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S J Peroutka

Publications and source records attributed to S J Peroutka.

At least 127 records · Page 7Linked to original sources
PubMed1987

Identification of 5-hydroxytryptamine binding site subtypes in rat spinal cord.

High-affinity, specific [3H]5-hydroxytryptamine (5-HT) binding was analyzed in rat spinal cord homogenates. Drug competition studies were performed using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to compete selectively for 5-HT1A sites, RU 24969 to compete for 5-HT1B sites and mesulergine to compete for 5-HT1C sites. Competition data were analyzed by computer-assisted iterative curve-fitting analysis. The results demonstrate that 5-HT1A, 5-HT1B and 5-HT1C binding sites are present in rat spinal cord. In addition, approximately 33% of total 5-HT1 sites do not appear to represent either 5-HT1A, 5-HT1B or 5-HT1C binding sites. Therefore, 5-HT1D and/or some other 5-HT1 binding site subtype may also be present in rat spinal cord.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Two distinct effects of 5-hydroxytryptamine on single cortical neurons.

The ability of the indoleamine serotonin (5-hydroxytryptamine; 5-HT) to alter membrane characteristics of neocortical neurons was analyzed using intracellular recording techniques. The present study demonstrates that 5-HT primarily depolarized 68% of cortical neurons probably by decreasing a resting K+ conductance, an effect blocked by the antagonists ritanserin and cinanserin and apparently mediated by 5-HT2 receptors. A hyperpolarization associated with an increased conductance state and insensitive to 5-HT2 antagonists was observed in 26% of the neurons and could be mimicked by the selective 5-HT1A agonist (+/-)-8-hydroxy-2-(di-N-propyl-amino)tetralin (8-OH-DPAT). Therefore cortical pyramidal neurons contain at least two distinct functional 5-HT receptors whose activation produces opposing effects on membrane potential and conductance.

Animals↗
PubMed1987

[3H]3,4-methylenedioxymethamphetamine (MDMA) interactions with brain membranes and glass fiber filter paper.

The binding of [3H]3,4-methylenedioxymethamphetamine [( 3H]MDMA) to both rat brain membrane preparations and glass fiber filter papers was analyzed in the present study. Saturation studies indicate that [3H]MDMA binding is saturable and monophasic in both the presence and absence of rat brain membranes. This apparent 'specific' binding of [3H]MDMA in both the presence and absence of brain homogenates was totally eliminated by pretreating glass fiber filter papers with polyethylenimine. Drug competition studies demonstrated that [3H]MDMA binding displays a distinct 'pharmacological' profile in the absence of brain tissue. These data indicate that apparent [3H]MDMA binding to rat brain homogenates results from artifactual of [3H]MDMA to glass fiber filter paper. In addition, uptake of [3H]MDMA into rat brain synaptosomes could not be detected. We conclude the [3H]MDMA has limited usefulness in radioligand binding studies.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Chemotherapeutic agents do not interact with neurotransmitter receptors.

The interactions of cisplatin, 5-fluorouracil, doxorubicin, mitomycin, carmustine (BCNU), cyclophosphamide, methotrexate and thio-TEPA were assessed at three neurotransmitter receptor binding sites. Each drug was inactive at concentrations as high as 10(-4) M in displacing the specific binding of 3H-spiperone to dopamine D2, 3H-pyrilamine to histamine H1, and 3H-quinuclidinyl benzilate to muscarinic cholinergic receptors. These data suggest that chemotherapy-induced nausea and vomiting are not due to interactions with neurotransmitter receptors.

Animals↗
PubMed1987

Modulation of postdecapitation convulsions in rats by alpha-adrenergic and 5-hydroxytryptamine1A agents.

