Autoradiographic Evidence of [3H]SCH 23390 Binding Site; in Human Prefrontal Cortex (Brodmann''s Area 9)

The distribution of dopamine D-1 receptors has been determined in human prefrontal cortex (Brodmann's area 9) by an in vitro light microscopic autoradiographic method. Dopamine D-1 receptors were localized by using [3H]SCH 23390 as a ligand. Our results indicated that [3H]SCH 23390 binding to slide-mounted tissue sections of human brain is specific, saturable, and of high affinity. Lamina Va contained the highest density of D-1 receptors, with a Bmax value of 11.2 +/- 1.3 fmol/mg tissue. The KD values for [3H]SCH 23390 in all laminae ranged from 2.6 to 3.2 nM. Competition studies performed with [3H]SCH 23390 indicated a pharmacologic profile consistent with labeling of the D-1 receptor.     

Comparison of 125I-SCH 23982 and [3H]SCH 23390 as Ligands for the D-1 Dopamine Receptor

125I-SCH 23982, an antagonist with high affinity and selectivity for the D-1 subtype of dopamine receptors, has recently been synthesized. Densities of D-1 receptors in rat brain obtained from autoradiographic studies using this iodinated ligand are 5- to 10-fold less than densities reported with tritiated analogues such as [3H]SCH 23390. A direct comparison of these two ligands using striatal homogenates confirmed this discrepancy. One explanation for this difference is that 125I-SCH 23982 labels a subset of the sites labeled by [3H]SCH 23390. However, the distributions of sites labeled by the ligands in autoradiograms of horizontal sections of rat brain were virtually identical. Furthermore, 127I-SCH 23982 displaced 100% of the specifically bound [3H]SCH 23390 in striatal homogenates with a Hill coefficient of approximately 1. These results are not consistent with the existence of a subset of receptors recognized by 125I-SCH 23982 and suggest that both ligands label the same population of receptors. An alternative explanation for the discrepancy in Bmax values is that an unlabeled inhibitor is present in commercial preparations of 125I-SCH 23982. When all of the solvent (including any volatile inhibitors) was removed from commercial preparations of 125I-SCH 23982 prior to use in radioligand binding experiments, the discrepancy in Bmax values was eliminated.     

Functional antagonism of D-1 and D-2 dopaminergic mechanisms affecting striatal acetylcholine release

Rat striatal slices prelabelled with [3H]choline were superfused with dopamine D-1 and D-2 agonists and antagonists, separately and in combination, during measurement of [3H]acetylcholine (ACh) release. SKF38393 (D-1 agonist), 10(-7)-10(-4) M, and SCH23390 (D-1 antagonist), 10(-7)-10(-5) M, produced a dose-dependent increase in [3H]ACh release when given separately. The increased [3H]ACh release induced by either drug could not be attenuated by sufficient L-sulpiride to block D-2 receptors. Yet both SKF38393, 10(-6)-10(-5) M, and SCH23390, 10(-6)-10(-5) M, were able to partially or fully overcome the [3H]ACh release-depressant effect of cosuperfused LY171555 (D-2 agonist), 10(-6) M. This suggests that a functional antagonism regarding striatal ACh release exists between D-1 and D-2 dopaminergic receptor-mediated mechanisms, but that D-1 modulation of local ACh release does not occur at the level of the recognition site of the striatal D-2 receptor. Finally, although attenuation of the increased release of striatal [3H]ACh induced by 10(-5) M SCH23390 by SKF38393 was seen, it is possible that such functional antagonism is not mediated by exclusively D-1 dopaminergic means.     

