioned above, the activity of horizontal cells seems to be regulated by inputs from photoreceptors and interplexiform cells. In retinas of fish, rat, and Cebus monkey, only the latter cells use dopamine as their neurotransmitter, whereas in the cat retina dopamine is probably contained in both amacrine and interplexiform cells. However, in retinas of other species, such as frog, hen, turtle, and rabbit, dopamine is contained in a subpopulation of amacrine cells (see Ehinger, 1983). Since no evidence has been provided yet for a direct connection between horizontal cells and amacrine cells, dopamine, originating from the dopaminergic amacrines, has to diffuse within the tissue to reach the target cells, i.e., horizontal cells for D1 receptors and photoreceptor cells for D2 receptors, implicating a local hormone-like action of the catecholamine at least in retinas of several species. In summary, the various physiological data discussed in this section strongly suggest that both dopamine D1 and D2 receptors may be involved in the regulation of the horizontal cell activity, strengthening their importance in visual processing. Regulation of Retinomotor Movements: Role of Dz Receptors Light/dark-adaptive movements of photoreceptors (e.g., elongation/contraction) and pigment (melanin) granules in the retinal pigment epithelium (RPE)

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cells (e.g., aggregation/dispersion) appear to be other retinal events regulated by dopamine. All these events clearly occur in retinas of lower vertebrates (e.g., amphibians, fish) in response to changes in environmental lighting and time of the day. In the dark phase of any imposed light:dark illumination cycle, or at night, cones elongate, rods contract, and melanin pigment aggregates, cAMP seems to be involved in the regulation of these dark-dependent events since they are all provoked by agents which increase its intracellular levels, namely dibutyryl cyclic AMP (d,b-cAMP), forskolin, and PDE inhibitors. The opposite movements (inhibited by cAMP) take place in the light phase of a given illumination cycle or during the daytime (see the reviews by Besharse, 1982; Burnside and Nagle, 1983; Besharse et al., 1988; Dearry and Burnside, 1988). It has recently been shown, mainly by the work of Burnside and Besharse, that dopamine can mimic the effects of light in the dark-adapted retinas of teleost fish and amphibians by inducing the light-adaptive movements, such as cone contraction, rod elongation, and RPE pigment dispersion (Dearry and Burnside, 1985, 1986a,b; Pierce and Besharse, 1985; 1986). These effects of dopamine are obviously mediated by the D2 subtype of receptors since (1) they were mimicked by LY 171555, and not by SKF 38393, selective D2 and D1 agonists, respectively; (2) the effects of dopamine and apomorphine--a nonselective receptor agonist-were not affected by a D1 antagonist (SCH23390), but they were markedly reduced by the D2 antagonists S-sulpiride and spiroperidol; and (3) the effects of light, similarly to those of dopamine and apomorphine, were also antagonized by S-sulpiride and spiroperidol. A detailed pharmacological characterization of the dopamine-evoked cone contraction in isolated dark-cultured retinas of green sunfish (Lepomis cyanellus), performed with a series of selective D1and D2-receptor antagonists, has revealed the following order of potency: Ssulpiride > haloperidol >> domperidone = metoclopramide > fluphenazine > SCH 23390 (Dearry and Burnside, 1986a); this rank order of potency is in accordance with that proposed earlier for D2-receptor antagonists (Stool and Kebabian, 1984). It seems likely that the D2 receptors, whose activation is connected with the induction of the light-adaptive cone and RPE retinomotor movements in the dark-adapted retinas, are negatively linked to adenylate cyclase. Dopamine has, in fact, been able to inhibit similar movements induced by forskolin and IBMX, and not those evoked by d,b-cAMP (Dearry and Burnside, 1985; see also Dearry and Burnside, 1988). Although direct evidence for the D2 receptor-mediated inhibition of adenylate cyclase activity, or cAMP accumulation, in green sunfish retina is lacking, this type of negative biochemical signal was demonstrated in retinas of frog (Iuvone, 1986), hen (Nowak et al., 1990b), and rat (Qu et aI., 1989; Nowak et al., 1990a). The light/dark-adaptive photoreceptor movements occur only in lower vertebrates. Yet the movements of melanin pigment granules in RPE cells appear to take place in many vertebrate species, including mammals. Therefore, it cannot be excluded that dopamine D2 receptors might be involved in the regulation of the light/dark-dependent pigment migration in retinas of primates and man. In support of such a suggestion are recent pharmacological as well as


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clinical studies which showed that dopamine is able to increase visual acuity in both MPTP-treated monkeys and parkinsonian patients (Bodis-Wollner et al., 1986; Bodis-Wollner, 1988; Iuvone et al., 1989).

