Cerebellar and striatal dopamine receptors: Effects of reeler and weaver murine mutations

The presence and the binding characteristics of D₁ and D₂ receptors were investigated in normal-reeler and normal-weaver mutant mice utilizing [³H]spiperone (D₂ antagonist), [³H]SKF 38393 (D₁ agonist), and [³H]DA as ligands. Analysis of the binding data showed that in the cerebellum there are two binding components for all [³H]ligands. Comparison of the binding constants from cerebellum and striatum showed that in cerebellum the high affinity-low capacity component has similar affinity with that of striatum. The reeler and weaver mutations affected the binding of all ligands: In reeler, total cerebellar specific binding sites for [³H]spiperone and [³H]SKF 38393 decrease significantly (≈50% and ≈70%, respectively), while those for [³H]DA show a small (≈10–15%) but not significant decrease. In weaver, total cerebellar specific binding sites for [³H]spiperone, [³H]SKF 38393, and [³H]DA also decrease significantly (≈60%, ≈70%, and ≈50%, respectively). In reeler striatum [³H]SKF 38393 binding (B_max) is significantly decreased (≈24%), while [³H]spiperone and [³H]DA binding (B_max) is not affected. In weaver striatum, [³H]SKF 38393 binding is significantly increases significantly (≈40%), while [³H]DA binding (B_max) decreases significantly (≈70%). On the basis of the cytoarchitectural aberrations that characterize the cerebellum of these mutants and some well-established information regarding the dopaminergic system of the cerebellum, the above results indicate that in this region (a) D₁ receptors are mainly localized on granule cells and (b) D₂ receptors are localized postsynaptically on granule cells and presynaptically on the DA fibers innervating the cerebellum. © 1993 Wiley-Liss, Inc.     

Cholecystokinin Octapeptide In Vitro and Ex Vivo Strongly Modulates Striatal Dopamine D2 Receptors in Rat Forebrain Sections

Receptor autoradiographic experiments together with the filter wipe-off technique were performed to investigate the effects of cholecystokinin octapeptide (CCK-8) on dopamine D₂ receptors. In vitro studies showed that 1 nM CCK-8 significantly increased the K_D value of binding sites for the D₂ agonist [³H]N-propylnorapomorphine (NPA) in the rostral and caudal parts of the nucleus accumbens by 48 and 148% respectively. In contrast, 1 nM CCK-8 significantly decreased the IC₅₀ value of dopamine for binding sites for the D₂ antagonist [¹²⁵I]iodosulpride in the rostral and caudal parts of the caudate-putamen by 46 and 56% respectively, and in the rostral and caudal parts of the nucleus accumbens (areas of CCK-dopamine coexistence) by 57 and 75% respectively. Ex vivo studies demonstrated that 30 min after an intraventricular injection of 1 nmol/rat CCK-8 the K_D value of [³H]NPA binding sites in the caudal part of the forebrain and the IC50 value of dopamine for [¹²⁵I]iodosulpride binding sites in the caudal part of the nucleus accumbens were significantly increased by 160% and decreased by 77% respectively. These results indicate for the first time that in sections CCK-8 in vitro and ex vivo can strongly regulate D₂ receptor affinity in the striatum. The present studies also provide evidence for stronger modulation of D₂ receptors by CCK-8 in the area of CCW-dopamine coexistence in the nucleus accumbens than in other basal ganglion areas, supporting the existence of CCWD₂ receptor interactions in cotransmission. The stronger interactions found in sections than in membrane preparations may indicate the requirement of intracellular mechanisms and/or a more intact membrane structure for optimal receptor-receptor interactions.     

D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists,but not by sibutramine hydrochloride,antidepressants or treatments which enhance central dopaminergic function

Summary [³H]SCH 23390 is a selective high affinity ligand for D₁ receptors in vitro. Using this ligand persistent blockade of D₁ receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D₁ receptor binding sites in rat striatum. In contrast, repeated administration of the D₂-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D₂-selective antagonist, haloperidol, the non-selective D₁/D₂ receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D₁ receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D₁ sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D₁ receptor binding in rat striatum.     

