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PubMed1988

Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus.

The binding of [3H]mianserin to rat choroid plexus was characterized and compared with two other radioligands that label the 5-HT (serotonin)-1c receptor ([3H]mesulergine and [125I] lysergic acid diethylamide). [3H]Mianserin binding to a crude membrane preparation of choroid plexus from rat brain was rapid, saturable and of high affinity (Kd = 1 nM). The density of sites labeled by [3H]mianserin and [3H]mesulergine was equal. Furthermore, an excellent correlation was found between the potencies of drugs in competing for [3H]mianserin binding and for [125]lysergic acid diethylamide binding. Based on these data, it was concluded that [3H]mianserin labels the 5-HT-1c binding site. Using this ligand, the binding of the putative selective 5-HT-2 antagonist ritanserin to the 5-HT-1c site was evaluated. Ritanserin was a potent inhibitor of [3H]mianserin binding with a Ki value of 0.2 nM. Functional studies of 5-HT-stimulated phosphoinositide hydrolysis, the transmembrane signaling pathway for the 5-HT-1c receptor, showed that ritanserin blocks the effect of 5-HT and that it functions as a competitive antagonist of the 5-HT-1c receptor in intact choroid plexus. The potencies of ritanserin and several other drugs, including other 5-HT-2 antagonists, at the 5-HT-1c binding site correlated with their potencies at blocking 5-HT-stimulated phosphoinositide hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Adenylate cyclase and acetylcholine release regulated by separate serotonin receptors of somatic cell hybrids.

Serotonin activates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of NCB-20 neuroblastoma--brain hybrid cells with an activation constant of 530 nM, but has little or no effect on cellular cyclic AMP or cyclic GMP content of NIE-115 neuroblastoma or NG108-15 hybrid cells. In homogenates of NCB-20 hybrid cells, lysergic acid diethylamide stimulates adenylate cyclase activity (Kact = 12 nM) and partially inhibits (Ki = 10 nM) the stimulation of adenylate cyclase activity by serotonin. No desensitization was detected of serotonin receptors coupled to adenylate cyclase. Serotonin also depolarizes NCB-20, NG108-15, and NIE-115 cells and increases acetylcholine release. Serotonin receptors mediating depolarizing responses desensitize rapidly and reversibly, and the depolarizing effects of serotonin are neither mimicked nor inhibited by lysergic acid diethylamide. These results indicate that (i) NCB-20 cells possess at least two species of serotonin receptors, which independently regulate cellular functions, (ii) activation of adenylate cyclase does not directly affect membrane potential or acetylcholine release, and (iii) serotonin-dependent cell depolarization does not affect cyclic AMP or cyclic GMP synthesis in the cell lines tested.

Acetylcholine↗
PubMed2005

The stimulus properties of LSD in C57BL/6 mice.

RATIONALE: Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice. OBJECTIVE: To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species. METHODS: Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, s.c.; 15 min pretreatment] or vehicle. RESULTS: Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose-effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [-]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed. CONCLUSIONS: The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well.

Animals↗
PubMed1986

Possible 5-hydroxytryptamine1 (5-HT1) receptor involvement in the stimulus properties of 1-(m-trifluoromethylphenyl)piperazine (TFMPP).