Inhibition of Serotonin N-Acetyitransferase Activity: A Event

D 2

Receptor-Mediated

A number of studies has shown that retinas of both lower and higher vertebrates are able to synthesize melatonin locally (for reviews, see Pang and Allen, 1986; Wiechmann, 1986; Besharse et al., 1988; Nowak et al., 1989; Nowak, 1990). The melatonin-generating system in retina is similar to that operating in the pineal gland and consists of four enzymes which convert L-tryptophan to melatonin: L-tryptophan hydroxylase, aromatic amino acid decarboxylase, serotonin N-acetyltransferase (NAT), and hydroxyindole-Omethyltransferase (HIOMT). Among these four enzymes, NAT is considered to play the key regulatory role in melatonin biosynthesis. Only its activity, in parallel with melatonin levels, fluctuates rhythmically and distinctly throughout the day and displays low and high values during subjective day and night hours, respectively, of a given light:dark illumination cycle (Reiter, 1984; Besharse et al., 1988; Nowak et al., 1989). The experimental induction of NAT activity, with subsequent stimulation of melatonin biosynthesis, can be achieved in vitro and in vivo by agents that increase the concentration of cAMP, such as forskolin, PDE inhibitors or d,b-cAMP, in the retina of frog (Iuvone and Besharse, 1986), hen (Nowak et al., 1990b), and rat (Zurawaska and Nowak, 1990; Nowak, 1990). It should be noted, however, that although D 1 receptors are positively coupled to adenylate cyclase in vertebrate retina and their stimulation leads to marked increases in retinal cAMP levels, these receptors are not functionally connected with the melatoningenerating system (Nowak and Zurawska, 1989b; Zawilska and Iuvone, 1989). It is likely that different cell compartments are involved in melatonin biosynthesis (photoreceptors) and Dl-dependent generation of cAMP (probably a subpopulation of amacrine cells and horizontal cells). The- drug- or night-stimulated NAT activity can be dramatically reduced in vitro by either dopamine or selective D2 agonists (bromocriptine, LY 171555), but not by a selective D1 agonist (SKF 38393) in retinas of Xenopus laevis (Iuvone, 1986) and hen (Nowak et al., 1989). Similar effects were observed in experiments in oivo where the nighttime peak of NAT activity in retinas of chicken (Zawilska and Iuvone, 1989) and adult hen (Nowak, 1990; Nowak and Zurawska, 1990b) was substantially decreased to approximately the same level by both light exposure and treatment of the animals with selective D2 agonists. Since the induction of NAT is a cAMP-dependent process, and a selective stimulation of D2 receptors in frog eye-cups (Iuvone, 1986) as well as in whole hen retinas (Nowak et al., 1989) decreases simultaneously NAT activity and cAMP accumulation, it is believed that these two D2 receptor-dependent biochemical events are functionally interrelated. A crucial role of dopamine (and D2 receptors) in the regulation of retinal melatonin biosynthesis is also supported by experiments showing that selective D2 an-

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tagonists, when combined with PDE inhibitors, were capable of effectively and substantially increasing NAT activity in the retinas of frogs and hens maintained under light conditions (Iuvone et al., 1987; Nowak and Zurawska, 1989b). Several reports suggest that the photoreceptors are the major site of melatonin synthesis in the retina (Wiechmann, 1986; Besharse et al., 1988). It is therefore assumed that the D2 receptors mediating the inhibitory effects of dopamine on NAT activity are located on photoreceptors. Their stimulation by dopamine itself or a D2-agonist evokes the following sequence of events: (1) inhibition of adenylate cylase activity linked to D2 receptors; (2) decrease in cAMP levels inside the photoreceptors; (3) inhibition of NAT induction (inhibition of the de novo synthesis of the enzyme protein); and (4) block of the melatonin biosynthesis at the step of serotonin acetylation (NAT). Since melatonin plays a role of local neuromodulator for some rhythmic retinal events (such as photoreceptor outer segment disk shedding, retinomotor movements; see Regulation of Retinomotor Movements: Role of D2 Receptors), with its synthesis being controlled by the dopamine input (through D2 receptors), it is postulated that dopamine D2 receptors are functionally implicated in all those retinal phenomena which follow circadian rhythmicity and which are dependent on light/dark conditions.

Other D~ Receptor-Mediated Events [3H]Acetylcholine Release f r o m Rabbit Retina Hensler and Dubocovich (1986) and Hensler et al. (1987) have recently reported that an incubation of rabbit retinal pieces (preloaded with [3H]choline) with dopamine (0.001-10mM) increases the calcium-dependent release of [3H]acetylcholine in a concentration-dependent manner (the efflux of [3H]choline was unaffected). The action of dopamine was obviously mediated through the D1 subtype of receptors, since it was blocked by SCH 23390 (and not by S-sulpiride) and it was mimicked by selective D1 agonists such as SKF 38393 and SKF 82526. It also was not influenced by the stimulation of Dz-, tr2-, and fl-adrenergic receptors. The dopamine action is most probably dependent on cAMP, since forskolin, IBMX, and 8-bromo-cAMP also provoked the release of [3H]acetylcholine (Hensler and Dubocovich, 1986). Furthermore, the comparable releasing effects (sensitive to SCH 23390) of tyramine and d-amphetamine suggest a possible involvement of endogenous dopamine for the action of these indirect sympathomimetic agents (Hensler and Dubocovich, 1986). In other experiments, the same authors have demonstrated the effectiveness of two GABA-receptor antagonists (picrotoxin and bicuculline) to increase the spontaneous release of the labeled acetylcholine and to potentiate the acetylcholine releasing effect of dopamine. All these data may be indicative of a physiological importance of the D1 receptor-mediated release of [3H]acetylcholine in rabbit retina. Inhibition of Neuronal Growth Cones in Embryonic Avian Retina It has recently been shown by several authors (De Mello, 1978; Agui et al., 1988) that dopamine strongly stimulates adenylate cyclase activity in chicken embryo retina by interacting with D1 receptors. Similar effects were also observed in the cultured embryonic tissue of the same species (De Mello et al., 1982). The

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functional significance of this D1 receptor-mediated activation of the cAMPgenerating system at a stage of early embryonic development remained unclear. An additional recent report by Lankford et al. (1988), who have used low-density monolayer cultures of embryonic chicken retina, has proven that about 25% of the growing retinal neurons responded to 1/tM dopamine as expressed by an inhibition of filopodial motility, followed by a flattening and retraction of growth cones. The incorporation into the culture medium of haloperidol or SCH 23390 inhibited the effects of dopamine, whereas forskolin mimicked the catecholamine action. Thus, these data suggest that, in addition to its known neuromodulator role demonstrated in vertebrate retina (Dowling, 1986), dopamine may function as a morphogenic growth regulator, through a possible interaction with Dx receptors. CONCLUSIONS AND PERSPECTIVES

