[3H]8-OH-DPAT labels the serotonin transporter in the rat striatum.
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8-Hydroxy-2-(di-n-propylamino)tetralin↗
Biomedical subjects
S Z Langer
Publications and source records attributed to S Z Langer.
Solubilization and characterization of the 5-hydroxytryptamine transporter complex from rat cerebral cortical membranes.
The 5-hydroxytryptamine transporter complex from rat cerebral cortical membranes was solubilized with digitonin. The affinity of the solubilized transporter complex for [3H]paroxetine, a very selective and potent inhibitor of 5-hydroxytryptamine uptake, was not affected and remained unchanged when compared with the parent membrane preparation. The solubilization yield of membrane-bound [3H]paroxetine binding sites was 42%. The pharmacological profile of the solubilized transporter complex was similar to that of the intact transporter in membranes of the cerebral cortex, with the exception of tryptamine, which exhibited a 10-fold loss in potency to inhibit [3H]paroxetine binding to the solubilized transporter when compared to membranes. The Stokes radius determined by gel filtration was 7.6 nm. This successful solubilization of the neuronal 5-hydroxytryptamine transporter complex is the starting point for purification of this macromolecular moiety.
Animals↗
Reserpine-resistant responses to nerve stimulation in the cat nictitating membrane involve the release of newly synthesized noradrenaline.
Preganglionic sympathetic nerve stimulation in cats pretreated with reserpine resulted in significant frequency-dependent contractions of the nictitating membrane, despite a severe depletion of tissue noradrenaline content. These residual responses to sympathetic nerve stimulation were potentiated by cocaine or pargyline, and were antagonised by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. In contrast to the residual responses to sympathetic stimulation in the nictitating membrane, the tachycardia evoked by postganglionic cardiac nerve stimulation was totally abolished by pretreatment with reserpine, even after the administration of cocaine. The alpha-adrenoceptor antagonists phentolamine or prazosin reduced, but did not abolish the reserpine-resistant responses of the nictitating membrane, suggesting the nerve-mediated release of a co-transmitter. In addition to this co-transmitter, a neuronal pool of neurotransmitter which is reserpine-resistant and involves newly synthesised noradrenaline, contributes to the residual responses of the nictitating membrane, following depletion of the neurotransmitter stores by the administration of reserpine. administration of reserpine.
Adrenergic alpha-Antagonists↗
Electroconvulsive shock therapy and maximum binding of platelet tritiated imipramine binding in depression.
We studied the tritiated imipramine binding values in platelets from 12 hospitalized untreated patients with endogenous depression and found a significant decrease in maximum binding (Bmax) values compared with a control population of the same age and sex. There were no changes in the equilibrium dissociation affinity constant values between the untreated depressives and the control population. After at least six sessions of electroconvulsive therapy and at the time when a significant clinical improvement of depression was confirmed, the Bmax value of tritiated imipramine binding in platelets was slightly increased but was still significantly below that of the control values. However, when six of these patients were reexamined after 12 to 18 months, at a time when they were euthymic, the Bmax of tritiated imipramine binding in platelets was found in the same range as the values of the control population. Our results indicate that clinical improvement precedes the changes in Bmax of tritiated imipramine binding in platelets from depressed patients. The tritiated imipramine binding in platelets is a useful biologic marker in affective disorders. Furthermore, our results suggest that tritiated imipramine binding in platelets may be a state-dependent biologic marker in depression.
Aged↗
Antidepressant-binding sites in brain and platelets.
[3H]Imipramine and [3H]paroxetine label with high affinity a site associated with the serotonin transporter in brain and platelets. The maximum binding capacity (Bmax) of [3H]imipramine in platelets is reduced in untreated depressed patients, and it may represent a useful biological marker in depression. The existence of an endogenous ligand acting on the [3H]imipramine-recognition site to modulate the serotonin transporter has been proposed by several laboratories. 5-Methoxytryptoline inhibits [3H]imipramine binding and [3H]serotonin uptake in the nanomolar range. This compound has been reported to occur in the pineal gland, but probably only in trace amounts. While the physiological relevance of 5-methoxytryptoline or a close analogue remains an open question, the possibility exists that the 'endocoid' for the [3H]imipramine-recognition site plays a role in the pathogenesis of depression.
Animals↗
Platelet 3H-imipramine binding and steroid hormones serum concentrations during the menstrual cycle.
The presence of high affinity binding sites for 3H-imipramine (3H-IMI) in human platelets is by now well established. This recognition site is associated with the transporter for 5HT, and may be a biological marker in depression. Fluctuations of other putative biological markers of depression (i.e. platelet MAO activity) have been demonstrated and shown to be correlated with variations in steroid hormones. Therefore, the KD and Bmax of 3H-IMI binding was determined in platelets of young women during the menstrual cycle. Our results indicate that within the limits of intraindividual variations, neither the KD or the Bmax of 3H-IMI binding in platelets is significantly modified during the menstrual cycle.