Male rats (N = 24) were trained to discriminate 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (0.8 mg/kg) from saline in a two-lever, drug discrimination situation. 5-Hydroxytryptamine (5-HT) agonists such as fenfluramine (0.8-1.6 mg/kg), m-chlorophenylpiperazine (0.1-1.6 mg/kg) and RU 24969 (0.1-1.6 mg/kg) mimicked TFMPP; 8-hydroxy-2-(di-n-propylamino)tetralin (0.02-0.32 mg/kg) and quipazine (0.2-3.2 mg/kg) elicited saline lever responding; d-lysergic acid diethylamide (0.1-0.16 mg/kg) produced intermediate results. The 5-HT antagonists BC 105 (1.6-12.8 mg/kg), bromolysergic diethylamide (0.8-1.28 mg/kg), ketanserin (0.8-6.4 mg/kg), Ly 53857 (0.2-1.6 mg/kg) and pirenperone (0.08-0.64 mg/kg) failed to attenuate the TFMPP cue; metergoline (0.4-6.4 mg/kg) and spiperone (0.08-1.28 mg/kg) decreased drug lever responding by as much as 60%. These data suggest that 5-HT agonists are not identical and that drug discrimination procedures can differentiate among them. Given that there is strong evidence to support the existence of heterogeneous 5-HT receptors, the present results also suggest that TFMPP acts through mechanism(s) similar to those of the novel 5-HT1 agonists m-chlorophenylpiperazine and RU 24969; these actions can be differentiated from those underlying d-lysergic acid diethylamide, quipazine and 2,5-dimethoxy-4-methylamphetamine, which are attenuated by putative 5-HT2 antagonists. Thus, the authors propose a role for 5-HT1 receptors in mediating the stimulus effects of TFMPP, although further research is necessary to identify functional antagonists of such systems.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1984

Effect of some serotoninergic agents on the rectal temperature of the domestic fowl (Gallus domesticus).

The information currently available in the literature on the effects of serotonergic drugs on thermoregulation in the avian species is very scanty. Therefore, it was the objective in this project to study the influence of 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP), benserazide, carbidopa (Mk 486), citalopram, cyproheptadine, methysergide, xylamidine, p-chlorophenylalanine (PCPA) and lysergic acid diethylamide (LSD-25) on the rectal temperature of young chicks. 5-hydroxytryptamine (0.8 mg/kg), produced significant dose-dependent hypothermia in young chicks. Similarly, 5-HTP (16 mg/kg) profoundly lowered the rectal temperature of young chicks. The hypothermic effect of 5-HTP was potentiated by benserazide (1.25-2.5 mg/kg). Pretreatment with carbidopa (50 mg/kg) potentiated 5-HTP induced hypothermia. Citalopram (5 mg/kg) significantly potentiated hypothermia induced by 5-HT. Pretreatment with PCPA (200 mg/kg, 24 hr previously) alone resulted in hyperthermia while the hypothermic effect of 5-HTP (16 mg/kg) was antagonised by pretreatment with PCPA. Cyproheptadine (1.25 mg/kg) antagonised the hypothermic effect of 5-HT (0.1 and 0.8 mg/kg). The antagonistic effect was weak when the chicks were pretreated with larger doses of cyproheptadine (i.e. 2.5-10 mg/kg). The hypothermia induced by 5-HT (0.8 mg/kg) was antagonised by smaller doses of methysergide (0.125-1.0 mg/kg) but potentiated by larger doses of methysergide (2.0 and 4.0 mg/kg). Xylamidine (1-2 mg/kg) alone induced hyperthermia and effectively antagonised hypothermia induced by 5-HT (0.8 mg/kg). D-Lysergic acid diethylamide (2.5-10 micrograms/kg) alone induced hypothermia. The interaction between LSD and 5-HT was dose-dependent and biphasic.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1985

Interaction between tricyclic and nontricyclic 5-hydroxytryptamine uptake inhibitors and the presynaptic 5-hydroxytryptamine inhibitory autoreceptors in the rat hypothalamus.