In recent years, the cellular mechanisms underlying the physiological actions of dopamine in vertebrate retina have been intensively studied in a great number of laboratories. As in the brain, the retinal dopamine is contained in specific cells (either amacrine or interplexiform, or both), where its biological actions are mediated through two different subtypes of receptors, named D1 and D2. Among pharmacologically distinguishable D2 receptors, a subclass that is not linked to adenylate cyclase seems to exist. Defined as autoreceptors, these D2 receptors are possibly involved in the autoregulation of the calcium-dependent synthesis and release of dopamine in specific neuronal cells. A thorough and sustained investigation devoted to retinal dopamine receptors may have at least three advantages. The first is that it should improve the understanding of the mechanism(s) of action of this neurotransmitter, particularly at various levels of the complex retinal machinery. The second is related to the functioning of central dopamine receptors in general; by changing lighting conditions under which the animals of various species are housed, one can trigger various physiological adaptive processes implying a modulation of the synaptic homeostasis of dopamine~an endogenous ligand--and a concomitant regulation of the degree of ligand-receptor interaction. The modulation of the synaptic adaptation by light:dark conditioning can thus be achieved without any pharmacological treatment in order to investigate various receptor adaptive phenomena such as supersensitivity or desensitization. The last advantage lies in the fact that the retina, as an integral part of the central nervous system, is offering an appropriate neuronal network to study the characteristics of dopamine receptors and to screen for potential agonists and/or antagonists of very distinct selectivity toward one or the other receptor subtype. ACKNOWLEDGMENTS

This work was supported by Swiss National Science Foundation Grant 31-25625-88 to M.S. and by Grants CPBP 04.01.6.14 and 06.03.1.3 to J.Z.N. The authors wish to thank Ms Sylvianne Bonnet for her excellent secretarial assistance.

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REFERENCES Agui, T., Chase, T. N., and Kebabian, J. W. (1988). Identification of Dl-dopamine receptor in chicken embryo retina with [12SI]SCH 23982. Brain Res. 452:49-56. Amlaiky, N., and Caron, M. G. (1986). Identification of the D2-dopamine receptor binding subunit in several mammalian tissues and species by photoaffinity labeling. J. Neurochem. 47:196-204. Bauer, B., Ehinger, B., and Aberg, L. (1980). [3H]dopamine release from the rabbit retina. Albrecht Graefes Arch. Klin. Ophthalmol. 215:71-78. Besharse, J. C. (1982). The daily light-dark cycle and rhythmic metabolism in the photoreceptorpigment epithelial complex. Prog. Retin. Res. 1:81-124. Besharse, J. C., Iuvone, P. M., and Pierce, M. E. (1988). Regulation of rythmic photoreceptor metabolism: A role for post-receptoral neurons. Prog. Retin. Res. 7:21-61. Bischoff, S. (1986). Mesohippocampal dopamine system. Characterization, functional and clinical implications. In The Hippocampus, Vol. 3. (R. L. Isaacson and K. H. Pribram, Eds.). Plenum, New York, pp. 1-32. Bodis-Wollner, I. (1988). Altered spatio-temporal contrast vision in Parkinson's disease and MPTP treated monkeys: The role of dopamine. In Dopaminergic Mechanisms in Vision (I. BodisWollner and M. Piccolino, Eds.), Alan R. Liss, New York, pp. 205-220. Bodis-Wollner, I., and Piccolino, M. (Eds.) (1988). Dopaminergic Mechanisms in Vision, Alan R. Liss, New York. Bodis-Wollner, I., Onofrj, M. C., Marx, M. S., and Mylin, A. T. (1986). Visual evoked potentials in Parkinson's disease: Spatial frequency, temporal rate, contrast and the effect of dopaminergic drugs. In Evoked Potentials. Frontiers o f Clinical Neuroscience, Vol. 3 (R. O. Cracco and I. Bodis-Wollner, Eds.), Alan R. Liss, New York, pp. 307-319. Boatright, J. H., Hoel, M. J., and Iuvone, P. M. (1989). Stimulation of endogenous dopamine release and metabolism in amphibian retina by light- and K+-evoked depolarization. Brain Res. 482:164-168. Bowyer, J. F., and Weiner, N. (1989). K ÷ channel and adenylate cyclase involvement in regulation of Ca÷+-evoked release of [3H]dopamine from synaptosomes. J. Pharmacol. Exp. Ther. 248:514520. Brainard, G. C., and Morgan, W. W. (1987). Light-induced stimulation of retinal dopamine: A dose-response relationship. Brain Res. 424:199-203. Brann, M. R., and Young, W. S., III, (1986). Dopamine receptors are located on rods in bovine retina. Neurosci. Lett. 69:221-226. Brown, J. H., and Makman, M. H. (1972). Stimulation by dopamine of adenylate cyclase in retinal homogenates and of adenosine-3':5'-cyclic monophosphate formation in intact retina. Proc. Natl. Acad. Sci. USA 69:539-543. Burnside, B., and Nagle, B. (1983). Retinomotor movements of photoreceptors and retinal pigment epithelium: Mechanisms and regulation. Prog. Retin. Res. 3:67-109. Carlsson, A. (1975). Dopaminergic autoreceptors. In Chemical Tools in Catecholamine Research 1I, Vol. 2 (O. Almgren, A. Carlsson, and J. Engel, Eds.), North-Holland, Amsterdam, pp. 219-225. Carlsson, A., and Lindquist, M. (1963). Effect of chlorpromazine and haloperidol on the formation of 3-methoxytyramine and normethanephrine in mouse brain. Acta Pharmacol. Toxicol. 20:140144. Chesselet, M. F. (1984). Presynaptic regulation of neurotransmitter release in the brain: Facts and hypotheses. Neuroscience 12:347-375. Clement-Cormier, Y., and Redburn, D. A. (1978). Dopamine-sensitive adenylate cyclase in retina-subcellular distribution. Biochem. Pharmacol. 27:2281-2282. Cohen, J., Hadjiconstantinou, M., and Neff, N. H. (1983). Activation of dopamine-containing amacrine cells of retina: Light-induced increase of acidic dopamine metabolites. Brain Res. 260:125-127. Creese, I., Sibley, D. R., Hamblin, M. W., and Left, S. E. (1983). The classification of dopamine receptors: Relationship to radioligand binding. Annu. Rev. Neurosci. 6:43-71. Daw, N. W., Brunken, W. J., and Parkinson, D. (1989). The function of synaptic transmitters in the retina. Annu. Rev. Neurosci. 12:205-225. Dearry, A., and Burnside, B. (1985). Dopamine inhibits forskolin- and 3-isobutyi-l-methylxanthineinduced dark-adaptive retinomotor movements in isolated teleost retina. J. Neurochem. 44:1753-1763. Dearry, A., and Burnside, B. (1986a). Dopaminergic regulation of cone retinomotor movement in isolated teleost retinas. I. Induction of cone contraction is mediated by D z receptors. J. Neurochem. 46:1006-1021.