SDZ GLC 756, a novel octahydrobenzo[g]quinoline derivative exerts opposing effects on dopamine D1 and D2 receptors

Summary SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [³H]SCH23390 from dopamine D₁ receptors and [³H]205–501 from dopamine D₂ receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D₁ receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D₂ receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D₂ receptor activation. The opposing action of SDZ GLC 756 on dopamine D₁ and D₂ receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D₂ receptors. This drug might be a new tool to study linkage between dopamine D₁ and D₂ receptors.     

Role of dopamine D1- and NMDA receptors in regulating neurotensin release in the striatum and nucleus accumbens

Stimulation of dopamine D₁-receptors by SKF 82958 increased extracellular neurotensin (NT) levels in the striatum and nucleus accumbens as measured by in vivo microdialysis while blockade of D₁-receptors had no effect. Antagonism of NMDA receptors with MK 801 completely prevented the increased NT release induced by D₁-stimulation in both structures. Tissue content of striatal NT anterior and posterior to the microdialysis probe was oppositely altered by D₁-stimulation: increases were observed in the anterior striatum with decreased NT levels in the posterior striatum.     

Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D₁ family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18–22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D₁ ligand [³H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D₁ binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D₁ binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D₁ receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use. Synapse 28:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies

The role of the dopamine D₃ receptor subtype in the central nervous system is still not well understood. It has a distinct and restricted distribution, mostly associated with limbic territories of the striatum (olfactory tubercle and the shell of nucleus accumbens) in rat brain. Dopaminergic denervation induced by a 6-hydroxydopamine lesion of the nigrostriatal system in rat down-regulates the expression of the D₃ receptor. In the present study, we investigated the functional neuroanatomy of the dopamine D₃ receptor subtype in the monkey (Macaca fascicularis) basal ganglia. We also studied the effect of administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic D₁-like (SKF 82958) or D₂-like (cabergoline) agonist treatments on dopamine D₃ receptor levels using receptor autoradiography. Our results clearly show that the distribution of D₃ receptors in the monkey is more closely related to associative and limbic components of the striatum (caudate-putamen), as compared with its sensorimotor counterpart. Hence, D₃ receptors may be more specifically involved in cognitive and motivational aspects of striatal functions, which are elaborated in prefrontal, temporal, parietal, cingulate and limbic cortices. Moreover, MPTP administration significantly decreased levels of D₃ receptors and this effect was reversed or compensated by a chronic treatment with a D₁-like, but not a D₂-like, receptor agonist. The D₃ receptor may represent an important target for adjunct or direct therapy designed to improve cognitive deficits observed in patients with Parkinson's disease, schizophrenia and other illnesses with frontal lobe cognitive disturbances.     

Characteristics of dopamine and β-adrenergic sensitive adenylate cyclases in the frontal cerebral cortex of the rat. Comparative effects of neuroleptics on frontal cortex and striatal dopamine sensitive adenylate cyclases