In slices of the rat hypothalamus prelabeled with [3H]-5-hydroxytryptamine [( 3H]-5-HT), exposure to lysergic acid diethylamide or 5-methoxytryptamine decreased, in a concentration-dependent manner, the release of 3H-transmitter elicited by electrical stimulation. These inhibitory effects were antagonized by the 5-HT receptor antagonist methiothepin (1 microM). Exposure to methiothepin on its own increased in a concentration-dependent manner the electrically evoked overflow of [3H]-5-HT. Exposure to tricyclic antidepressants, like imipramine and amitriptyline, and to nontricyclic 5-HT uptake inhibitors, like paroxetine and citalopram, did not modify by themselves the electrically evoked overflow of [3H]-5-HT. Yet, the four inhibitors of neuronal uptake of 5-HT, antagonized the inhibition by lysergic acid diethylamide or 5-methoxytryptamine of the electrically induced release of [3H]-5-HT. After depletion of endogenous stores of 5-HT by pretreatment with para-chlorophenylalanine (300 mg/kg i.p.), the inhibitors of 5-HT uptake increased the electrically evoked release of [3H]-5-HT in a concentration-dependent manner. Their order of potency to enhance 5-HT overflow after pretreatment with parachlorophenylalanine paralleled their potency at inhibiting neuronal uptake of 5-HT (paroxetine = citalopram greater than imipramine greater than amitriptyline). In para-chlorophenylalanine-treated rat hypothalamic slices, these inhibitors of 5-HT uptake antagonized the inhibition by 5-HT autoreceptor agonists of the electrically evoked release of [3H]-5-HT to a similar extent than was observed in control rats. It is concluded that inhibition of 5-HT uptake reduces the effectiveness of 5-HT autoreceptor agonists to inhibit the electrically evoked release of [3H]-5-HT, irrespective of the chemical structure of the uptake inhibitor or of the levels of endogenous 5-HT achieved in the synaptic gap.

5-Methoxytryptamine↗
PubMed1996

Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus.

An important determinant of the neurobehavioral responses induced by a drug is its relative receptor selectivity. The molecular basis of ligand selectivity of hallucinogenic and nonhallucinogenic compounds of varying structural classes for the human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors was investigated with the use of reciprocal site-directed mutagenesis. Because these two closely related receptor subtypes differ in the amino acid present at position 5.46 (residues 242 and 222 in the sequences, respectively), the effects of corresponding substitutions in the 5-HT2A[S5.46(242)-->A] and 5-HT2C[A5.46(222)-->S] receptors were studied in tandem. By studying both receptors, the direct and indirect effects of mutations on affinity and selectivity can be distinguished. The ergolines studied, mesulergine (selective for the 5-HT2C receptor) and d-lysergic acid diethylamide (selective for the 5-HT2A receptor), reversed their relative affinity with mutations in each receptor, supporting a direct role of this locus in the selectivity of these ligands. However, interchange mutations in either receptor led to decreased or unchanged affinity for (+/-)-1-)(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and ketanserin, which have higher affinity for the 5-HT2A receptor, consistent with little contribution of this locus to the selectivity of these ligands. The indoleamines studied were affected differently by mutations in each receptor, suggesting that they bind differently to the two receptor subtypes. Mutation of this locus in the 5-HT2A receptor decreased the affinity of all indoleamines, whereas the interchange mutation of the 5-HT2C receptor did not affect indoleamine affinity. These results are consistent with a direct interaction between this side chain and indoleamines for the 5-HT2A receptor but not for the 5-HT2C receptor. Furthermore, this analysis shows that the higher affinity of 5-HT and tryptamine for the 5-HT2C receptor than for the 5-HT2A receptors is not due to the difference at this locus. The hallucinogens studied [d-lysergic acid diethylamide, psilocin, bufotenin, and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] fell into different classes in this analysis. For the classes of ligand studied, the side-chain difference at this position directly determines relative ligand selectivity only for ergolines and may contribute to the specific effects of hallucinogens in this class.

Amino Acid Sequence↗
PubMed1983

Inhibition of synaptosomal neurotransmitter uptake by hallucinogens.

The effect of 13 hallucinogens on the uptake of serotonin and norepinephrine into hippocampal synaptosomes and of serotonin and dopamine into caudate synaptosomes was found to be inhibitory, except for lysergic acid diethylamide and 2-bromolysergic acid diethylamide, which were inactive. The indolealkylamines were generally more potent than the phenylethylamines. The reported inhibition of uptake of serotonin by 5-methoxy-N,N-dimethyltryptamine and lysergic acid diethylamide into whole brain synaptosomes was not reproducible at concentrations 10(2) to 10(4) times higher than those stated in the literature.