Retinal Dopamine Di and D2 Receptors

321

Dearry, A., and Burnside, B. (1986b). Dopaminergic regulation of cone retinomotor movement in isolated teleost retinas. II. Modulation by gamma-aminobutyric acid and serotonin. J. Neurochern. 46:1022-1031. Dearry, A., and Burnside, B. (1988). Dopamine induces light-adaptive retinomotor movements in teleost photoreceptors and retinal pigment epithelium. In Dopaminergic Mechanisms in Vision (I. Bodis-Wollner and M. Piccolino, Eds.), Alan R. Liss, New York, pp. 109-135. De Keyser, J., Dierckx, R., Vanderheyden, P., Ebinger, G., and Vauquelin, G. (1988). D1 dopamine receptors in human putamen, frontal cortex and calf retina. Differences in guanine nucleotide regulation of agonist binding and adenylate cyclase stimulation. Brain Res. 443:77-84. De Mello, F. G. (1978). The ontogeny of dopamine-dependent increase of adenosine 3'-5'-cyclic monophosphate in the chick retina. J. Neurochem. 31:1049-1053. De Mello, M. C. F., Ventura, A. L. M., Paes de Carvalho, R., Klein, W. L., and De Mello, F. G. (1982). Regulation of dopamine- and adenosine-dependent adenylate cyclase systems of chicken embryo retina cells in culture. Proc. Natl. Acad. Sci. USA 79:5708-5712. De Montis, G., Porceddu, M. L., Pepitoni, S., Serra, G. P., and Biggio, G. (1988). D1 dopamine receptors in the retina of adult and senescent rats: Physiological and pharmacological modulation. In Doparninergic Mechanisms in Vision (I. Bodis-Wollner and M. Piccolino, Eds.), Alan R. Liss, New York, pp. 71-93. Dowling, J. E. (1986). Dopamine: A retinal neuromodulator ?. TINS 9:236-240. Dowling, J. E., and Watling, K. J. (1981). Dopaminergic mechanisms in the teleost retina. II. Factors affecting the accumulation of cyclic AMP in pieces of intact carp retina. J. Neuroehem. 36"569-579. Dubocovich, M. L., and Weiner, N. (1981). Modulation of the stimulation-evoked release of [3H]dopamine in the rabbit retina. J. Pharmacol. Exp. Ther. 219:701-707. Dubocovich, M. L., and Weiner, N. (1982). Modulation of the stimulation-evoked release of [3H]dopamine through activation of dopamine autoreceptors of the D2 subtype in the isolated rabbit retina. In Advances in the Biosciences, Vol. 3Z Advances in Dopamine Research, (M. Kohsaka, T. Shohmori, Y. Tsukada, and G. N. Woodruff, Eds.), Pergamon Press, Oxford, pp. 273-278. Dubocovich, M. L., and Weiner, N. (1985). Pharmacological differences between the D2 autoreceptor and the D~ dopamine receptor in rabbit retina. J. Pharrnacol. Exp. Ther. 2,33:747-754. Dubocovich, M. L., and Zahniser, N. R. (1982). [3H]Spiperone can be used to label either a single or multiple dopaminergic sites in rabbit retina and striatum. Br. J. Pharrnacol. 77:367P. Dubocovich, M. L., Lucas, R. C., and Takahashi, J. S. (1985). Light-dependent regulation of dopamine receptors in mammalian retina. Brain Res. 335:321-325. Ehinger, B. (1983). Functional role of dopamine in the retina. Prog. Retin. Res. 2:213-232. Elena, P. P., Denis, P., Kosina-Boix, M., and Lapalus, P. (1989). Dopamine receptors in rabbit and rat eye: Characterization and localization of DAm and DA2 binding sites. Curr. Eye Res. 8:75-83. Feenstra, M. G. P., Sumners, C., Goedemoed, J. H., de Vries, J. B., Rollema, H., and Horn, A. S. (1983). A comparison of the potencies of various dopamine receptor agonists in models for preand postsynaptic receptor activity. Naunyn Schmiedebergs Arch. Pharmacol. 324:108-115. Fliickiger, E., Briner, U., Clark, B., Closse, A., Enz, A., Gull, P., Hoffmann, A., Markstein, R., Tolcsvai, L., and Wagner, H. R. (1988). Pharmacodynamic profile of COP 201-403, a novel 8o;-amino-ergoline. Experientia 44:431-436. Gnegy, M. E., Murihead, N., and Harrison, J. K. (1984). Regulation of calmodulin- and dopamine-stimulated adenylate cyclase activities by light in bovine retina. J. Neurochem. 42:1632-1640. Godley, B. F., and Wurtman, R. J. (1988). Release of endogenous dopamine from the superfused rabbit retina in vitro: Effect of light stimulation. Brain Res. 452:393-395. Gredal, O., Parkinson, D., and Nielsen, M. (1987). Binding of [3H]SCH 23390 to dopamine D 1 receptors in rat retina in vitro. Eur. J. Pharmacol. 137:241-245. Haubrich, D. R., and Pflueger, A. B. (1982). The autoreceptor control of dopamine synthesis. An in vitro and in vivo comparison of dopamine agonists. Mol. Pharmacol. 21:114-120. Hensler, J. G., and Dubocovich, M. L. (1986). Dl-dopamine receptor activation mediates [3H]acetylcholine release from rabbit retina. Brain Res. 398:407-412. Hensler, J. G., CottereU, D. J., and Dubocovich, M. L. (1987). Pharmacological and biochemical characterization of the D1 dopamine receptor mediating acetylcholine release in rabbit retina. J. Pharmacol. Exp. Ther. 243:857-867. Herdon, H., Strupish, J., and Nahorski, S. R. (1985). Differences between the release of radiolabelled and endogenous dopamine from superfused rat brain slices: Effects of depolarizing stimuli, amphetamine and synthesis inhibition. Brain Res. 348:309-320.

