[125I]SCH 23982, a ‘selective’ D-1 receptor antagonist, labels with high affinity 5-HT1C sites in pig choroid plexus

doi:10.1016/0014-2999(88)90766-2

European Journal of Pharmacology

Volume 150, Issues 1–2, 20 May 1988, Pages 181-184

https://doi.org/10.1016/0014-2999(88)90766-2 Get rights and content

Abstract

[¹²⁵I]SCH 23982, a ligand reported to be very selective for dopamine D-1 receptors, binds with high affinity to membranes of pig choroid plexus (K_D = 186 pM, B_max = 142 fmol/mg protein). Saturation and competition experiments suggested that [¹²⁵I]SCH 23982 labels a homogeneous population of sites. The rank order for affinity of agonists, 5-HT ≥ DOI (1-(,5-dimethoxy-4-iodophenyl)-2-aminopropane) ⪢ dopamine > fenoldopam, and antagonists, metergoline > mesulergine = mianserin > SCH 23390 > methiothepin > ketanserin > fluphenazine ⪢ (−)-sulpiride > (+)-sulpiride, was compatible with labelling of 5-HT_1C receptors by [¹²⁵I]SCH 23982. It also correlates very significantly with [³H]mesulergine binding to pig choroid plexus membranes. The effects of SCH 23390 and its analogues should not be systematically attributed to an interaction with D-1 receptors.

