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Biomedical subjects

S J Peroutka

Publications and source records attributed to S J Peroutka.

At least 109 records · Page 6Linked to original sources
PubMed1988

Ring-substituted amphetamine interactions with neurotransmitter receptor binding sites in human cortex.

The binding affinities of 3 ring-substituted amphetamine compounds were determined at 9 neurotransmitter binding sites in human cortex. (+/-)-3,4-Methylenedioxyamphetamine (MDA), (+/-)-3,4-methylenedioxyethamphetamine (MDE), and (+/-)-3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') all display highest affinity (approximately 1 microM) for the recently identified 'DOB binding site' labeled by [77Br]R(-)4-bromo-2,5-dimethoxyphenylisopropylamine [( 77Br]R(-)DOB). MDA displays moderate affinity (4-5 microM) for the 5-hydroxytryptamine1A (5-HT1A), 5-HT1D, and alpha 2-adrenergic sites in human cortex. MDE and MDMA display lower affinity or are inactive at all other sites tested in the present study. These observations are discussed in relation to the novel psychoactive effects of the ring-substituted amphetamines.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Buspirone, 8-OH-DPAT and ipsapirone: effects on hippocampal cerebellar and sciatic fiber excitability.

The effects of serotonin (5-hydroxytryptamine; 5-HT), and the novel anxiolytics buspirone, 8-OH-DPAT (8-hydroxy-2-[N,N-dipropylamino]-tetralin) and ipsapirone (TVXQ 7821, 2-[4-[4-[2-pyrimidinyl]-1-piperazinyl] butyl]-1,2-benzisothiazol-3[2H]one-1,1-dioxide-hydrochloride) on fiber excitability were studied in three axon systems; hippocampal Schaffer collateral fibers, cerebellar parallel fibers, and sciatic nerves. In the hippocampus, application of buspirone, 8-OH-DPAT and ipsapirone resulted in reversible, dose-dependent reductions in the amplitude and conduction velocity of action potentials recorded from presynaptic afferent fibers. Although these agents bind to 5-HT1A receptors, 5-HT application, even at very high (1 mM) concentrations, did not alter axonal responses. This suggests that buspirone, 8-OH-DPAT and ipsapirone exert an action independent of a serotonergic mechanism. Similar effects were observed on the cerebellar parallel fibers although the cerebellum does not have an appreciable number of 5-HT1A receptors. To examine the generalized effects of these agents on nerve excitability, rat sciatic compound action potentials were studied with sucrose gap recordings. Whereas 5-HT, 8-OH-DPAT and ipsapirone had no effects even at high concentrations (1 mM), application of buspirone led to reversible decrement of the responses without appreciable change in membrane potential. These results indicate that buspirone, 8-OH-DPAT and ipsapirone have actions on the excitability of hippocampal and cerebellar neurons independent of serotonergic mechanisms. Moreover, buspirone, but not 8-OH-DPAT or ipsapirone, produces decreased sciatic nerve excitability. NS 20393

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Antagonism of 5-hydroxytryptamine1A (5-HT1A) receptor-mediated modulation of adenylate cyclase activity by pindolol and propranolol isomers.

The interactions of the stereoisomers of pindolol and propranolol with 5-hydroxytryptamine1A (5-HT1A) binding sites and adenylate cyclase activity were examined in rat hippocampus. (-)Pindolol and (-)propranolol displayed high affinity for 5-HT1A binding sites, and their affinities were not affected significantly by the addition of 10(-4) M GTP to the radioligand assay. The selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased forskolin-stimulated adenylate cyclase activity. The (-)isomers of pindolol and propranolol did not affect basal or forskolin-stimulated activity but, at a concentration of 10(-5) M, they reversed the 8-OH-DPAT inhibition of the forskolin-stimulated cyclase activity. The (+)isomers were less potent in producing this effect. These data suggest that (-)pindolol and (-)propranolol are potent antagonists at 5-HT1A receptors in rat hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

5-Hydroxytryptamine1A receptors are linked to a Gi-adenylate cyclase complex in rat hippocampus.

