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Biomedical subjects

S J Peroutka

Publications and source records attributed to S J Peroutka.

At least 163 records · Page 9Linked to original sources
PubMed1983

Multiple serotonin receptors and their physiological significance.

Identification of multiple receptors for neurotransmitters has had important theoretical and practical therapeutic relevance. With the advent of receptor-binding techniques, the ability to detect heterogeneity of receptors has been greatly enhanced. There appear to be multiple serotonin (5-HT) receptors in the central nervous system. At least two distinct 5-HT receptors can be differentiated by binding techniques. 5-HT1 sites are labeled preferentially by [3H]5-HT, whereas [3H]spiroperidol selectively labels 5-HT2 receptors. 5-HT and other agonists display 50-1000 times greater affinity for 5-HT1 than 5-HT2 sites, whereas most known 5-HT antagonists have 100-1000 times greater affinity for 5-HT2 than 5-HT1 receptors. Ergot-related drugs, such as LSD and lisuride, have similar affinities for 5-HT1 and 5-HT2 receptors. Drug potencies in blocking 5-HT behavioral effects in rodents and in antagonizing vascular effects of 5-HT in several blood vessel systems correlate best with influences on 5-HT2 receptors. In some adenylate cyclase systems drug effects on the 5-HT response of adenylate cyclase correlate with 5-HT1 receptor affinity. Chronic treatment with antidepressants lowers the numbers of 5-HT2 but not 5-HT1 receptors. With most antidepressants the reduction of 5-HT2 receptor site number is greater than the reduction in beta-adrenergic receptors. Thus, influences of antidepressants on 5-HT2 receptors may provide a useful predictive test for antidepressant drug action.

Adenylyl Cyclases↗
PubMed1981

Two distinct central serotonin receptors with different physiological functions.

Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the "serotonin behavioral syndrome," indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.

Adenylyl Cyclases↗
PubMed1981

Two distinct serotonin receptors: regional variations in receptor binding in mammalian brain.

Two distinct serotonin receptors in mammalian brain are labeled respectively with [3H]serotonin (5-HT1) and [3H]spiperone (5-HT2). In general agonists display highest affinities for 5-HT1 while antagonists prefer 5-HT2 sites. To conduct regional studies of 5-HT receptors, we estimated 5-HT2 sites with [3H]spiperone, using the 5-HT2 specific antagonist cinanserin to displace binding to 5-HT2 but not dopamine receptors and sulpiride to displace [3H]spiperone from dopamine but not 5-HT receptors. About 15% of cerebral cortical [3H]spiperone binding appears to involve dopamine sites and the remainder involves 5-HT2 receptors. In the corpus striatum about 80% of [3H]spiperone binding labels dopamine receptors and the rest involves 5-HT2 sites. [3H]mianserin binds about equally to 5-HT2 and histamine H1-receptors. [3H]mianserin interactions with 5-HT2 sites are studied selectively by displacing histamine H1-receptor binding with the H1-antihistamine triprolidine. [3H]LSD labels both 5-HT1 and 5-HT2 receptors. Its binding to 5-HT1 sites is displaced selectively with 5-HT, while its binding to 5-HT2 receptors is displaced with cinanserin. [3H]5-HT labels only 5-HT1 receptors. The regional distribution of the two 5-HT receptors is similar in rat, guinea pig and bovine brain. However, the regional patterns of 5-HT1 and 5-HT2 receptors differ considerably in all 3 species. The hippocampus is quite high in 5-HT1 receptors but low in 5-HT2 sites. The cerebellum contains the lowest levels of both 5-HT1 and 5-HT2 receptors. In bovine brain, most areas contain similar numbers of 5-HT1 and 5-HT2 receptors. However, the substantia nigra, the richest 5-HT1 area in bovine brain, possesses 10 times more 5-HT1 than 5-HT2 sites.

Animals↗
PubMed1981

[3H]Mianserin: differential labeling of serotonin and histamine receptors in rat brain.

Mianserin, a tetracyclic antidepressant, is a potent serotonin (5-HT) and histamine H1 antagonist in peripheral smooth muscle systems. Mianserin was found to possess high affinity for 5-HT2 and histamine H1 receptor binding sites in brain membranes. By using [3H]mianserin, both 5-HT2 and histamine H1 receptors can be specifically labeled in rat cerebral cortex membranes. Simultaneous incubation of brain membranes with 300 nM triprolidine or 30 nM spiroperidol enables the selective labeling of 5-HT2 or histamine H1 receptors, respectively. In the guinea-pig cerebellum, [3H]mianserin exclusively labels histamine H1 receptors, since 5-HT2 sites are virtually absent in this area.

Animals↗
PubMed1980

Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding.

Antidepressants compete at several neurotransmitter receptor binding site, but drug affinities do not correlate with clinical efficacy. Long-term, but not short-term, antidepressant treatment decreases the numbers of both serotonin and beta-adrenergic receptors. The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.

Animals↗
PubMed1980

Neurotransmitter receptor binding in bovine cerebral microvessels.

Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

Animals↗
PubMed1980

Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency.

The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes. They found that although many neuroleptics are quite potent in competing at several of these receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol At clinically effective doses, however, substantial occupancy of serotonin, alpha-adrenergic, and histamine receptors often occurs and may account for some of the auxiliary actions of neuroleptics.

Animals↗
PubMed1980

Regulation of serotonin2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline.

Recently, we reported that chronic administration of several antidepressants of different classes produced larger reductions in numbers of serotonin2 (5-HT2) receptors in rat brain labeled by [3H[spiroperidol than in beta adrenergic receptors. In the present study, we examine detailed properties of 5-HT2 receptor regulation by chronic treatment with amitriptyline. Chronic but not acute treatment with the tricyclic antidepressant amitriptyline reduces binding to 5-HT2 receptors by [3H]spiroperidol and beta adrenergic receptor binding of [3H]dihydroalprenolol in brain membranes. The decrease is time-dependent, gradually reversible and represents a change in the number of binding sites with no alteration in drug affinities for 5-HT2 receptors. The effect can be observed at daily doses of 2.5 mg/kg, similar to clinically effective doses in humans. At all doses and time intervals, the decrease in 5-HT2 receptors is more marked than the concurrent change in total beta adrenergic receptor binding. The properties of 5-HT2 receptor reduction after chronic antidepressant treatment indicate that this alteration could be associated with therapeutic response.

Amitriptyline↗