Postdecapitation convulsions were analyzed in rats after the administration of a variety of adrenergic and serotonergic agents. Drugs were selected on the basis of their relative affinities for 5-hydroxytryptamine1A, alpha 2-adrenergic and/or alpha 1-adrenergic receptors. The 5-hydroxytryptamine1A-selective agonists, 8-hydroxy-N,N-dipropyl-2-aminotetralin and buspirone, significantly increased the duration of the convulsions. The alpha 2-adrenergic antagonists, yohimbine and corynanthine, had no affect on either the latency or duration of the convulsions. By contrast, each of the three alpha 1-adrenergic agents increased the latency and decreased their duration. However, the order of potency was WB 4101 greater than ipsapirone greater than prazosin and this rank order did not correlate with drug potencies for the alpha 1-adrenergic receptor as determined by radioligand binding studies. The high potency of both ipsapirone and WB 4101 in inhibiting the postdecapitation convulsions may relate to the combined effects of the drugs at both alpha 1-adrenergic and 5-hydroxytryptamine1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists.

We studied mortality after pertussis immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of pertussis immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in pertussis immunization-induced encephalopathy in mice.

Animals↗
PubMed1987

Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes.

3H-5-Hydroxytryptamine (5-HT) binding sites were analyzed in bovine brain membranes. The addition of either the 5-HT1A-selective drug 8-OH-DPAT (100 nM) or the 5-HT1C-selective drug mesulergine (100 nM) to the assay resulted in a 5-10% decrease in specific 3H-5-HT binding. Scatchard analysis revealed that the simultaneous addition of both drugs decreased the Bmax of 3H-5-HT binding by 10-15% without affecting the KD value (1.8 +/- 0.3 nM). Competition studies using a series of pharmacologic agents revealed that the sites labeled by 3H-5-HT in bovine caudate in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine appear to be homogeneous. 5-HT1A selective agents such as 8-OH-DPAT, ipsapirone, and buspirone display micromolar affinities for these sites. RU 24969 and (-)pindolol are approximately 2 orders of magnitude less potent at these sites than at 5-HT1B sites which have been identified in rat brain. Agents displaying nanomolar potencies for 5-HT1C sites such as mianserin and mesulergine are 2-3 orders of magnitude less potent at the 3H-5-HT binding sites in bovine caudate. In addition, both 5-HT2- and 5-HT3-selective agents are essentially inactive at these binding sites. These 3H-5-HT sites display nanomolar affinity for 5-carboxyamidotryptamine, 5-methoxytryptamine, metergoline, and 5-HT. Apparent Ki values of 10-100 nM are obtained for d-LSD, RU 24969, methiothepin, tryptamine, methysergide, and yohimbine, whereas I-LSD and corynanthine are significantly less potent. In addition, these 3H-5-HT labeled sites are regulated by guanine nucleotides and calcium. Regional studies indicate that this class of sites is most dense in the basal ganglia but exists in all regions of bovine brain. These data therefore demonstrate the presence of a homogeneous class of 5-HT1 binding sites in bovine caudate that is pharmacologically distinct from previously defined 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, and 5-HT3 receptor subtypes. We therefore suggest that this class of sites be designated the 5-HT1D subtype of binding sites labeled by 3H-5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

The effects of buspirone on sleep in the rat.

Buspirone is a novel anxiolytic compound that does not produce the sedation often associated with the use of benzodiazepines. The present study evaluated the effects of this anxiolytic on sleep in rats surgically prepared for long-term recordings. Buspirone, at a dose of 3 mg/kg i.p., produced a significant increase in total wake time (P less than 0.05) compared with drug-free controls. At a dose of 10 mg/kg i.p., rats displayed altered sleep patterns with the most significant effects observed in the first third of recording period. These animals displayed increased wakefulness (P less than 0.001), decreased non-REM sleep (P less than 0.001), and an obliteration of REM sleep (P less than 0.02). These data support the suggestion that the clinically useful anxiolytic buspirone, unlike the benzodiazepines, does not induce sleep.