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Maternal treatment with cocaine or the D₁-dopamine receptor agonist, SKF 38393, induces expression of the immediate-early gene, c-fos, in fetal rodent brain. Our previous studies have focused on the suprachiasmatic nucleus late in gestation. In the present report, we examined the anatomical distribution of functional D₁-dopamine receptors throughout fetal rat brain. Functional D₁ receptors were defined using three complementary methods: in situ hybridization to detect D₁ receptor mRNA, autoradiographic detection of ¹²⁵I-SCH 23982 binding, and in situ hybridization to detect c-fos gene expression induced by maternal treatment with SKF 38393. D₁-dopamine receptor binding, receptor mRNA, and SKF 38393-induced c-fos gene expression are widespread in fetal brain by late gestation. These data indicate that the fetal brain is sensitive to dopamine receptor activation, and suggest that gestational exposure to drugs of abuse acting via dopaminergic mechanisms may influence fetal brain function.
Temporal differential adaptation of head-twitch and ear-scratch responses following administration of challenge doses of DOI
1995, Pharmacology, Biochemistry and Behavior
Previously, we reported that administration of the $5-HT_{2AC}$ receptor agonist, DOI [(±)-1-(2,5-Dimethoxy-4-iodophenyl)-2aminopropane], can simultaneously produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. Our recent studies have indicated that the HTR is a 5-HT_2A receptor-mediated phenomenon, whereas the ESR is probably a 5-HT_2C receptor-mediated event. The HTR and ESR exhibit subsensitivity to a challenge dose of DOI (2.5 mg/kg) administered 24 h after its acute or termination of its chronic (2.5 mg/kg, once daily for 13 days) administration. When the dose interval for the challenge dose of DOI was increased to 48 h, both the acute- and chronically treated mice exhibited a simultaneous supersensitive HTR response and a subsensitive ESR effect. The purpose of the present study was to investigate the dose-response effects of lower challenge doses of DOI 48 h following their respective first injections as well as determining the effects of repeated DOI injections at 2-h intervals for 8 h. Thus, in the present study, initial administration of DOI produced a dose-and time-dependent increase in the mean frequencies of both HTR and ESR. Significant HTRs were observed after administration of the lowest tested dose of DOI (0.25 mg/kg), whereas a robust frequency of ESR was only evident at 1 mg/kg or greater doses of DOI. A 48-h challenge administration of lower doses of DOI (0.25 and 0.5 mg/kg) did not significantly affect their respective first injection HTR scores. However, larger challenge doses of DOI (1 and 2.5 mg/kg) produced supersensitivity in the mean HTR score (+46% and +40%, respectively, p < 0.05) and subsensitivity in the mean ESR frequency (−92% and −67%, respectively, p < 0.05) relative to their first injection control values. All administered doses of DOI (0.25, 0.5, or 1 mg/kg) eventually significantly reduced their first injection (control) HTR scores when injected repeatedly at 2-h intervals. Significant HTR reductions were attained quicker for the larger DOI doses. It appears that a mouse needs to receive either cumulatively or in a single injection about 1 mg/kg dose of DOI prior to exhibiting a significant reduction in the HTR score in response to further administration of DOI. As with their initial first injection ESR scores, repeated administration of lower doses of DOI (0.25 and 0.5 mg/kg) did not produce a significant effect. However, the 1 mg/kg challenge dose of DOI, 2 h following its first injection, nearly completely attenuated its first injection control ESR score. Further repeated injections of DOI at 2-h intervals did not cause additional alteration in the mean ESR score. The present results indicate that adaptation mechanisms for the DOI-induced HTR and ESR are different, and this difference is probably a reflection of the adaptation mechanisms of the 5-HT_2A- and 5-HT_2C-receptor function.
The head-twitch response in the least shrew (Cryptotis parva) is a 5-HT<inf>2-</inf> and not a 5-HT<inf>1C</inf>-mediated phenomenon
1994, Pharmacology, Biochemistry and Behavior
Our initial studies suggested that the 5-HT_2/1C agonist (±)-1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane[(±)-DOI] produces both the head-twitch response (HTR) and the ear-scratch response (ESR) in mice via stimulation of 5-HT₂ receptors. However, challenge studies revealed that these behaviors are produced via two different receptors (possibly 5-HT₂ and 5-HT_1C). Due to a lack of selective agents one cannot designate a particular response for the activation of a specific receptor. The purpose of the present study was to investigate such behaviors in the least shrew, which is more sensitive to (±)-DOI than rodents. IP injection of (±)-DOI in shrews produced a dose-dependent (bell-shaped) and time-dependent increase in the HTR frequency. The (±)-DOI-induced HTR was equipotently and completely attenuated by the 5-HT_2/1C antagonists ketanserin and spiperone. The 5-HT_1C antagonists with 5-HT₂ agonist action, lisuride, also produced the HTR in a bell-shaped dose- and time-dependent fashion. Central injections of both (±)-DOI (0.2 μg) and lisuride (0.5 μg) also induced the behavior. Both peripheral and central administration of lisuride failed to produce the ESR. (±)-DOI significantly induced the ESR only at the highest dose tested (2.5 mg/kg, IP). Centrally administered (±)-DOI (0.2 μg) produced more ESRs relative to vehicle controls; however, the difference did not attain significance. At low doses (0.31 and 0.63 mg/kg), (±)-DOI had no effect on locomotor activity, but it significantly attenuated the behavior at larger doses. Both low and high doses of lisuride increased the motor activity. Spiperone dose-dependently suppressed locomotion, whereas ketanserin had no effect. The present results suggest that the HTR is a 5-HT₂ receptor-mediated event and changes in locomotor activity do not affect the induced HTR.