Pharmacologic evidence for direct dopaminergic regulation of striatal acetylcholine release

This study was done to provide pharmacologic evidence for the location of those striatal dopamine D-1 and D-2 receptors that participate in the regulation of local acetylcholine (ACh) release. Striatal tissue slices from adult male Sprague-Dawley rats were preloaded with [3H]choline and superfused in separate experiments with buffer containing either: a D-2-specific agonist (LY141865 or LY171555), a D-2 specific antagonist (L-sulpiride), a D-1 specific agonist (SKF38393), or a D-1 antagonist (SCH23390), in the presence or absence of tetrodotoxin (TTX), used to block interneuronal activity. With either D-2 agonist there was a dose-dependent decrease in K+-stimulated [3H]ACh release, maximally at 5 X 10(-7)-10(-6) M [agonist] and to the same extent with each drug. Both SKF38393 and SCH23390 increased [3H]ACh release at tested concentrations of these agents. Results were unchanged when any of the drugs used was superfused in the presence of TTX, 5 X 10(-7) M. These data are consistent with the hypothesis that populations of striatal D-1 and D-2 receptors exist on local cholinergic neurons, where they regulate ACh release. Alternative interpretations are discussed.     

Dopamine D1 receptors characterized with [3H]SCH 23390. Solubilization of a guanine nucleotide-sensitive form of the receptor

Dopamine D1 receptors were solubilized from canine and bovine striatal membranes with the detergent digitonin. The receptors retained the pharmacological characteristics of membrane-bound D1 receptors, as assessed by the binding of the selective antagonist [3H]SCH 23390. The binding of [3H]SCH 23390 to solubilized receptor preparations was specific, saturable, and reversible, with a dissociation constant of 5 nM. Dopaminergic antagonists and agonists inhibited [3H]SCH 23390 binding in a stereoselective and concentration-dependent manner with an appropriate rank order of potency for D1 receptors. Moreover, agonist high affinity binding to D1 receptors and its sensitivity to guanine nucleotides was preserved following solubilization, with agonist dissociation constants virtually identical to those observed with membrane-bound receptors. To ascertain the molecular basis for the existence of an agonist-high affinity receptor complex, D1 receptors labeled with [3H] dopamine (agonist) or [3H]SCH 23390 (antagonist) prior to, or following, solubilization were subjected to high pressure liquid steric-exclusion chromatography. All agonist- and antagonist-labeled receptor species elute as the same apparent molecular size. Treatment of brain membranes with the guanine nucleotide guanyl-5'-yl imidodiphosphate prior to solubilization prevented the retention of [3H]dopamine but not [3H]SCH 23390-labeled soluble receptors. This suggests that the same guanine nucleotide-dopamine D1 receptor complex formed in membranes is stable to solubilization and confers agonist high affinity binding in soluble preparations. These results contrast with those reported on the digitonin-solubilized dopamine D2 receptor, and the molecular mechanism responsible for this difference remains to be elucidated.     

Role of estrogens on striatal dopaminergic activity

Studies were undertaken to evaluate the effects of estradiol and prolactin on striatal dopamine receptor activity. Dopamine receptors were quantified in partially purified striatal membranes by equilibrium binding using [3H]spiroperidol. When we investigated whether the D-2 dopamine receptor activity changes during the estrous cycle, the results suggest an increase in dopamine receptor density in diestrous, without modifications in the affinity. The finding that in ovariectomized rats the dopamine receptor binding parameters remained unchanged, suggests that gonadal steroids are not essential in the mechanism of action of this receptor. Results of activity of D-2 dopamine receptors showing that hyperprolactinemia fails to increase the number of these receptors do not support the hypothesis that circulating prolactin regulates the activity of these striatal dopamine receptors. Administration of estradiol benzoate (250 micrograms/kg per day) to hyperprolactinemic rats, by s.c. injection, significantly decreased both the density and the affinity of the striatal dopamine receptors. The present data indicate that, although prolactin does not seem to modify the activity of striatal dopamine receptors, it could modulate the estrogen-induced hypersensitivity of these receptors.     

D-2 dopamine antagonist-like effects of SCH 23390 on A9 and A10 dopamine neurons

The effects of SCH 23390 on d-amphetamine-induced suppression of A9 and A10 DA neuronal firing were determined. SCH 23390 potently reversed d-amphetamine on both A9 and A10 DA neurons. Compared to haloperidol, SCH 23390 was 5 times more potent on A9 DA neurons and 20 times more potent on A10 DA neurons. However, the magnitude of the reversal effect was greater with haloperidol than SCH 23390. In addition, haloperidol produced a further increase in firing of both A9 and A10 DA neurons after SCH 23390 maximally increased firing. It was concluded that SCH 23390 has D-2 DA antagonist-like properties, possibly mediated via an interaction at D-1 DA receptors, which may be functionally linked with D-2 DA receptors. The marked potency of SCH 23390 in reversing d-amphetamine could be due to its combined antagonist effects at 5HT2 and D-1 DA receptor sites.     