Animals↗
PubMed1991

Desensitization and down-regulation of 5-HT2 receptors in P11 cells.

P11 cells express a high density of 5-hydroxytryptamine2 (5-HT2) receptors coupled to phosphoinositide hydrolysis. The effect of exposure to 5-HT on the expression and function of 5-HT2 receptors in P11 cells was investigated. Exposure of P11 cells to 10 microM 5-HT for as short a time as 20 min led to a decrease in the ability of 5-HT to stimulate phosphoinositide hydrolysis. After 8 hr, phosphoinositide hydrolysis stimulated by 5-HT was greatly reduced or absent. Concentrations of 5-HT as low as 100 nM caused desensitization of phosphoinositide hydrolysis. Stimulation of phosphoinositide hydrolysis by 6-fluoronorepinephrine, an alpha-1 adrenergic agonist, was not affected by prior exposure of cells to 5-HT. Therefore, the decrease in response to 5-HT represented a selective, homologous desensitization of 5-HT2 receptor-mediated phosphoinositide hydrolysis. The density of 5-HT2 receptors in membranes prepared from P11 cells was measured using [125I]lysergic acid diethylamide. Exposure of P11 cells to 5-HT resulted in a decrease in the density of 5-HT2 receptors with no change in the affinity of the receptors for [125I]lysergic acid diethylamide. A decrease in the density of receptors was observed after exposure to 10 microM 5-HT for 1 hr, and after 24 hr the density of 5-HT2 receptors was approximately 30% of the original value. Down-regulation of 5-HT2 receptors in P11 cells may be involved in homologous desensitization of 5-HT2 receptor-mediated phosphoinositide hydrolysis.

Brain↗
PubMed1991

Discriminative-stimulus effects of quipazine and l-5-hydroxytryptophan in relation to serotonin binding sites in the pigeon.

The 5-hydroxytryptamine (serotonin; 5-HT) agonists, RU-24969 [5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole, succinate], ipsapirone [2-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-1,2- benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride], 8-hydroxy-N,N-dipropyl-2-aminotetralin, lysergic acid diethylamide, fenfluramine and N,N-dimethyltryptamine were studied in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline and in pigeons trained to discriminate I-5-HTP (18.0 mg/kg) from saline. Lysergic acid diethylamide, quipazine and fenfluramine generalized to the training stimulus in both groups of pigeons. N,N-dimethyltryptamine generalized to quipazine in all pigeons tested whereas N,N-dimethyltryptamine generalized to I-5-HTP in most pigeons tested. The natural substrate 5-HT and agonists with affinities for the 5-HT1 receptor and its subtypes (8-hydroxy-N,N-dipropyl-2-aminotetralin, ipsapirone, and RU-24969) only generalized in the I-5-HTP-trained pigeons. Equilibrium binding experiments using the ligands [3H]-5-HT and [3H]ketanserin were performed with six areas of pigeon brain and six homologous areas of rat brain. Two populations of 5-HT binding sites were found in brains of both species; one defined by high-affinity binding of [3H]-5-HT and the other defined by high-affinity binding of [3H]ketanserin. Kd values were similar for the two ligands in brains of both species. 5-HT, RU-24969 and ipsapirone displaced [3H]-5-HT but not [3H]ketanserin from pigeon brain membranes. The present study suggests that, in the pigeon, the 5-HT2 receptor might mediate the discriminative-stimulus effects of quipazine, whereas the 5-HT1 receptor might mediate the effects of I-5-HTP.

5-Hydroxytryptophan↗
PubMed1998

The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum.