Homogenates of frontal cerebral cortex of the rat were prepared from microdiscs punched out in areas rich in dopaminergic terminals. Under optimal assay conditions, dopamine (10^?4M) stimulated an adenylate cyclase present in these homogenates by 80–100%. This stimulation reached 200% when microdiscs were punched out from the medial part of the frontal cerebral cortex, adjacent to the forceps minor.Dopamine interacted with an homogeneous population of receptor sites which had an apparent affinity (K_D) of 3.8 ± 0.9 × 10^?6M (N= 4). The dopamine receptor was blocked by fluphenazine and phentolamine but had no affinity for pindolol, propranolol orl-isoproterenol.The affinities of several neuroleptics having different chemical structures were simultaneously determined on striatal and on frontal cerebral cortex dopamine sensitive adenylate cyclases. Fluphenazine was more potent in blocking the striatal than the frontal cerebral cortex dopaminergic receptors. In contrast, in all experiments, haloperidol had an higher affinity for the cerebral frontal cortex than for the striatal dopaminergic receptors. Thus, haloperidol was less effective than fluphenazine in blocking the striatal dopaminergic receptors, and equally potent than fluphanazine in inhibiting the frontal cerebral cortex dopamine sensitive adenylate cyclase. Chlorpromazine, thioridazine and clozapine had the same affinity for the two dopaminergic adenylate cyclase systems.l-Isoproterenol interacted with an homogeneous population of β-adrenergic receptor sites (K_D = 3 ± 2 × 10^?7M; N = 4) coupled with adenylate cyclase distinct from the dopamine sensitive adenylate cyclase. This β-receptor had no affinity for dopamine or fluphenazine but was blocked by propranolol or pindolol.l-Norepinephrine was shown to stimulate both the dopamine (K_D = 1.8 ± 1 × 10^?5;N =4 and the β-adrenergic (K_D = 8 ± 3 × 10^?7M; N = 4) senstive adenylate cyclases. Thus, thel-norepinephrine effect was totally blocke in the combined presence of fluphenazine and pindolol.     

Evidence for selective loss of brain dopamine- and histamine-stimulated adenylate cyclase activities in rabbits with aging

Dopamine-stimulated adenylate cyclase activity in striatum and both dopamine-and histamine-stimulated adenylate cyclase activity in hypothalamus, frontal cortex and anterior limbic cortex declined by about 50% as rabbits aged from 5.5 months to 5.5 years of age. These changes were primarily in maximal response to amine although an additional component involving decreased affinity in the case of dopamine may also be present. In contrast, dopamine-stimulated adenylate cyclase of retina and both basal and guanyl-5′-yl-imidodiphosphate (Gpp(NH)p)-stimulated activity in these regions were not altered with age. There was no measurable decrease in the old animals in either dopamine or norepinephrine concentration in striatum, anterior limbic cortex or retina, or in choline acetylase activity or [³H]quinuclidinylbenzilate binding in striatum, anterior limbic cortex or frontal cortex. It is proposed that selective age-dependent decreases in transmitter receptors coupled to adenylate cyclase occur in the absence of or independent from neuronal cell loss, as evidenced by the retention of the other biochemical markers.     

Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: Assessment of the role of D1 dopamine receptor stimulation

Previous research has revealed a role of repeated D₁ dopamine receptor stimulation in the development of behavioral sensitization to the D₁/D₂ agonist apomorphine. The present experiments assessed the role of repeated D₁ receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D₁ stimulation on dopamine synthesis, rats were injected with the D₁ agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D₁ agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [³H]SCH 23390 binding to D₁ receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels. In the VM, DOPAC levels were enhanced following repeated apomorphine, but not repeated SKF 38393, whereas dopamine levels were not affected by either drug treatment. D₁ binding was not altered by the repeated drug treatments. Since repeated D₁ stimulation by SKF 38393 did not produce the same alterations in dopamine synthesis and DOPAC levels as repeated apomorphine, the neurochemical effects accompanying locomotor sensitization to apomorphine probably are not mediated by D₁ receptors. © 1993 Wiley-Liss, Inc.     

Autoradiographic localization and quantification of dopamine D2 receptors in normal human brain with [H]N-n-propylnorapomorphine