Effect of Unilateral Perinatal Hypoxic-Ischemic Brain Injury in the Rat on Dopamine D1 and D2 Receptors and Uptake Sites: A Quantitative Autoradiographic Study

The effect of a unilateral perinatal hypoxic-ischemic brain injury on dopamine D1 and D2 receptors and uptake sites was investigated in rats by using in vitro quantitative binding autoradiography, 2-3 weeks after the insult. We observed significant decreases in the Bmax and KD for [3H]SCH 23390-labeled D1 and in the Bmax for [3H]spiperone-labeled D2 receptors in the lesioned caudate-putamen in rats with moderate brain injury (visible loss in hemispheric volume ipsilateral to the injury) compared with the nonlesioned contralateral caudate-putamen or with control rats. Changes in [3H]SCH 23390 and [3H]spiperone binding predominated in the dorsolateral part of the lesioned caudate-putamen. Pronounced reduction in [3H]SCH 23390 binding was also observed in the substantia nigra pars reticulata on the side of the lesion. In contrast, we did not observe any significant change in Bmax or KD for [3H]mazindol-labeled dopamine uptake sites. Similarly, no significant changes in the levels of dopamine or its metabolites were found on the side of the lesion. The observed reductions in striatal dopamine D1 and D2 receptors are a reflection of striatal cell loss induced by the hypoxic-ischemic injury. The absence of changes in [3H]mazindol binding or dopamine levels in the lesioned caudate-putamen indicates that the dopaminergic presynaptic structures are preserved.     

In Vivo Partial Inactivation of Dopamine D1 Receptors Induces Hypersensitivity of Cortical Dopamine-Sensitive Adenylate Cyclase: Permissive Role of α1-Adrenergic Receptors

As shown by autoradiography, peripheral injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induced a dose-dependent decrease of [3H]SCH 23390 and [3H]prazosin high-affinity binding sites in the rat prefrontal cortex. EEDQ showed similar efficacy in inactivating cortical and striatal dopamine (DA) D1 receptors, whereas prazosin-sensitive alpha 1-adrenergic receptors were more sensitive to the action of the alkylating agent, as for all doses of EEDQ tested (from 0.8 to 3 mg/kg, i.p.), the decrease in cortical [3H]SCH 23390 binding was less pronounced than that of [3H]prazosin. The effects of EEDQ on [3H]SCH 23390 binding and DA-sensitive adenylate cyclase activity were then simultaneously compared in individual rats. In the striatum, whatever the dose of EEDQ used, the decrease of DA-sensitive adenylate cyclase activity was always lower than that of D1 binding sites, suggesting the occurrence of a large proportion of spare D1 receptors. In the prefrontal cortex, a significant increase in DA-sensitive adenylate cyclase activity was observed in rats treated with a low dose of EEDQ (0.8 mg/kg), this effect being associated with a slight reduction in [3H]SCH 23390 binding sites (-20%). Parallel decreases in the enzyme activity and D1 binding sites were observed with higher doses. The EEDQ-induced supersensitivity of DA-sensitive adenylate cyclase did not occur in rats in which the decrease in [3H]prazosin binding sites was higher than 35%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation of D-1 antagonist-induced D-1 receptor upregulation by concomitant D-2 receptor blockade

The effect of chronic selective D-1 and/or D-2 dopamine receptor blockade on regional D-1 receptor binding was studied in rat brain following chronic treatment with the specific D-1 antagonist SCH 23390 and/or the predominantly D-2 antagonist haloperidol. D-1 receptor density and affinity were evaluated by quantitative autoradiography using 125I-SCH 23982. Chronic SCH 23390 treatment increased D-1 receptor density by 30 to 40% in the striatum, accumbens and tuberculum olfactorium; receptor affinity remained unchanged. Haloperidol had no effect on D-1 receptor Bmax or Kd values, although, when administered with SCH 23390, reduced the D-1 receptor upregulation induced by the D-1 antagonist in striatum and tuberculum olfactorium, but not in nucleus accumbens. These results may be attributable to D-1/D-2 dopamine receptor interactions occurring in the striatum and tuberculum olfactorium and may have implications for the prevention and treatment of drug-induced extrapyramidal disorders.     