Enhanced oral activity response to A77636 in neonatal 6-hydroxydopamine-lesioned rats
1994, European Journal of Pharmacology
To study the role of dopamine D₁ receptors in enhanced oral activity effects of SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) in neonatal 6-hydroxydopamine-lesioned rats, SKF 38393 was compared to the full agonist, A77636 ((1R,3S)-3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran). At 3 days after birth rats were treated with 6-hydroxydopamine HBr (200 μg, salt form, i.c.v.; desipramine (20 mg/kg i.p.), 1 h) or vehicle. At 6–8 months a 0.01 mg/kg dose of A77636 HCl increased oral activity in 6-hydroxydopamine vs. control rats (P < 0.01). A77636 and SKF 38393 produced identical maximal responses of 35–36 oral movements at 0.1 and 1.0 mg/kg, respectively. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) HCl (0.3 mg/kg i.p.) attenuated the response to A77636. Neither A77636 HCl (0.01–1.0 mg/kg i.p.) nor SKF 38393 HCl (0.03–3.0 mg/kg i.p.) induced oral activity in intact rats. The findings demonstrate that A77636 is more potent than SKF 38393, and that supersensitized dopamine D₁ receptors are involved in the induction of oral behavior in neonatal 6-hydroxydopamine-lesioned rats.
5-HT<inf>1C</inf>/5-HT<inf>2</inf> receptor blockade prevents 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane-, but not stress-induced increases in brain tryptophan
1993, European Journal of Pharmacology
We have previously shown that acute administration of the 5-HT_1C/5-HT₂ receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI), elevates brain tryptophan levels. The present work aimed to investigate the mechanisms responsible for this elevation. Acute s.c. administration of a 2-mg/kg dose of DOI increased brain tryptophan levels but did not affect either plasma free tryptophan, plasma total tryptophan, brain 5-HT, or brain 5-hydroxyindoleacetic acid. Pretreatment with the 5-HT_1C/5-HT₂ receptor antagonist, LY 53857, prevented the DOI-induced increase in brain tryptophan levels, whilst the increase was reduced by the 5-HT₂ receptor/α₁-adrenoceptor antagonist, ketanserin, and to a lesser extent, by the ganglionic blocker, chlorisondamine. On the other hand, pretreatment with either the peripherally acting 5-HT_1C/5-HT₂ receptor blocker, BW 501C67, the 5-HT uptake enhancer, tianeptine, the 5-HT uptake blocker, paroxetine, or the β₂-adrenoceptor antagonist, ICI 118.551, proved ineffective. Lastly, pretreatment with LY 53857 did not affect the immobilization-induced elevation in brain tryptophan levels. It is concluded that the elevation in brain tryptophan levels induced by DOI but not that induced by stress is due to central 5-HT_1C and 5-HT₂ receptor stimulation.
5-HT<inf>1A</inf> and 5-HT<inf>2</inf> receptors mediate discrete behaviors in the Mongolian Gerbil
1992, Pharmacology, Biochemistry and Behavior
Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT_1A/5-HT₂ agonist 5-methoxy, N-N dimethyltryptamine (5-MeODMT) (0.5–8 mg/kg, SC), the specific 5-HT_1A agonist 8-hydroxy (di-n-propylamino)tetralin (8-OH-DPAT) (0.125–16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100–250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT_1A antagonist NAN-190 (0.25–8 mg/kg, SC) when doses 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT_1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT₂ agonists such as quipazine (2–16 mg/kg, SC) and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125–8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT₂ antagonist ritanserin (0.0125–0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreament with the selective 5-HT_1A agonist 8-OH-DPAT (0.005–0.04 mg/kg, SC), demonstrating a 5-HT_1A/5-HT₂ receptor subtype interaction. Simultaneous administration of the 5-HT₂ agonist DOI (1 mg/kg, SC) with 8-OH-DPAT (0.5 mg/kg, SC) significantly potentiated both RFT and BT behaviors of the 5-HT syndrome in gerbils, as has been reported in rats. Furthermore, pretreatment with the selective 5-HT₂ antagonist ritanserin (0.5 mg/kg, SC) resulted in nearly complete inhibition of the potentiation of RFT and BT by DOI and 8-OH-DPAT. Ritanserin pretreatment also shifted the dose-response curve for the 5-MeODMT-induced 5-HT syndrome to the right. These data suggest that 5-HT₂ receptor activation facilitates the expression of some 5-HT_1A receptor-mediated behaviors of the 5-HT syndrome and may explain why 5-MeODMT has greater potency than 8-OH-DPAT in the gerbil.

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Short communication[125I]SCH 23982, a ‘selective’ D-1 receptor antagonist, labels with high affinity 5-HT1C sites in pig choroid plexus

Abstract

Characterization of the binding of [3H]SCH 23390, a selective D-1 receptor antagonist ligand in rat striatum

Life Sci.

Quantitative autoradiographic localization of the D-1 and D-2 subtypes of dopamine receptors in rat brain

J. Neurosci.

A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding

Anal. Biochem.

Molecular pharmacology and biology of 5-HT1C receptors

Trends Pharmacol. Sci.

Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin

European J. Pharmacol.

Short communication
[¹²⁵I]SCH 23982, a ‘selective’ D-1 receptor antagonist, labels with high affinity 5-HT_1C sites in pig choroid plexus

Characterization of the binding of [³H]SCH 23390, a selective D-1 receptor antagonist ligand in rat striatum

Molecular pharmacology and biology of 5-HT_1C receptors

Molecular pharmacology of 5-HT₁ and 5-HT₂ recognition sites in rat and pig brain membranes: radioligand binding studies with [³H]5-HT, [³H]8-OH-DPAT, (−)[¹²⁵I]iodocyanopindolol, [³H]mesulergine and [³H]ketanserin