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H Gozlan

Publications and source records attributed to H Gozlan.

At least 91 records · Page 5Linked to original sources
PubMed1987

Transient expression of 5-HT1A receptor binding sites in some areas of the rat CNS during postnatal development.

The developmental evolution of 5-HT1A receptor binding sites was examined in the rat CNS during the early postnatal period using quantitative autoradiography and binding assays with 3H-8-OH-DPAT as the selective ligand. A progressive increase in the density of 5-HT1A sites was observed in the hippocampus, septum and cerebral cortex, up to adult levels which were reached around the third postnatal week. In contrast, complex biphasic (increase then decrease) changes were noted in other structures (for instance the nucleus of the lateral lemniscus), and even a progressive decrease in the density of 5-HT1A sites took place in the cerebellum during the first two postnatal weeks. The transient expression of 5-HT1A receptor binding sites in a structure such as the cerebellum which develops exclusively for the postnatal period further supports that 5-HT might play a trophic role during maturation of the CNS.

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

Chronic chlorimipramine does not reverse the reduction of cerebrospinal fluid Met-enkephalin-like immunoreactivity in chronic-pain patients.

Chronic-pain patients were treated for 10 days with chlorimipramine (100 mg i.v. daily), and their plasma levels of the drug and cerebrospinal fluid (CSF) levels of Met-enkephalin-like material (MELM) were measured for a comparison with those found in untreated chronic-pain patients and in control subjects. Pain relief in chlorimipramine-treated patients was apparently not associated with pronounced changes in the activity of enkephalinergic systems since the mean CSF levels of MELM were reduced to the same extent in treated (-49%) and untreated (-45%) pain patients as compared with controls. However, subtle chlorimipramine-induced alterations likely occurred as revealed by the simultaneous measurement of the CSF levels of 5-hydroxyindoleacetic acid (5-HIAA) in the same patients. Indeed, a positive correlation (r = 0.667) was found between CSF 5-HIAA and MELM levels in control subjects, whereas a negative correlation (r = 0.691) between these two parameters was detected in chlorimipramine-treated patients. These data suggest that chlorimipramine alters probable functional serotonin-enkephalin interactions in pain patients.

Adult↗
PubMed1987

Identification of the 5-HT1A receptor binding subunit in rat brain membranes using the photoaffinity probe [3H]8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin.

The synthesis of a tritiated derivative of the 5-HT1A photoaffinity probe 8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin ([3H]8-methoxy-3'-NAP-amino-PAT) allowed the use of this probe for attempting the irreversible labeling of specific binding sites in rat brain membranes. Sodium dodecyl-sulfate-polyacrylamide gel electrophoresis of proteins solubilized from hippocampal microsomal membranes that had been incubated with 20 nM [3H]8-methoxy-3'-NAP-amino-PAT under UV light revealed a marked incorporation of 3H label into a 63-kilodalton protein termed PI. As expected of a possible correspondence between PI and 5-HT1A receptor binding sites, 3H labeling by the photoaffinity probe could be prevented by selective 5-HT1A ligands such as 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, buspirone, and gepirone and by N-ethylmaleimide, but not by the 5-HT2 antagonist ketanserin, noradrenaline- and dopamine-related drugs, monoamine oxidase inhibitors, and chlorimipramine. Furthermore, the regional and subcellular distributions of PI were identical to those of specific 5-HT1A binding sites. These results indicated that the binding subunit of the 5-HT1A receptor is a 63-kilodalton protein with a functionally important sulfhydryl group(s).

Affinity Labels↗
PubMed1987

Photoaffinity labelling and solubilization on the central 5-HT1A receptor binding site.

Two complementary approaches, covalent labelling and solubilization, have been used to study the biochemical properties of the central 5-HT1A receptor binding site. We have first designed a photoaffinity ligand containing the structure of 8-OH-DPAT, a potent and specific agonist of 5-HT1A sites. Thus, 8-methoxy-2[N-n-propyl,N-3-(2-nitro-4-azido-phenyl)- aminopropyl]aminotetralin or 8-methoxy-3'-NAP-amino-PAT, was found to displace, in the dark, [3H]8-OH-DPAT from 5-HT1A sites in rat hippocampal membranes with an IC50 of 6.6 nM. Under two cumulative UV irradiations (366 nm, for 20 min at 4 degrees C), 8-methoxy-3-'-NAP-amino-PAT (30 nM) blocked irreversibly 55-60% of 5-HT1A binding sites. This blockade was specific of 5-HT1A sites since the other serotoninergic sites, 5-HT1B, 5-HT2 and also the presynaptic 5-HT3 sites were not affected by the treatment. In addition, the binding of [3H]Spiperone and [3H]7-OH-DPAT to striatal dopamine sites remained unchanged under similar photolysis conditions. The tritiated derivative of the photoaffinity ligand (92 Ci/mmol) was then synthesized for the identification of the covalently bound protein(s). SDS-PAGE of solubilized membranes irradiated in the presence of 20 nM 3H-8-methoxy-3'-NAP-amino-PAT allowed the detection of a 63 kD protein whose labelling appeared specific. Thus, 3H-incorporation into the 63 kD band could be prevented by microM concentrations of 5-HT, 8-OH-DPAT and other selective 5-HT1A ligands such as isapirone. In contrast, the 5-HT2 antagonist ketanserin, norepinephrine and dopamine-related ligands (including 7-OH-DPAT) were ineffective. Direct solubilization of 5-HT1A receptor binding sites was also attempted from rat hippocampal membranes. The best results were obtained using CHAPS (10 mM) plus NaCl (0.2 M), which led to 50% recovery of 5-HT1A sites in the 100,000 g supernatant. The pharmacological properties and sensitivity to N-ethyl-maleimide and GppNHp of soluble sites appeared near identical to those of membrane-bound 5-HT1A sites.