The ability of 5-hydroxytryptamine (5-HT) and the 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to modulate adenylate cyclase activity was measured in rat hippocampus. In vitro ADP ribosylation of GTP-binding proteins by pertussis toxin in this tissue abolished both 5-HT- and 8-OH-DPAT-induced inhibition of forskolin-stimulated adenylate cyclase activity. These findings indicate that 5-HT1A receptors are linked a pertussis-sensitive Gi protein in rat hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Distribution of muscarinic cholinergic receptors in the dorsal vagal complex and other selected nuclei in the human medulla.

Muscarinic cholinergic receptors were localized in human brainstem by quantitative autoradiography, using the radioligand [3H]quinuclidinyl benzilate. Receptor densities were highest in the hypoglossal nucleus. The second highest density was found in the medial region of the nucleus of the solitary tract (NTS). Moderately high numbers of receptors were present in the dorsal motor nucleus of the vagus, the dorsal NTS, subpostremal NTS, lateral NTS and ventral NTS. Intermediate densities were present in the dorsal and medial accessory nuclei of the inferior olive and the spinal trigeminal nucleus pars interpolaris. Low densities were found in the area postrema, principle nucleus of the inferior olive, gracile nucleus, cuneate nucleus and the tractus of the NTS. Muscarinic cholinergic receptors in the dorsal vagal complex are an important component of the neural substrate governing visceral function. These receptors may be the central site of action of anticholinergic medications in suppressing emesis.

Autoradiography↗
PubMed1988

Orally administered MDMA causes a long-term depletion of serotonin in rat brain.

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Antimigraine drug interactions with serotonin receptor subtypes in human brain.

The interactions of antimigraine agents with serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes were analyzed in human frontal cortex membranes. The drugs studied included 5-HT antagonists, beta-adrenergic antagonists, and calcium channel blockers. At 5-HT1A sites labeled by 3H-8-hydroxy-2-(N,N-dipropylamino)-tetralin, (-)pindolol, alprenolol, (-)propranolol, methysergide, cyproheptadine, and pizotifen are similar in that they display affinities of approximately 100 nM for this receptor. By contrast, only methysergide displays relatively high affinity (120 +/- 60 nM), whereas all other drugs have affinities greater than 1,000 nM for non-5-HT1A sites labeled by 3H-5-HT in human cortex. Finally, at 5-HT2 receptors labeled by 3H-spiperone, cyproheptadine, methysergide, and pizotifen are extremely potent agents (affinity constants of 1 to 10 nM), whereas amitriptyline (23 +/- 4 nM), verapamil (140 +/- 50 nM), and nifedipine (320 +/- 80 nM) are moderately potent. All other drugs are inactive at concentrations below 1,000 nM. These data demonstrate that most antimigraine drugs display high affinity for the 5-HT1A and/or 5-HT2 receptor subtypes in human brain. However, antimigraine efficacy cannot be explained by drug interactions with a single 5-HT receptor subtype.

Adrenergic beta-Antagonists↗
PubMed1988

R(-)-2,5-dimethoxy-4-77 bromoamphetamine [77Br-R(-)DOB]: a novel radioligand which labels a 5-HT binding site subtype.

R(-)-2,5-Dimethoxy-4-77Br-amphetamine [77Br-R(-)DOB], a radioligand of high specific activity (1500 +/- 200 Ci/mmol), was used to label membrane-associated recognition sites in rat brain. 77Br-R(-)DOB sites were of high affinity (KD = 0.19 nM) but low density (Bmax = 0.32 pmol/g tissue) in rat brain preparations. Competition experiments show that both 5-hydroxytryptamine (5-HT) and 5-HT2 antagonists display nanomolar potency for these sites. We conclude that 77Br-R(-)DOB labels 5-HT recognition sites in rat brain which do not fit into current classifications of 5-HT binding subtypes. This finding may be of aid in deciphering the mechanism of action of hallucinogens in man.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1988

Species variations in 5-HT3 recognition sites labeled by 3H-quipazine in the central nervous system.