Adult↗
Possible involvement of presynaptic alpha 1-adrenoceptors in the effects of idazoxan and prazosin on 3H-noradrenaline release from tail arteries of SHR.
The effects of several alpha-adrenoceptor antagonists have been examined on tritium release elicited by electrical stimulation from isolated perfused SHR tail artery preparations prelabelled with 3H-noradrenaline (3H-NA). Phentolamine and yohimbine potently facilitated the stimulation evoked release of tritium at low frequencies of stimulation, but the alpha 2-adrenoceptor antagonist idazoxan was only weakly active at 1 mumol/l, despite antagonising the clonidine-evoked inhibition of 3H-release at a lower concentration of 0.1 mumol/l. The alpha 1-adrenoceptor antagonists prazosin and corynanthine also increased stimulation evoked tritium release in this preparation, suggesting the presence of prejunctional alpha 1-adrenoceptors. Furthermore, the alpha 1-adrenoceptor agonist methoxamine (3 mumol/l) caused a significant inhibition of tritium-evoked release, an effect which was blocked by prazosin (10 nmol/l). When alpha 1-adrenoceptors were blocked in the presence of prazosin, idazoxan (0.1 mumol/l) produced a significant facilitatory effect on the electrically-evoked release of 3H-transmitter. On the other hand, when alpha 2-adrenoceptors were blocked in the presence of yohimbine, exposure to idazoxan (0.1 mumol/l) reduced significantly the stimulation-evoked release of tritium elicited by electrical stimulation. The results indicate that in the SHR tail arteries, idazoxan has a partial agonist inhibitory activity on transmitter release, which can mask the facilitatory effects due to blockade of presynaptic alpha 2-adrenoceptors. The inhibitory effects of idazoxan appear to involve presynaptic alpha 1-adrenoceptors, which when stimulated, reduce 3H-NA release in SHR tail arteries.
Adrenergic alpha-Antagonists↗
Differential effects of alpha-beta-methylene ATP on responses to nerve stimulation in SHR and WKY tail arteries.
The effects of alpha,beta-,methylene-adenosine triphosphate, (alpha,beta-methylene ATP, a P2-receptor desensitising agent) have been evaluated on vasoconstrictor responses elicited by exogenous agonists or electrical field stimulation in isolated perfused SHR or WKY tail arteries and on tritium release elicited by electrical field stimulation in SHR-tail arteries pre-labeled with 3H-noradrenaline. Exposure to alpha,beta-methylene ATP (0.1 mumol/l) significantly inhibited vasoconstrictor responses to electrical field stimulation in SHR tail arteries. These inhibitory effects were not further increased at a higher concentration of alpha,beta-methylene ATP (1 mumol/l). In WKY tail arteries, alpha,beta-methylene ATP (1 mumol/l) failed to significantly inhibit vasoconstrictor responses to electrical stimulation. In SHR tail arteries prelabelled with 3H-noradrenaline, alpha,beta-methylene ATP (1 mumol/l) did not inhibit the stimulation evoked release of tritium. However, at this concentration, alpha,beta-methylene ATP significantly antagonized the vasoconstrictor responses of SHR tail arteries induced by exogenous ATP (1 mumol/l), beta,gamma-methylene ATP (30 mumol/l), a stable agonist at P2-receptors, or 60 mmol/l KCl. These effects of alpha,beta-methylene ATP on contractile responses to KCl were not observed in WKY-tail arteries. In tail arteries obtained from reserpine pretreated SHR, despite a 85-95% decrease in endogenous noradrenaline tissue content, the vasoconstrictor responses induced by periarterial field stimulation were greatly diminished, but not abolished. These residual responses to periarterial field stimulation were not antagonized by prazosin (0.1 mumol/l), but were practically abolished by the addition of alpha,beta-methylene ATP (1 mumol/l). In tail arteries from WKY rats pretreated with reserpine, exposure to prazosin (0.1 mumol/l) further reduced the residual responses elicited by electrical field stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Electrical stimulation releases 3H-betaxolol from rat atrial slices: possible role of noradrenergic nerves.
