Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata

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Abstract

Several phenyl-benzazepine compounds, putatively selective dopamine D1 receptor agonists, have been used to study the effects of dopamine D1 receptor stimulation in rodents and nonhuman primates. However, the dopamine receptor selectivities of these compounds have not been established in nonhuman primates. Accordingly, the relative selectivities of six phenyl-benzazepines for dopamine D1-like and D2-like receptors were assessed in rhesus monkey and, for comparison, rat striata. The compounds tested had higher affinity for D1 than D2 receptors in both species; however, their selectivity varied by up to three orders of magnitude. GTP (100 μM) reduced agonist binding at the high-affinity state of the dopamine D1 receptor, but the magnitude of the effect of GTP did not reliably predict a compound's efficacy. Furthermore, a history of cocaine self-administration did not appear to influence dopamine receptor binding characteristics in the rhesus monkeys in this study. The present results will aid the comparison of dopamine receptor binding characteristics and behavioral effects of D1 dopamine receptor agonists.

Introduction

Brain dopaminergic systems are implicated in a number of disorders, including psychomotor stimulant abuse, schizophrenia and Parkinson's disease. These disorders have often been studied using models developed in rodents. However, comparison of the anatomy of dopaminergic systems (Berger et al., 1991) and the effects of dopamine receptor stimulation (Pifl et al., 1991; Izenwasser and Katz, 1993; Vermeulen et al., 1994) have shown differences between rodents and primates that may have therapeutic importance. For instance, the prototypical selective dopamine D1 receptor agonist SKF 38393 demonstrated higher efficacy to stimulate the production of cAMP in rat caudate than in rhesus monkey striata (Andersen and Jansen, 1990; Pifl et al., 1991; Weed et al., 1997). Dopaminergic drugs can also have different behavioral effects in rodents and primates. For instance, the dopamine D1 receptor agonist SKF 77434, which has partial efficacy in both rats and rhesus monkeys (Weed et al., 1997), was shown to function as a positive reinforcer in rats (Self and Stein, 1992); however SKF 77434 failed to function as a reinforcer in rhesus monkeys (Weed and Woolverton, 1995) or squirrel monkeys (Grech et al., 1996). Therefore, evaluation of dopamine receptor binding characteristics using both rodent and nonhuman primate tissues may provide important information regarding the relationship between receptor stimulation and behavioral effects of dopaminergic compounds.

Central nervous system dopamine receptors are divided into two groups, the `D1-like' group: D1/D1a, D5/D1b, D1c and D1d; and the `D2-like' group: D2long and short, D3, D4 or D2al and s, D2b and D2c (Sibley and Monsma, 1992; Sugamori et al., 1994; Demchyshyn et al., 1995). D1-like receptors are differentiated from D2-like receptors by their structural homology and by their ability to stimulate production of cAMP (Kebabian and Calne, 1979; Sunahara et al., 1991; Tiberi et al., 1991). D2-like receptors either inhibit or have no effect upon cAMP production (Stoof and Kebabian, 1981). D1a/D1 and D1b/D5 receptors are the best characterized of the D1-like receptors, and to date the only D1 subtypes demonstrated in mammalian brain (Sugamori et al., 1994; Demchyshyn et al., 1995). For convenience, the terms `D1' and `D2' will be used here to refer to any of the receptors in the respective groups and not to indicate the D1a or D2a receptors specifically.

A number of phenyl-benzazepine compounds are available that have been found to be selective for dopamine D1 receptors in rodent tissue. These compounds have been used in a number of investigations of dopamine D1 receptor function, including studies of the behavioral effects of dopamine D1 receptor stimulation in nonhuman primates (Bergman et al., 1996; Grech et al., 1996; Weed et al., 1997). However, the selectivities of these compounds for subtypes of dopamine receptors have not been widely studied in primate tissue. Moreover, important species differences in the radioligand binding characteristics of previously identified phenyl-benzazepine dopamine D1 receptor agonists have been reported in primates and rodents. For instance, SKF 38393 has been reported to have lower selectivity for dopamine D1 receptors in human postmortem putamen than either SKF 82958 or SKF 77434 (O'Boyle and Waddington, 1987). In contrast, studies performed using rodent striata consistently report SKF 38393 as being more selective for dopamine D1 receptors than either SKF 82958 or SKF 77434 (Arnt et al., 1988; Andersen and Jansen, 1990; Neumeyer et al., 1992). Interpretation of species differences such as these is confounded by variation in results due to the use of different assay systems by different laboratories. The primary goal of the present study was to assess the radioligand binding characteristics of a series of phenyl-benzazepine dopamine D1 receptor agonists in rhesus monkey striata. An additional goal was to compare the radioligand binding characteristics of these compounds in primate and rodent striata. Although a substantial literature exists on the radioligand binding characteristics of these compounds in rodent tissue, these results were replicated in order to compare primate and rodent data from the same assay system.