Ro 63-0563 [4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide] is a high affinity 5-hydroxytryptamine6 (HT6) receptor antagonist with more than 100-fold selectivity for the 5-HT6 receptor compared with 69 other receptors and binding sites. The present study describes the properties of [3H]Ro 63-0563, the first selective 5-HT6 receptor radioligand. Specific binding of [3H]Ro 63-0563 (nonspecific binding defined in the presence of 10 microM methiothepin) to recombinant rat and human 5-HT6 receptors was saturable, rapid, and reversible with equilibrium dissociation constants (Kd) of 6.8 nM and 4.96 nM, respectively. The pharmacological profile of the rat 5-HT6 receptor labeled with [3H]Ro 63-0563 (methiothepin > D-lysergic acid diethylamide > clozapine approximately Ro 63-0563 > lisuride > ergotamine approximately Ro 04-6790 > 5-HT > amitriptyline approximately metergoline approximately mianserin approximately ritanserin > methysergide > mesulergine) was similar to that obtained by using either [3H]D-lysergic acide diethylamide or [3H]5-HT as radioligand. In equilibrium binding studies with rat striatal membranes, [3H]Ro 63-0563 labeled a single binding site with Kd and Bmax values of 11. 7 nM and 175 fmol/mg protein, respectively. In porcine striatal membranes, [3H]Ro 63-0563 also labeled a single binding site with Kd and Bmax values of 8.0 nM and 130 fmol/mg protein, respectively. The affinities of 14 5-HT6 receptor ligands at this binding site were similar to those found for the recombinant rat and human 5-HT6 receptor, which suggested the presence of 5-HT6 receptors in porcine striatum.

Aminopyridines↗
PubMed2002

5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens.

The role of 5-HT2A-mediated stimulation of phosphoinositide hydrolysis in the discriminative effects of hallucinogens was investigated in PC12 cells stably expressing the rat 5-HT2A receptor (PC12-5-HT2A cells). The hallucinogenic compounds, D-lysergic acid diethylamide (LSD), (-)2,5-dimethoxy-4-methylamphetamine (DOM), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (MDMT) and N,N-diethyltryptamine (DET), all caused a concentration-dependent increase in the generation of [3H]inositol phosphates. The nonhallucinogenic compounds, 6-fluoro-N,N-diethyltryptamine (6-F-DET), lisuride and quipazine, also displayed significant efficacy in stimulating phosphoinositide hydrolysis, while 2-bromo-lysergic acid diethylamide (BOL), which is not a hallucinogen, did not alter inositol phosphate generation. The beta-carbolines, harmaline and harmane, also did not alter phosphoinositide hydrolysis. Comparison of these results with previous drug discrimination studies indicated the apparent lack of correlation between the degree of substitution in LSD- and DOM-trained animals and efficacy in stimulating phosphoinositide hydrolysis. The present study indicates that 5-HT2A-mediated stimulation of phosphoinositide hydrolysis does not appear to be the sole critical signaling mechanism involved in the discriminative effects of hallucinogens.

Animals↗
PubMed1991

Developmental regulation of 5-HT2 and 5-HT1c mRNA and receptor levels.

We investigated the regulation of 5-HT2 and 5-HT1c receptors and their corresponding mRNAs during rat brain development. This study showed that 5-HT2 and 5-HT1c receptors increased markedly during ontogeny. 5-HT2 receptors, measured with [3H]ketanserin or [125I]lysergic acid diethylamide binding, increased 8-fold between embryonic day 17 (E17) and postnatal day 13 (P13). 5-HT2 receptor mRNA levels, quantified by probing Northern blots of total RNA with a synthetic oligonucleotide cDNA probe, multiplied 13-fold between E17 and P5. The developmental pattern of 5-HT2 receptor and mRNA expression appeared to correlate with the serotonergic hyperinnervation of the cortex which occurs between P2 and P17. 5-HT1c receptors, measured with [125I]lysergic acid diethylamide under site-specific conditions, increased 2-fold between E17 and P27, 5-HT1c mRNA increased 5-fold between E17 and P27. Interestingly, the developmentally induced variations in 5-HT1c receptors did not precisely correlate with mRNA alterations. Further study of the factors responsible for these alterations could help to explain the molecular and biochemical mechanisms responsible for modulating receptor levels in vivo.