The specific binding of 3H-quipazine to putative 5-HT3 receptors was analyzed in multiple species. Specific and saturable binding of the radioligand could be detected in both rat (KD = 1.2 nM; Bmax = 3.0 pmol/g) and pig (KD = 1.3 +/- 0.2 nM; Bmax = 1.5 +/- 0.2 p/mol/g) cortical membranes. By contrast, no significant specific binding of 3H-quipazine could be detected in human, cow, dog, turtle, mouse, guinea pig, chicken or rabbit brain membranes. These data indicate that marked species variations exist in the presence and/or density of 5-HT3 membrane recognition sites in the central nervous system.

Animals↗
PubMed1988

Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users.

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a serotonergic neurotoxin in laboratory animals that has been used for recreational purposes by humans. The subjective effects of this drug were determined in recreational users at a university campus. Of individuals who had admitted to using MDMA recreationally, 100 of 143 agreed to complete a detailed questionnaire concerning the subjective effects of this Schedule I compound. The most common effect of MDMA was a heightened sense of "closeness" with other people (90% of subjects). Tachycardia, dry mouth, bruxism and/or trismus were reported by the majority of users. These effects probably result from the amphetaminelike properties of the drug. Visual hallucinations were reported by 20% of users. Untoward side effects were most common on the day following the use of MDMA, with complaints of muscle aches, fatiguability, depression, and difficulty concentrating noted by 21% to 36% of subjects. Sixty-seven percent of frequent users of the drug (six or more separate doses) reported that the "positive" effects of the drug decreased with successive doses while the "negative" effects increased. Although these observations should be considered preliminary, they represent the first documentation of the subjective effects of MDMA in recreational users and confirm previous reports obtained from patients treated with this drug.

3,4-Methylenedioxyamphetamine↗
PubMed1988

(R)-(-)-[77Br]4-bromo-2,5-dimethoxyamphetamine labels a novel 5-hydroxytryptamine binding site in brain membranes.

(R)-(-)-[77Br]4-Bromo-2,5-dimethoxyamphetamine [(R)-(-)-[77Br] DOB] was synthesized to a high specific activity (1875 +/- 50 Ci/mmol) and used to label membrane-associated recognition sites in rat brain. (R)-(-)-[77Br]DOB displayed high affinity (KD = 0.60 +/- 0.08 nM) for a relatively low density of binding sites (Bmax = 1.2 +/- 0.08 pmol/g of tissue) in rat cortical membranes as compared with [3H]ketanserin (KD = 0.65 +/- 0.1 nM; Bmax = 6.2 +/- 0.6 pmol/g of tissue). Guanine, but not adenine, nucleotides were found to inhibit specific (R)-(-)-[77Br]DOB binding. GTP (10(-4) M) did not eliminate specific (R)-(-)-[77Br]DOB binding but caused a competitive inhibition of the radioligand. Drug competition studies of 5-hydroxytryptamine (5-HT) and related agents indicate that both putative agonists and antagonists display nanomolar potency for these sites. A significant correlation (p less than 0.01) exists between drug potencies for (R)-(-)-[77Br]DOB-labeled sites and both 5-HT2 (r = 0.64) and 5-HT1C (r = 0.68) binding sites. However, the sites do not appear to be identical. Moreover, a significant correlation exists between drug potencies for (R)-(-)-[77Br]DOB-labeled sites and human hallucinogenic drug potencies (r = 0.89; p less than 0.01). We conclude that (R)-(-)-[77Br]DOB labels a unique 5-HT recognition site in rat brain that does not coincide with previously described 5-HT binding site subtypes. The (R)-(-)-[77Br]DOB site does not appear to be a high affinity "state" of the 5-HT2 receptor but may label a subset of heterogeneous 5-HT2 recognition sites.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1988

Antagonism of 5-hydroxytryptamine2 receptor-mediated phosphatidylinositol turnover by d-lysergic acid diethylamide.