[3H]SCH 23390 Binding to Human Putamen D-1 Dopamine Receptors: Stereochemical and Structure-Affinity Relationships Among l-Phenyl-1H-3-Benzazepine Derivatives as a Guide to D-l Receptor Topography

Abstract: A series of l-phenyl-1 H -3-benzazepine analogues were assessed for enantiomeric and structure-affinity relationships at human putamen D-1 dopamine receptors labelled with [³H]SCH 23390. Substitution at the 7-position of both 3-H and 3-methyl benzazepine molecules critically affected affinity for these receptors over a 500-fold range. The general rank order of potency of 7-substituents was Cl = Br ≫ CH₃ > OH ≥ H. 3-Methyl substituents increased the affinity of 7-H and 7-OH compounds two- to fivefold compared to desmethyl counterparts. The displacement of [³H]SCH 23390 binding showed substantial enantioselec-tivity; the R-enantiomer of SKF 83566 was 500-fold more potent that its S-antipode. However, the displacement of [³H]spiperone binding from D-2 sites in the same tissue showed negligible enantioselectivity. Through such structure-affinity relationships, these studies may help to define the topography of the human brain D-1 dopamine receptor and guide the design of more selecive agents for functional studies.     

Effects of Heavy Metal Cations and Other Sulfhydryl Reagents on Brain Dopamine D1 Receptors: Evidence for Involvement of a Thiol Group in the Conformation of the Active Site

To investigate aspects of the biochemical nature of membrane-bound dopamine D1 receptors, rat striatal homogenates were pretreated with heavy metal cations and some other chemical agents, and their effects on D1 receptors were subsequently determined using a standard [3H](R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-N-3- benzazepine([3H]SCH 23390) binding assay. Incubation of striatal membranes with as little as 1 microM Hg2+, 10 microM Cu2+, and 10 microM Cd2+ completely prevented specific [3H]SCH 23390 binding. The effect of Cu2+, 1.5 microM, was noncompetitive in nature, whereas 3-5 microM Cu2+ afforded mixed-type inhibition. The inhibitory effect of Cu2+ was fully reversed by dithiothreitol (0.1-1 mM). Cu2+ (2 microM) did not affect the affinity of cis-flupenthixol or clozapine for remaining [3H]SCH 23390 sites. A second series of cations, Co2+ (30 microM), Ni2+ (30 microM), Mn2+ (1 mM), Ca2+ (25 mM), and Ba2+ (20 mM), inhibited specific [3H]SCH 23390 binding by 50% at the concentrations indicated. The thiol alkylating reagent N-ethylmaleimide (NEM) (0.2 mM) reduced specific binding by 70%. The effect of NEM was completely prevented by coincubation with a D1 receptor saturating concentration of SCH 23390 (20 nM) or dopamine (10 microM). The results indicated that the dopamine D1 receptor is a thiol protein and that a thiol group is essential for the ligand binding.     

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

The biochemical properties of central nervous system (CNS) dopamine (DA) D1 and D2 receptors were examined using the specific antagonists [3H]SCH23390 and [3H]raclopride, respectively. There is a different participation of sulfhydryl (-SH) and disulfide (-SS-) groups in the binding site and/or coupling to second messenger systems of D1 and D2 receptors. The ionic studies with [3H]SCH23390 showed slight agonist and antagonist affinity shifts for the D1 receptor. On the other hand, the D2 receptor is very sensitive to cations; even if lithium and sodium influence specific [3H]raclopride binding in a similar manner, there appear to be quantitative differences between these two ions that cannot be explained by surface charge mechanisms. The distribution of D1 and D2 receptors was heterogenous in both species, with the greatest densities in the neostriatum, where the highest concentrations of DA and metabolites were measured. Regions with low endogenous DA content (cerebral cortex and hippocampus) had lower densities of DA receptors. Furthermore, these binding sites were differentially localized within the various regions, and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors can be related to dopaminergic innervation and turnover.     