322


Hjorth, S., Carlsson, A., Wikstrom, H., Lindberg, P., Sanchez, D., Hacksell, U., Arvidsson, L.-E., Svensson, U., and Nilsson, J. L. G. (1981). 3-PPP, a new centrally acting DA-receptor agonist with selectivity for autoreceptors. Life Sci. 28:1225-1238. Iuvone, P. M. (1984). Regulation of retinal dopamine biosynthesis and tyrosine hydroxylase activity by light. Fed. Proc. 43:2709-2713. Iuvone, P. M. (1986). Evidence for a D 2 dopamine receptor in frog retina that decreases cyclic AMP accumulation and serotonin N-acetyltransferase activity. Life Sci. 38:331-342. Iuvone, P. M., and Besharse, J. C. (1986). Cyclic AMP stimulates serotonin N-acetyltransferase activity in Xenopus retina in vitro. J. Neurochem. 46:82-88. Iuvone, P. M., Boatright, J. H., and Bloom, M. M. (1987). Dopamine mediates the light-evoked suppression of serotonin N-acetyltransferase activity in retina. Brain Res. 418:314-324. Iuvone, P. M., Tigges, M., Fernandes, A., Tigges, J. (1989). Dopamine synthesis and metabolism in rhesus monkey retina: Development, aging, and the effect of monoocular deprivation. V/s. Neurosci. 2:465-471. Jensen, R. J., and Daw, N. W. (1983). Towards an understanding of the role of dopamine in the mammalian retina. Vision Res. 23:1293-1298. Kamp, C. W. (1985). The dopamine system of the retina. In Retinal Transmitters and Modulators: Models for the Brain. Vol. H (W. W. Morgan, Ed.), CRC Press, Boca Raton, Fla. pp. 1-31. Kebabian, J. W., and Calne, D. B. (1979). Multiple receptors for dopamine. Nature 277:93-96. Kebabian, J. W., Petzold, G. L., and Greengard, P. (1972). Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the "dopamine receptor." Proc. Natl. Acad. Sci. USA 69:2145-2149. Kebabian, J. W., Agui, T., van Oene, J. C., Shigematsu, K., and Saavedra, J. M. (1986). The D 1 dopamine receptor: New perspectives. TIPS 7:96-99. Kramer, S. G. (1971). Dopamine: A retinal neurotransmitter. I. Retinal uptake, storage, and light-stimulated release of [3H]dopamine in vivo. Invest. Ophthalmol. 10:438-452. Lankford, K. L., De Mello, F. G., and Klein, W. L. (1988). Dl-type dopamine receptors inhibit growth cone motility in cultured retina neurons: Evidence that neurotransmitters act as morphogenic growth regulators in the developing central nervous system. Proc. Natl. Acad. Sci. USA 85:4567-4571. Lasater, E. M., and Dowling, J. E. (1985). Dopamine decreases conductance of the electrical junctions between cultured retinal horizontal cells. Proc. Natl. Acad. Sci. USA 82:30253029. Lidow, M. S., Goldman-Rakic, P. S., Rakic, P., and Innis, R. B. (1989). Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3H]raclopride. Proc. Natl. Acad. Sci. USA 86:6412-6416. Magistretti, P. J., and Schorderet, M. (1979). Dopamine receptors in bovine retina: Characterization of [3H]spiroperidol binding and its use for screening dopamine receptor affinity of drugs. Life Sci. 25:1675-1686. Makman, M. H., and Dvorkin, B. (1986). Binding sites for [3H]SCH 23390 in retina: Properties and possible relationship to dopamine Dl-receptors mediating stimulation of adenylate cyclase. Mol. Brain Res. 1:261-270. Makman, M. H., Brown, J. H., and Mishra, R. K. (1975). Cyclic AMP in retina and caudate nucleus: Influence of dopamine and other agents. Adv. Cyclic Nucleotide Res. 5:661-679. Makman, M. H., Dvorkin, B., Horowitz, S. G., and Thai, L. J. (1980a). Retina contains guanine nucleotide sensitive and insensitive classes of dopamine receptors. Eur. J. Pharmacol. 63:217222. Makman, M. H., Dvorkin, B., Horowitz, S. G., and Thai, L. J. (1980b). Properties of dopamine agonist and antagonist binding sites in mammalian retina. Brain Res. 194:403-418. Makman, M. H., Dvorkin, B., and Klein, P. N. (1982). Sodium ion modulates D 2 receptor characteristics of dopamine agonist and antagonist binding sites in striatum and retina. Proc. Natl. Acad. Sci. USA 79:4212-4216. Mangel, S. C., and Dowling, J. E. (1985). Responsiveness and receptive field size of carp horizontal cells are reduced by prolonged darkness and dopamine. Science 229:1107-1109. Markstein, R., Enz, A., Vigouret, J. M., Jaton, A., Closse, A., Briner, U., and Gull, P. (1987). Biochemical, behavioural, and endocrine effects of CK 204-933, a novel 8fl-ergolene. J. Neural Transm. 69:179-199. McGonigle, P., Wax, M. B., and Molinoff, P. B. (1988). Characterization of binding sites for [3H]spiroperidol in human retina. Invest. Ophthalmol. Vis. Sci. 29:687-694. Memo, M., Missale, C., Carruba, M. O., and Spano, P. F. (1986). D2 dopamine receptors associated with inhibition of dopamine release from rat neostriatum are independent of cyclic AMP. Neurosci. Lett. 71:192-196.