Under in vitro conditions, 3H-betaxolol was accumulated in rat atrial slices, reaching a tissue-medium ratio of 12.3 +/- 1.8 ml/g. This process was temperature-dependent, but ouabain-resistant. 3H-Betaxolol accumulated in atrial slices was subsequently released by electrical stimulation. The electrically-evoked release of 3H-betaxolol was abolished in the absence of calcium, and reduced in the presence of bretylium 10 microM. After surgical sympathetic denervation by stellate ganglionectomy there was a marked reduction in the endogenous content of noradrenaline and in the retention of 3H-noradrenaline in atrial slices. The concomitant decrease in the amount of 3H-noradrenaline released by electrical stimulation following denervation was modest, although statistically significant. Following sympathetic denervation, the tissue retention of 3H-betaxolol was not significantly affected, but the release of 3H-betaxolol by electrical stimulation was considerably reduced. After pretreatment with reserpine the amount of radioactivity released by electrical stimulation from slices labelled with 3H-betaxolol or 3H-noradrenaline was markedly reduced. The tissue retention of 3H-noradrenaline was reduced to a larger extent than that of 3H-betaxolol following the administration of reserpine. The simultaneous release of noradrenaline and betaxolol by nerve stimulation observed under our experimental conditions may represent a mechanism through which betaxolol can reach selectively the postsynaptic beta 1-adrenoceptors and reinforce beta-adrenoceptor blockade in the heart.
Adrenergic beta-Antagonists↗
Phenylethylamine-induced release of noradrenaline fails to stimulate alpha 1-adrenoceptors modulating [3H]-acetylcholine release in rat atria, but activates alpha 2-adrenoceptors modulating [3H]-serotonin release in the hippocampus.
The modulation of the depolarization induced release of [3H]-acetylcholine by agonists acting on alpha-adrenoceptors was studied in superfused rat atrial slices. In this model, noradrenaline and methoxamine, but not UK 14304 reduced the potassium evoked release of [3H]-acetylcholine. The inhibitory action of these drugs was antagonized by the alpha 1 selective adrenoceptor antagonist prazosin. Propranolol, idazoxan and sulpiride did not antagonize the inhibition by noradrenaline of the potassium-evoked release of [3H]-acetylcholine. Exposure to amphetamine, beta-phenylethylamine, m- or p-tyramine, increased in a concentration-dependent manner the spontaneous outflow of [3H]-noradrenaline from atrial slices. Yet, these concentrations of the indirectly acting sympathomimetic amines, tested in the presence of an inhibitor of monoamine oxidase (MAO), failed to modify the potassium evoked release of [3H]-acetylcholine. Desipramine 3 mumol/l or cocaine 10 mumol/l did not affect the release of [3H]-acetylcholine evoked by potassium stimulation. Under similar experimental conditions, beta-phenylethylamine facilitated the spontaneous outflow of [3H]-noradrenaline, and inhibited the electrically-evoked release of [3H]-serotonin from the hippocampus by activation of alpha 2-adrenoceptors. It is concluded that the release of acetylcholine from atrial cholinergic neurons can be modulated through inhibitory alpha 1-adrenoceptors, which are not activated when the release of noradrenaline is induced by indirectly acting sympathomimetic amines. In addition, amphetamine or structurally related amines do not activate directly recognition sites in the cholinergic postganglionic parasympathetic neuron to modify the release of [3H]-acetylcholine.
Acetylcholine↗
Potentiation by deprenyl of the autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release by 5-methoxytryptamine.
The 5-hydroxytryptamine (5HT) receptor agonist, 5-methoxytryptamine, inhibited in a concentration-dependent manner the electrically-evoked release of 3H-5HT from superfused rat hypothalamic slices, with an IC50 of 560 nmol/l, without affecting the spontaneous outflow of radioactivity. In the presence of the selective monoamine oxidase B (MAO B) inhibitor, (-)-deprenyl (1 mumol/l), the concentration-effect curve for 5-methoxytryptamine was shifted significantly to the left, and the IC50 was decreased to 25 nmol/l. Under the same experimental conditions, the potency of the 5HT receptor agonist lysergic acid diethylamide (LSD) at inhibiting the electrically-evoked release of 3H-5HT was the same in the presence as well as in the absence of (-)-deprenyl. The IC50 values for LSD were 34 nmol/l in the absence of deprenyl, and 31 nmol/l in the presence of the MAO B inhibitor. It is concluded that deprenyl potentiates the inhibition by 5-methoxytryptamine of 3H-5HT release, by preventing its inactivation through MAO B. Since 5-methoxytryptamine may be present in the pineal gland of some species, the potent effects of this 5-HT receptor agonist on serotoninergic neurotransmission may be of physiological relevance.
5-Methoxytryptamine↗
Influence of neuronal uptake on the contribution of smooth muscle alpha 2-adrenoceptors to vasoconstrictor responses to noradrenaline in SHR and WKY isolated tail arteries.