The modulation of brain dopamine and GABAA receptors by estradiol: A clue for CNS changes occurring at menopause

Summary 1. Tardive dyskinesia is more important in postmenopausal women than men of comparable age and a peak of first episodes of schizophrenia is observed in postmenopausal women. The effect of ovariectomy (2 weeks or 3 months) in rats was investigated as a model of decreased gonadal function associated with menopause.2. Frontal cortex D1 receptor density and affinity were similar in intact male compared to intact female rats and progressively decreased in density with time after ovariectomy, with no change of affinity. Striatal D1 and D2 receptors also decreased in density after ovariectomy for both receptor subtypes, with no change of affinity. Striatal D1 receptor density and affinity were similar in intact male and female rats, whereas the density of D2 receptors was higher in females. Treatment with estradiol for 2 weeks restored the D2 but not the D1 receptor changes.3. In the substantia nigra pars reticulata, striatum, nucleus accumbens, and entopeduncular nucleus, a progressive increase in [³H]flunitrazepam specific binding associated with GABA_A receptors was observed as a function of time following ovariectomy; this was corrected with estradiol treatment. In contrast, the opposite was observed for [³H] flunitrazepam binding in the globus pallidus, where ovariectomy decreased binding, which was corrected with estradiol replacement therapy.4. Low prefrontal cortex dopamine activity with implications of D1 receptors in negative symptoms of schizophrenia is hypothesized. Furthermore, GABAergic overactivity in the internal globus pallidus-substantia nigra pars reticulata complex is hypothesized in tardive dyskinesia.5. The present data suggest that gonadal hormone withdrawal by reducing brain dopamine receptors and producing an imbalance of GABA_A receptors in the output pathways of the striatum may predispose to schizophrenia and dyskinesia.     

Effect of prolactin and estradiol on rat striatal dopamine receptors

Chronic estrogen treatment has been found to increase the level of rat striatal dopamine receptors. Since it is well known that estrogen treatment increases circulating prolactin levels, we have investigated the possibility that the stimulatory effect of estrogens on dopamine receptors is exerted via prolactin. Ovariectomized female or intact male rats were implanted with three adenohypophyses under the kidney capsule or treated with 17 β-estradiol (10 μg, twice daily) for 2 weeks. In animals of both sexes, the pituitary-implanted and estradiol-treated rats showed higher levels of [³H]spiperone binding to striatal dopamine receptors. This effect of estradiol or pituitary implants on dopamine receptors was further investigated in ovariectomized rats. The pituitary-implanted and estradiol-treated rats had elevated plasma prolactin levels and an increased density of striatal dopamine receptors without alteration of their affinity. The role of the pituitary in the effect of estradiol was next investigated using hypophysectomized female rats treated with 17 β-estradiol (10 μg, twice daily), o-prolactin (500 μg, twice daily) or bearing three anterior pituitary implants. The implants as well as the treatment with estradiol or prolactin increased the level of striatal dopamine receptors in hypophysectomized rats while, as expected, the estradiol-treated animals did not have elevated plasma prolactin levels. The present data indicate that high prolactin levels lead, as observed with chronic estradiol treatment, to an increased density of striatal dopamine receptors. However, the effect of estradiol may not be explained exclusively by increased prolactin levels since a similar stimulatory effect is observed in hypophysectomized animals.     

[3H]Fluphenazine Binding to Brain Membranes: Simultaneous Measurement of D-1 and D-2 Receptor Sites