Retinal Dopamine D~ and D2 Receptors

323

Monsma, F. J. Jr., Brassard, D. L., and Sibley, D. R. (1989). Identification and characterization of D~ and D2 dopamine receptors in cultured neuroblastoma and retinoblastoma clonal cell lines. Brain Res. 492:314-324. Morgan, W. W. (1982). Dopamine neurons in the retina: A new pharmacological model. In Cell Biology o f the Eye (D. C. McDevitt, Ed.), Academic Press, New York, pp. 553-554. Niznik, H. B. (1987). Dopamine receptors: Molecular Structure and function. Mol. Cell. Endocrinol. 54:1-22. Nowak, J. Z. (1987). The retina as a model neural tissue: Comparative studies on retinal and brain aminergic mechanisms. Pol. J. Pharmacol. Pharm. 39:451-482. Nowak, J. Z. (1988). The isolated retina as a model of the CNS in pharmacology. TIPS 9:80-82. Nowak, J. Z. (1990). Control of melatonin formation in vertebrate retina. Adv. Pineal Res. 4:81-90. Nowak, J. Z., and Zurawska, E. (1989a). Dopamine in the rabbit retina and striatum: Diurnal rhythm and effect of light stimulation. J. Neural Transm. 75:201-212. Nowak, J. Z., and Zurawska, E. (1989b). Serotonin N-acetyltransferase (NAT) activity in hen retina and pineal gland: In vivo pharmacological induction at noon and antagonism of the light-evoked suppression at night. Neurochern. Int. 15:567-573. Nowak, J. Z., Zurawska, E., and Zawilska, J. (1989). Melatonin and its generating system in vertebrate retina: Circadian rhythm, effect of environmental lighting and interaction with dopamine. Neurochem. Int. 14:397-406. Nowak, J. Z., Sek, B., and Schorderet, M. (1990a). Bidirectional regulation of cAMP generating system by dopamine-Da and D2-receptors in the rat retina. J. Neural Transm. 81:235-240. Nowak, J. Z., Sek, B., and Zurawska, E. (1990b). Activation of D2 dopamine receptors in hen retina decreases forskolin-stimulated cyclic AMP accumulation and serotonin N-acetyltransferase (NAT) activity. Neurochem. Int. 16:73-80. Nowak, J. Z., Zawilska, J., Sek, B., and Schorderet, M. (1990c). Light modulates dopamine-rcgulated Walsh inhibitor activity and dopamine-dependent cyclic AMP accumulation in the rabbit retina. Pol. J. Pharmacol. Pharm. 42 (in press). Ofori, S., and Schorderet, M. (1988). The rabbit retina in vitro: A pharmacological model to study the synaptic regulation of dopamine synthesis and release. In Dopaminergic Mechanisms in Vision (I. Bodis-WoUner and M. Piccolino, Eds.), Alan R. Liss, New York, pp. 41-57. Ofori, S., Bretton, C., Hof, P., and Schorderet, M. (1986a). Investigation of dopamine content, synthesis, and release in the rabbit retina in virto. I. Effects of dopamine precursors, reserpine, amphetamine, and L-DOPA decarboxylase and monoamine oxidase inhibitors. J. Neurochem. 47:1199-1206. Ofori, S., Magistretti, P. J., and Schorderet, M. (1986b). Investigation of dopamine content, synthesis, and release in the rabbit retina in vitro. II. Effects of high potassium, adenylate cyclase activators, and N-n-propyl-3-(3-hydroxyphenyl)piperidine. J. Neurochem. 47:1207-1213. Osborne, N. N. (1981). Binding of [3H]-ADTN, a dopamine agonist, to membranes of the bovine retina. Cell. rnol. Neurobiol. 1:167-174. Pang, S. F., and Allen, A. E. (1986). Extra-pineal melatonin in the retina: Its regulation and physiological function. Pineal Res. Rev. 4:55-95. Parkinson, D., and Rando, R. R. (1983). Effect of light on dopamine turnover and metabolism in rabbit retina. Invest. Ophthalmol. Vis. Sci. 24:384-388. Piccolino, M. (1986). Horizontal cells of the retina: Historical controversies and new interest. Prog. Retin. Res. 5:147-161. Piccolino, M., and Demontis, G. (1988). Dopaminergic system and modulation of electrical transmission between horizontal cells in the turtle retina. In Dopaminergic Mechanisms in Vision (I. Bodis-Wollner and M. Piccolino, Eds.), Alan R. Liss, New York, pp. 137-162. Piccolino, M., Demontis, G., Witkovsky, P., Strettoi, E., Cappagli, G. C., Porceddu, M. L., De Montis, M. G., Pepitoni, S., Biggio, G., Meller, E., and Bohmaker, K. (1989). Involvement of D 1 and D 2 dopamine receptors in the control of horizontal cell electrical coupling in the turtle retina. Eur. J. Neurosci. 1:247-257. Pierce, M. E., and Besharse, J. C. (1985). Circadian regulation of retinomotor movements. I. Interaction of melatonin and dopamine in the control of cone length. J. Gen. Physiol. 86:671-689. Pierce, M. E., and Besharse, J. C. (1986). Melatonin and dopamine interactions in the regulation of rhythmic photoreceptor metabolism. In Pineal and Retinal Relationships (P. J. O'Brien and D. C. Klein, Eds.), Academic Press, New York, pp. 219-237. Porceddu, M. L., De Montis, G., Mele, S., Ongini, E., and Biggio, G. (1987). D t dopamine receptors in the rat retina: Effect of dark adaptation and chronic blockade by SCH 23390. Brain Res. 424:264-271.