Animals↗
PubMed1986

Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes.

The inhibition of forskolin-stimulated adenylate cyclase activity by 5-hydroxytryptamine (5-HT) receptor agonists was measured in guinea pig and rat hippocampal membranes. The results were consistent with the inhibition being mediated by a single, homogeneous population of receptors. In guinea pig hippocampal membranes 8-hydroxy-2-(di-n-propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent in inhibiting forskolin-stimulated adenylate cyclase activity, with EC50 values of 18, 24, 53 and 146 nM, respectively. Spiperone (Kb = 26 nM) and methiothepin (Kb = 13 nM) were potent competitive antagonists at this receptor whereas ketanserin, a high affinity 5-HT2 receptor ligand, and ICS 205-930, a high affinity peripheral neuronal (M) receptor ligand, were not. In rat hippocampal membranes, 8-hydroxy-2-(di-n-propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent agonists and exhibited the same rank order of potency as in guinea pig hippocampal membranes. The maximal percentage of inhibition by buspirone was significantly less than the maximal percentage of inhibition by 5-HT in rat membranes, suggesting that it is a partial agonist at this receptor, with an intrinsic activity relative to 5-HT of 0.5. The concentration-response data show that the inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes is mediated by a receptor with the characteristics of the 5-HT1A binding site. We propose that the inhibition of adenylate cyclase activity is a functional correlate of this binding site. This response is suitable for measuring activities and affinities of drugs acting at 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Alterations in monoamine receptors in the brain of suicide victims.

Suicide has been linked to alterations in the serotonergic and noradrenergic systems. Using in vitro quantitative receptor autoradiography, we compared the binding of 125I-lysergic acid diethylamide (5-hydroxytryptamine-2 sites) and 125I-pindolol (beta-adrenergic sites) with slide-mounted sections from the prefrontal and the temporal cortex of a group of suicide victims, matched to control specimens on postmortem interval, age, sex, and race. A specific laminar distribution of 5-hydroxytryptamine-2 binding was found in both groups, with layers III and IV having the highest level of binding, but beta-adrenergic binding did not differ across cortical layers. Binding to both 125I-lysergic acid diethylamide and 125I-pindolol was increased in the prefrontal cortex of the suicide victims, whereas only beta-adrenergic binding was increased in the temporal cortex of the suicide group.

Adolescent↗
PubMed1981

The interaction of lisuride, an ergot derivative, with serotonergic and dopaminergic receptors in rabbit brain.

The interaction of lisuride (Lysenyl, Spofa), an ergot derivative, with serotonergic and dopaminergic receptors and with adenylate cyclase was studied in homogenates of rabbit brain. In frontal cortex, lisuride interacts with serotonin receptors as shown by its ability to compete with [3H]serotonin, [3H]spiroperidol and [3H]lysergic acid diethylamide for their receptor binding sites, with respective IC50 values of 14, 1.0 and 3.7 nM. The IC50 for displacement of [3H]spiroperidol by lisuride in frontal cortex was increased by the GTP analog, 5'-guanylylimidodiphosphate, indicating an agonist-like interaction. Lisuride is extraordinarily potent in stimulating serotonin-sensitive adenylate cyclase in this brain region, with maximal stimulations occurring at 0.1 nM lisuride. In caudate nucleus, lisuride interacted with both serotonergic and dopaminergic receptor sites as labeled by [3H]serotonin, [3H]lysergic acid diethylamide and [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, with IC50 values ranging from 2.0 to 7 nM. Lisuride did not stimulate adenylate cyclase in caudate nucleus. In summary, lisuride is a very potent stimulator of serotonin-sensitive adenylate cyclase in rabbit frontal cortex and can interact with serotonin and dopamine receptor binding sites in rabbit cortex and caudate nucleus.