Animals↗
PubMed1986

Fate of nigrostriatal neurons in young mature mice given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a neurochemical and morphological reassessment.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on nigrostriatal dopaminergic neurons in the mouse was re-examined in view of recent conflicting reports regarding the neurotoxic effect of MPTP in this experimental animal. It was found that while MPTP destroyed a substantial number of dopaminergic nerve terminals in the striatum of young mature (6-8 weeks old) mice, it left the majority of cells in the pars compacta of the substantia nigra (SNc) unaffected. It was also found that 5 months after MPTP treatment there was substantial, although incomplete, recovery of striatal DA nerve terminal markers (DA level, metabolites, uptake, [3H]mazindol binding). Given these observations, it is concluded that while the young mature MPTP mouse may not be a valid animal model of Parkinson's disease (since it does not develop severe SNc cell loss characteristic of this disorder), it will be valuable for the study of how MPTP destroys dopaminergic nerve terminals and may prove useful as an experimental system for studying recovery of dopaminergic fibers after injury and for exploring ways to accelerate this recovery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Nucleotide interactions with 5-HT1A binding sites directly labeled by [3H]-8-hydroxy-2-(DI-n-propylamino)tetralin ([3H]-8-OH-DPAT).

Nucleotide interactions were examined at 5-hydroxytryptamine1A (5-HT1A) binding sites labeled by [3H]-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). At a 10(-4) M concentration, GTP and GDP decreased specific binding of 0.4 nM [3H]-8-OH-DPAT to 47 +/- 4 and 61 +/- 1% of control values respectively. This nucleotide effect was significantly greater (P less than 0.005) than observed at total 5-HT1 binding sites labeled by 1.5 nM [3H]-5-HT. GMP and adenine nucleotides had a minimal effect on [3H]-8-OH-DPAT binding at concentrations less than 10(-3) M. Saturation experiments demonstrated that 10(-4) M GTP increased the KD of [3H]-8-OH-DPAT for 5-HT1A binding sites (0.79 to 2.7 nM) without changing the number of binding sites (1.98 to 1.93 pmoles/g tissue). The Ki values of classic and novel putative 5-HT agonists were increased 2- to 4-fold in the presence of 10(-4) M GTP. Affinities of 5-HT antagonists for the [3H]-8-OH-DPAT site were not affected by the addition of 10(-4) M GTP to the binding assay.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Species variations in RU 24969 interactions with non-5-HT1A binding sites.

The interaction of RU 24969 with [3H]5-hydroxytryptamine ([3H]5-HT) binding to non-5-HT1A binding sites was analyzed in nine species. Non-5-HT1A binding was defined as specific [3H]5-HT binding observed in the presence of 100 nM 8-OH-DPAT. Computer-assisted iterative curve fitting of RU 24969 competition studies indicate that RU 24969 distinguishes two distinct components of non-5-HT1A sites in rat and mouse brain. These two binding components display apparent Ki values of 0.33-0.39 and 66-130 nM for RU 24969. By contrast, RU 24969 competition for non-5-HT1A binding in guinea-pig, cow, human, dog, chicken, turtle and frog brain membranes is consistent with a homogeneous population of [3H]5-HT binding sites. This population of sites displays apparent Ki values of 23-130 nM for RU 24969 and appear to be analogous to the low affinity component of non-5-HT1A sites identified in rat and mouse.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Antimigraine drug interactions with 5-hydroxytryptamine1A receptors.

The interactions of four antimigraine drugs with 5-hydroxytryptamine1A and beta-adrenergic receptors were analyzed in rat brain membranes. Methysergide, cyproheptadine, (-)propranolol, and pizotifen display similar affinities (IC50 values, 83 to 280 nM) for 5-hydroxytryptamine1A receptors labeled by [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin. Cyproheptadine, pizotifen, and methysergide are essentially inactive at beta-adrenergic receptors labeled by [3H]dihydroalprenolol (IC50 values, 8,700 to 87,000 nM). By contrast, (-)propranolol is an extremely potent beta-adrenergic agent (IC50, 3 nM). These data indicate that the 5-hydroxytryptamine1A receptor is a common site of action for (-)propranolol and other antimigraine agents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Differential modulation of dopamine D2 receptors by chronic haloperidol, nitrendipine, and pimozide.