The precise distribution of dopamine receptors has been studied autoradiographically in the normal human brain using [³H]N-n-propylnorapomorphine ([³H]NPA) as a ligand. Preliminary experiments aimed at optimizing the binding assay conditions revealed that preincubation washing of caudate nucleus sections was a prerequisite to obtain a good ratio of specific to non-specific binding. The binding of [³H]NPA to caudate-putamen sections was saturable, stereospecific, reversible, of high affinity (K_d = 0.27–0.35 nM) and occurred at a single population of sites. Competition experiments with various drugs indicated that in the caudate-putamen the specific [³H]NPA binding sites possess the pharmacological features of the dopamine D₂ receptor. The highest levels of [³H]NPA binding sites were found in the caudate nucleus, putamen, globus pallidus and nucleus accumbens. There were also intermediate to low concentrations of the ³H-ligand in the hippocampus, the insular and cingular cortices and in the occipito-temporal gyrus, while almost undetectable levels of binding were found in the anteior frontal cortex. Thorough examination of the subregional distribution of [³H]NPA binding sites in the caudate-putamen-pallidum complex revealed heterogenous patterns of radioactivity. In these brain regions, the distribution of autoradiographic grains was punctate and islands of high and low densities were observed. Moreover, in the caudate nucleus, there was a subtle high lateral to low medial gradient in the topography of the [³H]NPA binding sites and a more pronounced gradient along the rostrocaudal axis; the highest levels of binding being located at the midbody of the nucleus. No gradients of [³H]NPA binding were observed in the putamen. The present data indicate that [³H]NPA is a suitable ligand for accurate autoradiographic labeling of dopamine D₂ receptors in human postmortem brain tissue and that dopamine receptors are heterogeneously distributed and topographically organized in patches and gradients in the basal ganglia regions.     

Dopamine D2 receptors in brain and anterior pituitary recognize agonist and antagonist actions of (−)-3-PPP

Summary (–)-3-PPP, is a unique dopamine analogue, reported to have selective agonist actions at dopamine autoreceptors and antagonist actions at postsynaptic receptors. The interactions of D₂ dopamine receptors with (–)-3-PPPin vitro were examined, using [³H]spiperone to label D₂ receptors in brain regions containing both pre- and postsynaptic D₂ receptors (caudate nucleus, corpus striatum) and a region containing nonsynaptic D₂ receptors (anterior pituitary). In the absence of sodium ions, (–)-3-PPP detected D₂ receptors in high- and low-affinity states in all regions examined, as is typical of dopamine agonists. That these two subpopulations of (–)-3-PPP-detected sites were dopaminergic in nature was assured by precluding [³H]spiperone binding to serotonergic receptors. In the presence of sodium ions, there was a significant increase in the affinity of some D₂ receptors detected by (–)-3-PPP, and (–)-3-PPP in the presence of sodium was unable to discriminate between the two D₂ affinity states in pituitary and striatum. The addition of guanine nucleotide led to (–)-3-PPP recognition of a single D₂ binding site; the enhanced affinity of D₂ receptors for (–)-3-PPP in the presence of sodium was retained in the presence of guanine nucleotide. Thesein vitro characteristics of (–)-3-PPP recognition of dopamine D₂ receptor binding sites, when compared with dopamine and spiperone are seen to have clear features of both typical agonist and antagonist interactions with D₂ receptors in both brain and pituitary.     

B-HT 920 activates dopamine D2 receptors coupled to inhibition of adenylate cyclase activity

Summary In homogenates of female rat anterior pituitary, the azepine derivative B-HT 920 inhibited the forskolin-stimulated adenylate cyclase activity with an EC₅₀ value of 0.35 M. In male rat anterior pituitary, B-HT 920 curtailed the stimulation of adenylate cyclase activity by vasoactive intestinal peptide with an EC₅₀ of 0.20 M. In synaptic plasma membranes of rat striatum, B-HT 920 significantly reduced basal adenylate cyclase activity with an EC₅₀ of 0.68 M. Both in pituitary and striatum, the B-HT 920 inhibition was counteracted by the dopamine (DA) D₂ receptor antagonist 1-sulpiride, but not by the ₂-adrenergic antagonist yohimbine. These results indicate that B-HT 920 is capable of activating DA D₂ receptors negatively coupled to adenylate cyclase activity.     

The involvement of dopamine in nociception: the role of D1 and D2 receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D₁ antagonist SCH23390 or the D₁ agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D₂ antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D₂ agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D₂, but not D₁, dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.     