Adenylyl Cyclases↗
PubMed1991

Agonist and antagonist properties of serotonergic compounds in pigeons trained to discriminate either quipazine or L-5-hydroxytryptophan.

The serotonin (5-HT) receptor-related compounds metergoline, pirenperone, ketanserin, cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin were studied in pigeons trained to discriminate l-5-hydroxytryptophan (l-5-HTP) (18.0 mg/kg) from saline and in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline. Metergoline did not generalize to either quipazine or l-5-HTP but did antagonize drug-appropriate responding in both groups. Ketanserin potently blocked the quipazine discriminative stimulus and neither generalized to nor attenuated the l-5-HTP discriminative stimulus. Pirenperone, cinanserin, cyproheptadine, methylsergide, pizotyline and mianserin attenuated the quipazine discriminative stimulus at low doses and, at higher doses, generalized to the l-5-HTP discriminative stimulus. No antagonism of the l-5-HTP-discriminative stimulus or generalization to the quipazine-discriminative stimulus were observed with these compounds. A correlation coefficient of 0.93 was calculated between the potencies of 5-HT compounds to generalize to the l-5-HTP stimulus and the binding affinities of these compounds for a 5-HT1 receptor in rat brain. In addition, a correlation coefficient of 0.78 was calculated between the potencies of 5-HT compounds to attenuate the quipazine stimulus and the binding affinities of these compounds for the 5-HT2 receptor in rat brain. These observations suggest cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin are agonists at the 5-HT1 receptor in the l-5-HTP discrimination and antagonists at a 5-HT2 receptor in the quipazine discrimination in pigeons.

5-Hydroxytryptophan↗
PubMed1993

Possible novel action of ouabain: allosteric modulation of vascular serotonergic (5-HT2) and angiotensinergic (AT1) receptors.

Experiments were carried out to determine the effects of ouabain and dihydroouabain, both at 10 microM, on the vasoconstrictor responses of isolated rabbit blood vessel rings to both serotonin and angiotensin II. Ouabain plus dihydroouabain increased the sensitivity of central ear artery to serotonin and markedly reduced the antagonist potency of 0.1 microM prazosin against serotonin in this blood vessel; dihydroouabain alone had no effect. Ouabain, markedly reversed the reduction of maximal contractile response by both 2-brom-d-lysergic acid diethylamide against serotonin in aorta and 2-n-propyl-4-trifluoromethyl-1-[(2'-1H-tetrazol-5yl)biphenyl -4- yl)methyl]imidazole-5-carboxylic acid (EXP 3892) against angiotensin II in femoral artery; dihydroouabain had no effect. Whereas both 10 microM ouabain and dihydroouabain produced nearly maximal inhibition of Na+K+ATPase, dihydroouabain failed to modulate the vasoconstrictor responses to either serotonin or angiotensin II. Thus, it is concluded that the vasoconstrictor modulatory effects of ouabain are mediated by mechanisms unrelated to Na+K+ATPase inhibition. The present results are consistent with the hypothesis that both 5-hydroxytryptamine2 and angiotensinergic receptors can exist in high and low activity states. It is proposed that 5-hydroxytryptamine2 receptors exist in a low activity state in the ear artery, or are converted to the low activity state by 2-brom-d-lysergic acid diethylamide in the aorta. Hypothetically, 2-n-propyl-4-trifluoromethyl-1- [(2'-(1H-tetrazol-5yl)biphenyl-4-yl)methyl]imidazole-5-carbo xylic acid also converted the angiotensinergic receptor to the low activity state in femoral artery. In all three cases, ouabain enhanced vasoconstriction to serotonin and angiotensin II, respectively, possibly by allosterically modulating the respective receptors in these vessels to their high activity states.

Allosteric Regulation↗