[3H]Fluphenazine was used to label both D-1 and D-2 dopamine receptors in mouse striatal membranes. The D-1 and D-2 specific binding of [3H]fluphenazine was discriminated by the dopamine antagonists SCH-23390 (D-1 selective) and spiperone (D-2 selective). Saturation analyses of these two sites yielded a D-1 receptor density in mouse striatum of 1,400 fmol/mg of protein and a D-2 receptor density of 700 fmol/mg of protein. The affinity of [3H]fluphenazine for the D-2 site was slightly greater than for the D-1 site; the equilibrium dissociation constant (KD) was 0.7 versus 3.2 nM, respectively. Assay conditions are described that reduce nonspecific binding of [3H]fluphenazine to acceptable levels (35% of total binding at 1 nM [3H]fluphenazine). By comparison of displacement curves from a series of dopaminergic and nondopaminergic ligands, the pharmacological specificity of [3H]fluphenazine binding in mouse striatum was demonstrated to be dopaminergic. Only small amounts of dopamine-specific (apomorphine-sensitive) [3H]fluphenazine binding were found in other brain regions. However, chlorpromazine displaced considerable [3H]fluphenazine from all brain regions, including cerebellum, suggesting the presence of a [3H]fluphenazine binding site with a phenothiazine specificity.     

Interaction of the D1 Receptor Antagonist Sch 23390 with the Central 5-HT System: Radioligang Binding Studies,Measurements of Biochemical Parameters and Effects on L-5-HTP Syndrome

Abstract

The interaction of SCH 23390 with dopamine (DA) and serotonin (5-HT) systems has been examined in vivo and in vitro. Like selective 5-HT₂ blockers, SCH 23390 inhibited in vivo [³H]spiperone binding in the rat frontal cortex (ID₅₀: 1.5 mg/kg) without interacting at D₂ sites. SCH 23390 was equipotent to cinanserin and methysergide. In vitro, SCH 23390 inhibited [³H]ketanserin binding to 5-HT₂ sites (IC₅₀ = 30 nM). Biochemical parameters linked to DA and 5-HT were not changed excepted in striatum where SCH 23390 increased HVA and DOPAC. In the L-5-HTP syndrome model, SCH 23390 clearly showed antagonism of 5-HT₂ receptors. SCH 23390 had weak affinity for 5-HT_1B (IC₅₀ = 0.5 μM), 5-HT_1A (IC₅₀ = 2.6 μM) and α;₁-adenergic receptors (IC₅₀ = 4.4 μM).     

Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics

Neuroleptics such as thioxanthenes (cis($\text{Z}$)-flupentixol and cis($\text{Z}$)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiapines.     

Solubilization of dopamine D-1 receptors with a zwitterionic detergent DCHAPS and their reconstitution.

1. Dopamine D-1 receptors of the bovine caudate nucleus were solubilized with different detergents. They were labelled with [3H]SCH 23390 and assayed by filtration through PEI-coated glass fibre filters and Sephadex G-50 columns. 2. DCHAPS was the best solubilizer among all detergents used and at 0.075% DCHAPS, 10 mg/ml protein, 30 min, 4 degrees C, gave the yield of 48.7%. 3. Reconstitution of solubilized receptors was performed using SM-2 Bio-Beads. Phosphatidylcholine did not improve reconstitution suggesting that DCHAPS solubilized sufficient amounts of the membrane phospholipids. 4. Loss of affinity of solubilized receptors to [3H]SCH 23390 binding was reversible. Apparent Kd values of 0.36 +/- 0.02, 21.3 +/- 3.2 and 0.77 +/- 0.05 nM were obtained for membrane-bound, solubilized and reconstituted receptors, respectively.     

Effects of chronic antidepressant treatment on dopamine-related [3H]SCH 23390 and [3H]Spiperone binding in the rat striatum

1. The effects of chronic administration of antidepressants on dopamine-related [3H]SCH 23390 and [3H]spiperone binding to rat striatal membranes were assessed. 2. The monoamine oxidase inhibitors phenelzine (5 or 10 mg kg-1/day) and tranylcypromine (1 mg kg-1/day) and the tricyclic desipramine (10 mg kg-1/day) were administered for 28 days by constant subcutaneous infusion using Alzet (2ML4) osmotic minipumps. 3. These treatments did not alter Kd estimates for either [3H]SCH 23390 or [3H]spiperone binding sites. The monoamine oxidase inhibitors induced a decrease in the Bmax values for both [3H]SCH 23990 and [3H]spiperone binding sites. Desipramine induced a decrease in the Bmax value for [3H]SCH 23390 binding but had no effect on the Bmax value for [3H]spiperone binding.