Brain uptake and distribution of the dopamine D3/D2 receptor partial agonist [11C]cariprazine: An in vivo positron emission tomography study in nonhuman primates

Cariprazine is a dopamine D₃/D₂ receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D₃ and D₂ receptors (with ～10‐fold higher in vitro affinity to D₃ vs. D₂ receptors) and with moderate affinity to 5‐HT_1A receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11‐C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D₂ and D₃ receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [¹¹C]cariprazine. Of the total injected radioactivity, ～7% entered the brain and ～3–4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [¹¹C]cariprazine binds to dopamine D₃/D₂ receptors. Nondisplaceable binding potential (BP_ND) measurements, using a simplified reference tissue model and cerebellum as the reference region, yielded values of ～1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BP_ND values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D₃/D₂ receptors. Furthermore, in PET imaging [¹¹C]cariprazine can effectively visualize dopamine D₃/D₂ receptors in the nonhuman primate brain. Synapse 67:258–264, 2013. © 2013 Wiley Periodicals, Inc.     

Effects of GTP and sodium on rat striatal dopamine receptors labeled with lisuride

[³H]Lisuride binding to rat striatal membranes appeared to be stereospecifically displaced by the dopamine antagonist butaclamol.Sodium increased the number of [³H]lisuride binding sites (B_max) without changing the dissciation constant (K_d). GTP did not affect [³H]lisuride binding characteristics, either with or without sodium.These results suggest that dopamine receptor sites labeled by lisuride are at least in part sodium-dependent, possibly the D₂-receptors not involved in adenylate cyclase stimulation.     

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: Possible implications for the regulatory role of D2 receptors

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D₁ and D₂ receptors. In a Krebs-HEPES buffer, the K_i values of DA for D₁ binding sites (labelled with [³H]SCH23390) and D₂ binding sites (labelled with [³H]spiroperidol) in striatal membranes amounted to about 30 and.0.3 μM, respectively. However, the EC50s of DA (3 μM) and the DA releasing drug amphetamine (1 μM) were identical considering D₁ receptor-stimulated and D₂ receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC₅₀ values were also obtained studying DA- and amphetamine-induced D₂ receptor activation, resulting in inhibition of the electrically evoked release of [¹⁴C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D₁ and D₂ receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D₁ and D₂ receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D₁ and D₂ receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D₂ receptor activation, the degree of activation of D₁ and D₂ receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission. © 1994 Wiley-Liss, Inc.     

Bidirectional regulation of cAMP generating system by dopamine-D1 and D2-receptors in the rat retina

Summary Accumulation or inhibition of cAMP formation in response to dopamine or dopamine related drugs in the absence or in the presence of forskolin and/or IBMX was investigated in isolated rat retina. While the existence of D₁-receptors (positively coupled with adenylate cyclase) was confirmed, D₂-receptors (negatively coupled to adenylate cyclase) were also revealed by using a selective D₁-antagonist (SCH 23390), a D₂-agonist (LY 171555) or two D₂)-antagonists (S-sulpiride, spiroperidol). These results indicate that rat retina may be used for the study of both types of dopamine-receptors.     

D1 dopamine receptors in neurite regions of embryonic and differentiated retina are highly coupled to adenylate cyclase in the embryonic but not in the mature tissue

[³H]SCH 23390 binds stereospecifically and with high affinity to D₁ dopaminergic receptors in the developing chick retina. Autoradiographic experiments revealed that in retinas from 3-day-old chicken and embryos with 12, 14 and 16 days of development, specific labeling of [³H]SCH 23390 was mainly observed over the plexiform layers of the tissue, showing that dopaminergic D₁ receptors are localized in retina cell neurites since the initial stages of neurite formation. The total number of [³H]SCH 23390 binding sites increased 5-fold during the differentiation of the retina, while the dopamine-dependent cyclic adenosine monophosphate (AMP) accumulation was significantly decreased. Consequently, the ratio between dopamine-dependent cyclic AMP accumulation and [³H]SCH 23390 binding sites decreased 10-fold as retina differentiated, indicating that a significant portion of D₁ receptors in retinas from adult chicken are not effectively coupled to adenylate cyclase molecules.