The development of a radioligand binding assay to model the functional effects of dopamine D1 receptor agonists would be beneficial to the further investigation of dopaminergic activity, especially in primate tissue. Such an assay would be advantageous if it could provide functional information similar to a cAMP assay while being less expensive, technically easier to perform, and more readily accommodating of frozen tissue. The effect of guanyl-nucleotides upon dopamine D1 receptor agonist displacement of [3H]SCH 23390 has been proposed as a model of the functional effects of dopamine D1 receptor agonists which can be performed in a radioligand binding assay (Madras, 1993). Dopamine receptors belong to the `super-family' of receptors coupled to GTP-binding proteins (G-proteins). Agonists generally displace antagonists bound to G-protein-coupled receptors in a biphasic fashion, and guanyl-nucleotides generally reduce the potency of agonists at G-protein-coupled receptors (Hess et al., 1986; Zahniser and Molinoff, 1978). Conversely, guanyl-nucleotides have little effect upon the binding of antagonists to G-protein-coupled receptors, because antagonists do not preferentially bind to either the coupled or uncoupled conformation of the receptor (Hess et al., 1986; Zahniser and Molinoff, 1978). Therefore, another goal of the present study was to study the effects of GTP on the displacement of [3H]SCH 23390 by D1 agonists to determine if the magnitude of the GTP effect is related to the traditional measure of intrinsic activity at dopamine D1 receptors, stimulation of cAMP production. As with radioligand binding characteristics in rodents, effects of GTP on binding of some of these dopamine D1 agonists to rodent dopamine D1 receptors has been previously reported; however, to our knowledge this has yet to be studied in primate tissue. To facilitate inter-species comparisons, the rodent work was replicated in the same assay system used with the rhesus tissue.

Finally, although not a primary goal of the present study, brain tissue was available from monkeys with a variety of experimental histories. Roughly equal-sized groups of monkeys with histories of recent cocaine self-administration, cocaine self-administration at least two months prior to sacrifice, and cocaine-naı̈ve monkeys, permitted the evaluation of different drug histories on long-term radioligand binding properties of striatal dopamine receptors.

Section snippets

Tissue collection

Due to factors not related to this project, brain tissue was available from a number of rhesus monkeys, Macaca mulatta. The 12 rhesus monkeys with histories of cocaine self-administration and/or discriminative-stimulus training with psychomotor stimulants included nine males (12278, 972, 8713, 8805, 8217, 9165, 8236, 8711, 9001) and three females (11083, 7976, 8619). The drug histories of the drug-experienced monkeys divided naturally into three groups: monkeys which had self-administered

Analysis of [3H]SCH 23390 radioligand binding characteristics in rhesus and rat striata

Results of four saturation experiments using [3H]SCH 23390 in rhesus monkey and rat striata are presented in Fig. 2. Two of the rhesus monkeys had no history of dopaminergic drug administration and two monkeys had histories of cocaine self-administration. Based on overlapping 95% confidence intervals, no differences due to drug history were seen between these two groups of monkeys and the data were pooled for further analysis. The affinity of [3H]SCH 23390 was 1.02 nM (95% CI: 0.65 to 1.36) for

Discussion

The primary goal of the present study was to assess the radioligand binding characteristics of dopamine D1 receptor agonists in rhesus monkey striata. The dopamine D1 receptor agonists studied here all had greater affinity for D1 than for D2 sites; however dopamine D1:D2 receptor selectivities ranged widely. The rank order for dopamine D1:D2 receptor selectivity in rhesus striata was: SKF 81297>SKF 38393>>SKF 82958>SKF 77434>R(+) 6-BrAPB>S(−) 6-BrAPB>dopamine. The rank order for dopamine D1:D2

Acknowledgements

We gratefully acknowledge the assistance of Melissa Wellons, Lance Perkins, and Dr. Joseph Williams in the execution of these experiments. A portion of the control rhesus striatal tissue was provided through the Tissue Distribution Program of the Oregon Regional Primate Center (NIH grant RR 00163). SCH 39166 and SCH 23390 were the generous gifts of Schering-Plough. Supported by NIDA Grants DA-05616 (M.R.W.) and DA-10352 (W.L.W.)

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