Chronic administration of the neuroleptic haloperidol, the calcium channel antagonist nitrendipine, and the calcium channel antagonist neuroleptic pimozide produce differential effects on rat striatal 3H-spiperone binding. Following 7 days of 10 mg/kg i.p. administration, haloperidol significantly increases (p less than 0.01) dopamine D2 receptor binding to 123% +/- 6% of control values, whereas pimozide treatment significantly reduces (p less than 0.001) striatal 3H-spiperone binding to 46% +/- 6% of control values. Chronic administration of the calcium channel antagonist nitrendipine does not alter 3H-spiperone binding relative to control values. Saturation analysis reveals an increase in Bmax following chronic haloperidol and a decrease in Bmax following chronic pimozide treatment. No alterations in muscarinic cholinergic sites, dopamine uptake sites, or calcium channel antagonist sites result following chronic drug administration. These results are the first demonstration of a decrease in dopamine D2 binding sites after chronic neuroleptic treatment.

Animals↗
PubMed1986

Differential effects of 5-hydroxytryptamine1a selective drugs on the 5-HT behavioral syndrome.

The effects of 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), buspirone and isapirone were examined at 5-hydroxytryptamine1A (5-HT1A) binding sites and on the 5-HT behavioral syndrome in the rat. 8-OH-DPAT, 5-MeODMT, buspirone and isapirone are all potent inhibitors of 3H-8-OH-DPAT binding to rat brain membranes (Ki values = 1.9-13 nM). However, these drugs have differential effects on the 5-HT behavioral syndrome. 8-OH-DPAT, 5-MeODMT and buspirone induce hindlimb abduction, flattened body posture and Straub tail. Isapirone induces only a slight flattening of body posture. By contrast, 8-OH-DPAT and 5-MeODMT, but not buspirone and isapirone, and isapirone, also induce forepaw treading, head-weaving and tremor. However, both buspirone and isapirone antagonize the induction of these three behaviors by 8-OH-DPAT or 5-MeODMT. These data show that 8-OH-DPAT and 5-MeODMT are "full agonists" in relation to six components of the 5-HT behavioral syndrome. Buspirone and isapirone, on the other hand, act as "antagonists" in relation to forepaw treading, head-weaving and tremor. Therefore, these data suggest that specific components of the 5-HT behavioral syndrome are mediated by 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Differential interactions of "prosexual" drugs with 5-hydroxytryptamine1A and alpha 2-adrenergic receptors.

Radioligand binding studies were used to analyze the interactions of six "prosexual" drugs with 5-hydroxytryptamine1A (5-HT1A) and alpha 2-adrenergic receptors in rat brain membranes. Three drugs that facilitate seminal emissions and/or ejaculations [8-hydroxy-2-n-propylaminotetralin (8-OH-DPAT), 5-methoxy-dimethyltryptamine, and RDS-127] are potent and selective inhibitors of [3H]8-OH-DPAT binding to 5-HT1A receptors. By contrast, three drugs with primary sexual arousal effects (yohimbine, imiloxan, and idazoxan), are potent agents at alpha 2-adrenergic receptors labeled by [3H]yohimbine. These data suggest that radioligand binding analysis of prosexual agents may elucidate the pathophysiology of sexual behavior.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Artifactual high-affinity and saturable binding of [3H]5-hydroxytryptamine induced by radioligand oxidation.