The interactions of the indolealkylamine hallucinogen d-lysergic acid diethylamide (d-LSD) and two phenalkylamine hallucinogens, 2,5-dimethoxy-4-bromoamphetamine (DOB) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with 5-hydroxytryptamine2 (5-HT2) receptors were analyzed in rat cortex using both radioligand binding techniques and biochemical measurements of phosphatidylinositol (PI) turnover. 5-HT2 binding sites were labeled by [3H]ketanserin. DOB and DOI displayed decreased affinity for 5-HT2 sites in the presence of 10(-4) M GTP, whereas the ability of d-LSD to compete for these sites was not affected by the presence of 10(-4) M GTP. Moreover, the Hill slope of the d-LSD competition curve was unity in both the absence and presence of 10(-4) M GTP. These findings suggest that d-LSD is an antagonist at 5-HT2 receptors. PI turnover studies in rat cortex showed that at 10(-5) M concentrations d-LSD, DOB and DOI display partial agonist activity in comparison to 10(-5) 5-HT. Stimulation of PI turnover by 5-HT, DOB and DOI was inhibited by the 5-HT2 antagonist ketanserin (10(-6) M). The d-LSD PI signal was not affected by the presence of ketanserin. In addition, nanomolar concentrations of d-LSD did not stimulate PI turnover in rat cortex. Moreover, nanomolar concentrations of d-LSD are able to significantly antagonize the stimulatory effect of 10(-5) M 5-HT on PI turnover. These data suggest that d-LSD acts as an antagonist at 5-HT2 receptors in rat cortex. At high concentrations (greater than 1 microM) d-LSD stimulates low-level PI turnover via a non-5-HT2 receptor-mediated mechanism.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1988

Buspirone attenuates synaptic activation of hippocampal pyramidal cells.

The actions of 5-hydroxytryptamine (5-HT) and buspirone, an anxiolytic agent that displays high and selective affinity for 5-HT1A receptor sites, on synaptic activation of hippocampal CA1 pyramidal cells were studied in vitro. Whereas 5-HT application leads to a rapid hyperpolarization and decreased input resistance in pyramidal cells, buspirone has no measurable effects on membrane potential and input resistance. However, unlike 5-HT, buspirone application leads to a gradual and reversible reduction in excitatory postsynaptic potentials (EPSPs) elicited by stimulation of afferents in the stratum radiatum. Concurrent with this attenuation of the EPSP, buspirone decreases the excitability of afferent fibers in the stratum radiatum as evidenced by conduction slowing, increased refractory period, and decreased ability to generate repetitive impulses. 5-HT has no measurable effect on the afferent fibers. The attenuation of the EPSPs and the decrease in afferent fiber excitability appear to be independent of 5-HT receptors as 5-HT neither shares nor antagonizes the effects of buspirone. Thus, both 5-HT and buspirone can contribute to reduced spike activity in pyramidal cells, but they do so via different mechanisms: 5-HT hyperpolarizes pyramidal cells whereas buspirone attenuates their synaptic activation, possibly via action on the presynaptic fibers in the stratum radiatum.

Afferent Pathways↗
PubMed1988

Differentiation of muscarinic cholinergic receptor subtypes in human cortex and pons: implications for anti-motion sickness therapy.

Radioligand binding studies were used to analyze muscarinic cholinergic receptor subtypes in human cortex and pons. Muscarinic cholinergic receptors were labeled by 3H-quinuclidinyl benzilate (3H-QNB). Scopolamine was equipotent in both brain regions and did not discriminate subtypes of 3H-QNB binding. By contrast, the M1 selective antagonist pirenzepine was approximately 33-fold more potent in human cortex than pons. Carbachol, a putative M2 selective agonist, was more than 100-fold more potent in human pons than cortex. These results demonstrate that the human pons contains a relatively large proportion of carbachol sensitive muscarinic cholinergic receptors. Drugs targeted to this subpopulation of muscarinic cholinergic receptors may prove to be effective anti-motion sickness agents with less side effects than scopolamine.

Carbachol↗