324


Qu, Z.-X., Fertel, R., Neff, N. H., and Hadjiconstantinou, M. (1989). Pharmacological characterization of rat retinal dopamine receptors. J. Pharmacol. Exp. Ther. 248:621-625. Redburn, D. A., and Kyles, C. B. (1980). Localization and characterization of dopamine receptors within two synaptosomes fractions of rabbit and bovine retina. Exp. Eye Res. 30:699-708. Redburn, D. A., Clement-Cormier, Y., and Lam, D. M. K. (1980a). GABA and dopamine receptor binding in retinal synaptosomal fractions. Neurochemistry 1:167-181. Redburn, D. A., Clement-Cormier, Y., and Lam, D. M. K. (1980b). Dopamine receptors in the goldfish retina: [3H]spiroperidol and [3H]domperidone binding; and dopamine-stimulated adenylate cyclase activity. Life Sci. 27:23-31. Reiter, R. J. (1984). Pineal indoles: Production, secretion and actions. In Neuroendocrine Perspectives, Vol. 3 (E. E. Muller and R. M. MacLeod, Eds.), Elsevier, Amsterdam, pp. 345-377. Rogawski, M. A. (1987). New directions in neurotransmitter action: Dopamine provides some important clues. TINS 10:200-205. Schaeffer, J. M. (1980). Identification of dopamine receptors in the rat retina. Exp. Eye Res. 30:431-437. Schorderet, M. (1989). Receptors coupled to adenylate cyclase in isolated rabbit retina. Neurochem. Int. 14:387-395. Schorderet, M., and Magistretti, P. J. (1983). Comparative aspects of the adenylate cyclase system in retina. In Progress in Nonmammalian Brain Research (G. Nistico and L. Bolis, Eds.), CRC Press, Boca Raton, Fla., pp. 185-211. Schorderet, M., Sovilla, J. Y., and Magistretti, P. J. (1980). New findings related to a possible interaction of ergolines and ergopeptines with presynaptic dopamine receptors. Prog. Neuropsychopharmacol. Suppl.: 315. Seamon, K. B., and Daly, J. W. (1986). Forskolin: Its biological and chemical properties. Adv. Cyclic Nucleotide Protein Phosphorylation Res. 20:1-150. Seeman, P. (1981). Brain dopamine receptors. Pharmacol. Rev. 32:229-313. Seeman, P., ~.and Niznik, H. B. (1988). Dopamine D1 receptor pharmacology. 1SI Atlas Sci. Pharmacol. 161-170. Seiler, M. P., Markstein, R., Walkinshaw, M. D., and Boelsterli, J. J. (1989). Characterization of dopamine receptor subtypes by comparative structure-activity relationships: Dopaminomimetic activities and solid state conformation of monohydroxy-l,2,3,4,4a,5,10,10aoctahydrobenz[g]quinolines and its implications for a rotamer-based dopamine receptor model. Mol. Pharmacol. 35:643-651. Sovilla, J. Y., and Schorderet, M. (1982). L-dopa mediated accumulation of cyclic AMP in isolated rabbit retinae in vitro. Effects of light and/or pharmacological factors. Life Sci. 31:2081-2092. Spano, P. F., Kumakura, K., and Trabucchi, M. (1976). Dopamine-sensitive adenylate cyclase in the retina: A point of action for d-LSD. Adv. Biochem. Psychopharmacol. 15:357-365. Stoof, J. C., and Kebabian, J. W. (1984). Two dopamine receptors: Biochemistry, physiology and pharmacology. Life Sci. 35:2281-2296. Stool, J. C., Werkman, T. R., Lodder, J. C., and De Vlieger, T. (1986). Growth hormone producing ceils in Lymnaea stagnalis as a model system for mammalian dopamine receptors? TIPS 7:7-9. Teranishi, T., Negishi, K., and Kato, S. (1984). Regulatory effect of dopamine on spatial properties of horizontal ceils in carp retina. J. Neurosci. 4:1271-1280. Thai, L. J., Horowitz, S. G., Dvorkin, B., and Makman, M. H. (1980). Evidence for loss of brain [3H]spiroperidol and [3H]ADTN binding sites in rabbit brain with aging. Brain Res. 192:185-194. Tornqvist, K., Yang, X. L., and Dowling, J. E. (1988). Modulation of cone horizontal cell activity in the teleost fish retina. III. Effects of prolonged darkness and dopamine on electrical coupling between horizontal cells. J. Neurosci. 8:2279-2288. Van Buskirk, R., and Dowling, J. E. (1981). Isolated horizontal cells from carp retina demonstrate dopamine-dependent accumulation of cyclic AMP. Proc. Natl. Acad. Sci. USA 78:7825-7829. Vanderheyden, P., Ebinger, G., Kanarek, L., and Vauquelin, G. (1986). Epinephrine and norepinephrine stimulation of adenylate cyclase in bovine retina homogenate: Evidence for interaction with the dopamine D1 receptor. Life Sci. 38:1221-1227. Ventura, A. L. M., Cavalcante, L. A., and De Metlo, F. G. (1989). The ontogeny of dopaminergic D 1 receptors in the avian retina: Localization and kinetic properties. J. Neurochem. 52 Suppl.: S157. Watling, K. J. (1980). [3H]spiperone labels dopamine receptors in homogenates of bovine retina. Br. J. Pharmacol. 70:47P-48P. Watling, K. J. (1983). A function for dopamine-sensitive adenylate cyclase in the retina? TIPS 4:328-329.

