Activation of the 5‐HT_1c receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393

Abstract

1 A cloned 5-HT1c receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine Di-selective benzazepines at the 5-HT1c receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1c receptors was measured in the choroid plexus of the pig. 3 The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1c receptor. 4 Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1c receptors in the choroid plexus of the pig (K1 = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (K, = 2.0-2.2 pM). 5 It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

“…In DCs, recent pharmacological evidence suggests that the antagonism of D1R/D5R expressed on DCs could impair the polarization of naive CD4 + T cells toward the Th17 phenotype (24,25). However, as the D1R/D5R antagonist used in these studies is also an agonist for serotonin receptors (26,27) and serotonin receptors are also expressed on DCs (28), the individual contributions of specific DARs and serotonin receptors in this phenomenon are not clear (24).…”

“…However, this pharmacologic approach does not permit discrimination between the effects of D5R or D1R because the drug inhibits both type I DARs. In fact, SCH not only displays similar affinities for D1R and D5R (K i = 0.2 and 0.3 nM, respectively) (44) but also displays comparable affinities for serotonin receptors 5-HT1C and 5-HT2C (K i = 6.3 and 9.3 nM, respectively) (26,27). Furthermore, this study could not confine the cell type responsible for the amelioration effect.…”

A Sensitizing Regimen of Amphetamine Impairs Visual Attention in the 5-Choice Serial Reaction Time Test: Reversal by a D1 Receptor Agonist Injected into the Medial Prefrontal Cortex

“…This result is consistent with our previous finding that SKF38393 reverses an attentional setshifting deficit in amphetamine-treated rats. Secondly, in control rats SKF38393 completely reversed the deficits in attentional performance that resulted from lowering the stimulus duration from 1 to 0.25 s. Although SKF38393 is an agonist at D1 receptors it shows some affinity for 5-HT 2C , though not 5-HT 2A receptors, as well as alpha-2 adrenergic receptors (Briggs et al, 1991;Neumeyer et al, 2003). Manipulations of 5-HT systems affect primarily premature responding Passetti et al, 2003), while alpha-2 adrenergic ligands do not affect measures of choice accuracy (Sirvio et al, 1994), suggesting that actions at 5-HT and adrenergic receptors are not responsible for the reversal of attentional deficits by SKF38393.…”

Administration of SCH 23390 into the Medial Prefrontal Cortex Blocks the Expression of MDMA-Induced Behavioral Sensitization in Rats: An Effect Mediated by 5-HT2C Receptor Stimulation and not by D1 Receptor Blockade

“…The answer probably relies on its pharmacological properties. Thus, and although taken into account in very few studies, SCH 23390 also stimulates 5-HT 2C receptors, exhibiting a fairly good affinity for these receptors (K i E0.3 nM for D1 receptors vs K i E6.3 nM for 5-HT 2C receptors; Briggs et al, 1991;Bourne, 2001;Millan et al, 2001). Iontophoretic application of 5-HT ligands suppresses spontaneous firing of PFC neurons in a 5-HT 2C receptor-dependent manner (Bergqvist et al, 1999), suggesting that the 5-HT 2C receptor limits the excitability of cortical pyramidal neurons (Carr et al, 2002).…”

“…)), but blocks the sensitized response to a challenge dose of MDMA. SCH 23390 has been extensively used as a dopamine D1 receptor antagonist (Bourne, 2001); however, it also binds with high affinity to 5-HT 2C receptors (Briggs et al, 1991;Millan et al, 2001). For this reason, we went further to evaluate whether 5-HT 2C receptor stimulation by SCH 23390 could account for the blockade of the expression of MDMA-induced behavioral sensitization.…”