The binding of [3H]5-hydroxytryptamine (5-HT, serotonin) to cerebellar membranes was examined after preincubation of [3H]5-HT in the presence or absence of ascorbate. The tissue preparation was identical in all experiments and consisted of rat cerebellar homogenates in Tris-HCl buffer with 0.1% ascorbate. Cerebellar membranes were used because of their low density of 5-HT1 binding sites. In the presence of ascorbate during a 4-h preincubation period, minimal specific binding of 2 nM [3H]5-HT is detected. Similar results are obtained with equimolar concentrations of other antioxidants (butylated hydroxytoluene, sodium dithionite, and sodium metabisulfite). Apparent specific binding increases 14-fold following a 4-h preincubation of [3H]5-HT in the absence of ascorbate. The increase in apparent specific [3H]5-HT binding is time-dependent and plateaus after 4-6 h of preincubation. When ascorbate is present during the 4-h preincubation, Scatchard analysis of [3H]5-HT binding reveals a KD value of 3.0 +/- 0.3 nM and a Bmax value of 1.9 +/- 0.2 pmol/g tissue. When ascorbate is absent during the preincubation, the KD is essentially unchanged at 3.6 +/- 0.1 nM but the Bmax is significantly increased to 36.5 +/- 7 pmol/g tissue. Drug competition studies reveal that the apparent specific "[3H]5-HT binding" in the absence of ascorbate appears to be displaced by nanomolar concentrations of hydroxylated tryptamines (5-HT, bufotenine) but not by nonhydroxylated tryptamines (5-methoxytryptamine, tryptamine). HPLC analysis demonstrates that [3H]5-HT is essentially destroyed by a 4-h incubation at 22 degrees C in the absence of ascorbate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex.

Drug interactions with 5-HT1 (5-hydroxytryptamine type 1) binding site subtypes were analyzed in rat frontal cortex. 8-Hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) displays high affinity (Ki 3.3 +/- 1 nM) for 29 +/- 3% of total [3H]5-HT binding in rat frontal cortex and low affinity (Ki 9,300 +/- 1,000) for 71 +/- 4% of the remaining 5-HT1 sites. Therefore, non-5-HT1A binding in rat frontal cortex was defined as specific [3H]5-HT binding observed in the presence of 100 nM 8-OH-DPAT. 5-Methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl) 1 H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), mianserin, and methysergide produce shallow competition curves of [3H]5-HT binding from non-5-HT1A sites. Addition of 10(-3) M GTP does not increase the apparent Hill slopes of these competition curves. Computer-assisted iterative curve fitting suggests that these drugs can discriminate two distinct subpopulations of non-5-HT1A binding sites, each representing approximately 35% of the total [3H]5-HT binding in the rat frontal cortex. All three 5-HT1 binding site subtypes display nanomolar affinity for 5-HT and 5-methoxytryptamine. A homogeneous population of 5-HT1A sites can be directly labeled using [3H]8-OH-DPAT. These sites display nanomolar affinity for 8-OH-DPAT, WB 4101, RU 24969, 2-(4-[4-(2-pyrimidinyl)-1-piperazinyl] butyl)-1,2-benzisothiazol-3-(2H)one-1, 1-dioxidehydrochloride (TVX Q 7821), 5-methoxydimethyltryptamine, and d-lysergic acid diethylamide. The potencies of RU 24969, TFMPP, and quipazine for [3H]5-HT binding are increased by addition of 100 nM 8-OH-DPAT and 3,000 nM mianserin to the [3H]5-HT binding assay. Moreover, the drugs have apparent Hill slopes near 1 under these conditions. This subpopulation of total [3H]5-HT binding is designated 5-HT1B. By contrast, methysergide and mianserin become more potent inhibitors of residual [3H]5-HT binding to non-5-HT1A sites in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969. The drug competition curves under these conditions have apparent Hill slopes of near unity and these sites are designated 5-HT1C. Drug competition studies using a series of 24 agents reveals that each 5-HT1 subtype site has a unique pharmacological profile. These results suggest that radioligand studies can be used to differentiate three distinct subpopulations of 5-HT1 binding sites labeled by [3H]5-HT in rat frontal cortex.

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