Retinal Dopamine D 1 and Dz Receptors

325

Watling, K. J., and Dowling, J. E. (1981). Dopaminergic mechanisms in the teleost retina. I. Dopamine-sensitive adenylate cyclase in homogenates of carp retina; effects of agonists, antagonists and ergots. J. Neurochem. 36:559-568. Wafting, K. J., and Iversen, L. L. (1981). Comparison of the binding of [3H]spiperone and [3H]domperidone in homogenates of mammalian retina and caudate nucleus. J. Neurochem. 37:1130-1143. Wafting, K. J., Dowling, J. E., and Iversen, L. L. (1979). Dopamine receptors in the retina may be all linked to adenylate cyclase. Nature 281-578-580. Wiechmann, A. F. (1986). Melatonin: Parallels ,in pineal gland and retina. Exp. Eye Res. 42:507-527. Witkowsky, P., Stone, S., and Besharse, J. C. (1988a). The effects of dopamine and related ligands on photoreceptor to horizontal cell transfer in the Xenopus retina. Biomed. Res. 9 (Suppl. 2): 93-107. Witkowsky, P., Stone, S., and Besharse, J. C. (1988b). Dopamine modifies the balance of rod and cone inputs to horizontal cells of the Xenopus retina. Brain Res. 449"332-336. Yang, X. L., Tornqvist, K., and Dowling, J. E. (1988). Modulation of cone horizontal cell activity in the teleost fish retina. II. Role of interplexiform cells and dopamine in regulating light responsiveness. J. Neurosci. 8:2269-2278. Yeh, H. H., Battelle, B. A., and Puro, D. G. (1984). Dopamine regulates synaptic transmission mediated by cholinergic neurons of the rat retina. Neuroscience 13:901-909. Zarbin, M. A., Wamsley, J. K., Palacios, J. M., and Kuhar, M. J. (1986). Autoradiographic localization of high affinity GABA, benzodiazepine, dopaminergic, adrenergic and muscarinic cholinergic receptors in the rat, monkey and human retina. Brain Res. 374"75-92. Zawilska, J. and Iuvone, P. M. (1989). Catecholamine receptors regulating serotonin Nacetyltransferase activity and melatonin content of chicken retina pineal gland: Da-dopamine receptors in retina and alpha-2 adrenergic receptors in pineal gland. J. Pharmacol. Exp. Ther. 250:86-92. Zurawska, E., and Nowak, J. Z. (1990). Serotonin N-acetyltransferase (NAT) in mammalian retina: Role of cyclic AMP and calcium ions. Folia Histochem. Cytobiol. 28 (in press).

Dopamine D1 and D2 receptors mediate opposite functions in seizures induced by lithium-pilocarpine.

Interaction of flunarizine with dopamine D2 and D1 receptors.

Alan Horn Memorial Lecture. Selective probes for characterization of dopamine D1 and D2 receptors.

Striatal dopamine D1 and D2 receptors are differentially regulated following buprenorphine or methadone treatment.

Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors.

or D2 dopamine receptors during conditioning.

Differential Roles for Dopamine D1-Like and D2-Like Receptors in Mediating the Reinforcing Effects of Cocaine: Convergent Evidence from Pharmacological and Genetic Studies.

Stimulation of dopamine D1 receptors by the D2 agonist CV 205-502 in bovine retina homogenates.

D5 and D2 Receptors in Context-Dependent Extinction Learning and Memory Reinstatement.

Development of D1 and D2 dopamine receptors and associated second messenger systems in fetal striatal transplants.

D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons.

Effect of chronic nicotine treatment and withdrawal on rat striatal D1 and D2 dopamine receptors.

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions.

Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

Dopamine"autoreceptors": pharmacological characterization by microiontophoretic single cell recording studies.

D1 and D2 dopamine receptors stimulate hypothalamo-pituitary-adrenal activity in rats.

D2 dopamine receptors in neuroleptic catalepsy.

Comparative biochemical pharmacology of central nervous system dopamine D1 and D2 receptors.

Role of D1 and D2 dopamine receptors in the behavioral effects of cocaine.

Role of dopamine D1 and D2 receptors in mediating the d-amphetamine discriminative cue.

Dopamine D1 and D2 receptors in progressive supranuclear palsy: an autoradiographic study.

Quantitative autoradiographical analysis of the age-related modulation of central dopamine D1 and D2 receptors.

Autoradiographic localization of D1 and D2 dopamine binding sites in the human retina.

Effects of pertussis toxin on caudate neuron electrophysiology: studies with dopamine D1 and D2 agonists.