The effects of the selective alpha-adrenoceptor antagonists idazoxan (alpha 2) and prazosin (alpha 1) were examined on responses to exogenous noradrenaline and to sympathetic nerve stimulation in SHR and WKY rat isolated perfused proximal tail artery segments. The influence of inhibition of neuronal uptake with cocaine on the effects of these antagonists was also determined. The following results were obtained: Prazosin (10 nmol/l) was equieffective in antagonising responses to exogenous noradrenaline and sympathetic nerve stimulation in both SHR and WKY arteries and the degree of antagonism was similar in either the presence or the absence of neuronal uptake inhibition. In contrast to prazosin, the effects of idazoxan (100 nmol/l), on both exogenous noradrenaline and sympathetic nerve stimulation were dependent on the degree of inhibition of neuronal uptake. In SHR arteries, the degree of antagonism of responses to exogenous noradrenaline by idazoxan (100 nmol/l) decreased progressively as the concentration of cocaine was increased to 4 and 40 mumol/l; in WKY arteries, even in the absence of cocaine, idazoxan (100 nmol/l) did not antagonise responses to exogenous noradrenaline. In SHR arteries, the responses to sympathetic nerve stimulation were reduced to a lesser extent by idazoxan (100 nmol/l) when the concentration of cocaine was increased to 4 mumol/l than in the absence of cocaine. In WKY arteries, idazoxan (100 nmol/l) reduced the responses to sympathetic nerve stimulation in the absence of cocaine. However, this concentration of idazoxan increased the responses to nerve stimulation in the presence of cocaine. Our results indicate that smooth muscle alpha 2-adrenoceptors are present in SHR tail arteries, both intra- and extrajunctionally.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors.
The high-affinity binding sites for [3H]-imipramine (IMI) present in human platelets are associated with the neuronal uptake system for 5HT. It was recently demonstrated that previous antidepressant therapy with drugs which inhibit 5HT uptake could down-regulate [3H]-IMI binding and that this effect could persist up to 1 month after the end of treatment. We therefore re-examined the reported differences in Bmax of [3H]-IMI binding in platelets between control and depressed untreated patients, to evaluate the residual influence of previous antidepressant medication. The saturation characteristics of [3H]-IMI binding were compared in platelets from 17 depressed patients carefully selected according to previous antidepressant therapy and washout period, who were closely matched, for age and sex, with a group of control healthy volunteers. The results reveal a significant decrease by 47% in the Bmax of [3H]-IMI binding in platelets of untreated depressed patients when compared with controls. There was no significant modification of Kd values for platelet [3H]-IMI binding between the depressed and the control groups. Our results support the view that platelet [3H]-IMI binding is a useful tool as a biological marker in depression.
Adult↗
Lack of seasonal variation in platelet [3H]imipramine binding in humans.
The Bmax of [3H]imipramine (IMI) binding has been reported to be reduced in platelets of depressed untreated patients as compared with normal controls. However, it has also been suggested that this difference could be related to the failure to take into account seasonal variations in the binding parameters for [3H]IMI recognition sites in platelets. For this reason, [3H]IMI binding was studied throughout 1 year in platelet membranes from 11 control volunteers, with blood samples collected once a month. The Bmax and Kd values of [3H]IMI binding showed no significant variation throughout the 12-month period of the study. These results indicate that in the control population, the platelet [3H]IMI binding parameters remain stable, and that the decrease in Bmax observed in depressed untreated patients reflects a genuine difference, which may be considered to be a biological marker in depression.
Adult↗
Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.
Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.
Animals↗
Supersensitivity of alpha 2-adrenoceptors modulating [3H]5-HT release after noradrenergic denervation with DSP4.
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Adrenergic alpha-Antagonists↗
Characterization of [3H]paroxetine binding to rat cortical membranes.
Paroxetine is a selective and potent inhibitor of 5-hydroxytryptamine uptake into serotonergic neurons. The specific binding of [3H]paroxetine to rat cortical membranes at 22 degrees C was examined in this study. Our results indicate the presence of a single saturable high affinity binding component for [3H]paroxetine. Scatchard analysis revealed a Kd of 0.15 +/- 0.01 nM, and a Bmax of 549 +/- 36 fmol/mg protein. The kinetically derived dissociation constant was 0.034 +/- 0.008 nM. [3H]Paroxetine binding was inhibited selectively by 5-HT uptake blockers, and a good correlation was demonstrated between the potency of various drugs to inhibit [3H]paroxetine binding and [3H]5-hydroxytryptamine uptake. Also, lesions performed with the neurotoxin, 5,7-dihydroxytryptamine resulted in a 94% decrease in endogenous 5-hydroxytryptamine levels and concomitantly, a 90% reduction in [3H]paroxetine binding when compared to sham controls. These results indicate that the binding site labelled by [3H]paroxetine is associated with the neuronal 5-hydroxytryptamine transporter complex.
Animals↗
[3H]SCH 23390 labeled D1 dopamine receptors are unchanged in schizophrenia and Parkinson's disease.
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Aged↗