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

Irreversible blockade of central 5-HT1A receptor binding sites by the photoaffinity probe 8-methoxy-3'-NAP-amino-PAT.

A new photoaffinity ligand derived from the potent 5-HT agonist, 8-OH-DPAT, has been synthesized. In the dark, this compound, 8-methoxy-2-(N-n-propyl,N-3-(2-nitro-4-azidophenyl)aminopropyl) aminotetralin or 8-methoxy-3'-NAP-amino-PAT, displaced [3H]8-OH-DPAT and [3H]5-HT bound to 5-HT1A and 5-HT1 sites in hippocampal membranes with IC50 values of 6.6 and 18.1 nM respectively. The apparent affinity of 8-methoxy-3'-NAP-amino-PAT for the 5-HT1A binding sites was at least 20 times higher than for the other 5-HT receptor sites (5-HT2 and 5-HT3) or the dopamine-related [3H]spiperone and [3H]7-OH-DPAT binding sites. Under UV irradiation (lambda = 366 nm), 8-methoxy-3'-NAP-amino-PAT produced an irreversible blockade of 5-HT1A sites which could be prevented by prior site occupancy by a saturating concentration (10 microM) of reversible 5-HT ligands such as 5-HT itself, 8-OH-DPAT or LSD. The blockade of 5-HT1A binding sites was concentration-dependent, and two successive irradiations of rat brain membranes in the presence of 30 nM 8-methoxy-3'-NAP-amino-PAT were found to be more efficient that a single exposure to 100 nM of the photosensitive ligand. Thus, a 55-60% irreversible blockade of 5-HT1A binding sites was achieved following 2 cumulative irradiations of hippocampal membranes with 30 nM 8-methoxy-3'-NAP-amino-PAT. Under such conditions, cortical 5-HT2 receptor binding sites as well as striatal 5-HT3 and dopamine-related binding sites remained unaltered.

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

In situ molecular sizes of the various types of 5-HT binding sites in the rat brain.

The radiation inactivation technique has been used to estimate the molecular weights of 5-HT binding sites in various regions of the rat brain. Using 3H-5-HT or 3H-8-OH-DPAT as the ligand, the same molecular weight of 55,000-60,000 daltons was calculated for the postsynaptic 5-HT1A and 5-HT1B sites in the hippocampus and cerebral cortex. Studies with 3H-ketanserin as the selective ligand indicated a molecular weight in the same range for the post-synaptic 5-HT2 binding site in the cerebral cortex. In contrast, a higher value (67,000 daltons) was found for the presynaptic 5-HT3 site selectively labelled by 3H-8-OH-DPAT in the striatum and cerebral cortex. The curvilinear pattern of the radiation-induced inactivation of 5-HT1A and 5-HT1B binding sites suggested that both sites belong to complex polymeric structures. In contrast, the 5-HT2 and 5-HT3 sites may correspond to less cooperative structures since simple monoexponential inactivation curves were observed upon irradiation.

Animals↗
PubMed1986

Differentiation of pre- and post-synaptic high affinity serotonin receptor binding sites using physico-chemical parameters and modifying agents.

The two 3H-labeled agonists [3H]8-hydroxy-2-(di-n-propylamino) tetralin ([3H]8-OH-DPAT) and [3H]serotonin ([3H]5-HT) have been used to examine the effects of physico-chemical parameters and modulatory agents on the high affinity 5-HT receptor binding sites in various regions of the rat central nervous system. Sites labeled by [3H]8-OH-DPAT and [3H]5-HT were differentially sensitive to changes in incubation temperature and pH, such that the optimal interaction of [3H]8-OH-DPAT with specific sites in the striatum was at 30 degrees C and pH 7.4, whereas [3H]5-HT sites in the same region were most easily labeled at 2-23 degrees C and pH 8.2. Micromolar concentrations of Mn2+ enhanced [3H]5-HT binding but inhibited markedly [3H]8-OH-DPAT binding to striatal membranes. In contrast, both [3H]5-HT and [3H]8-OH-DPAT binding were increased by the cation in hippocampal membranes. Conversely, GTP reduced the binding of either ligand in the hippocampus but affected only [3H]5-HT binding in the striatum. Furthermore, N-ethylmaleimide inhibited equally [3H]5-HT and [3H]8-OH-DPAT binding to hippocampal membranes, but was markedly less potent against [3H]8-OH-DPAT binding to striatal membranes. These results led to the definition of assay conditions for studying separately [3H]8-OH-DPAT binding to "hippocampal-like" (HL) and "striatal-like" (SL) sites. [3H]8-OH-DPAT HL binding sites were particularly abundant in the hippocampus, septum and cerebral cortex, and exhibited pharmacological properties typical of the postsynaptic 5-HT1A subsites previously characterized with [3H]5-HT as the ligand. The regional distribution of [3H]8-OH-DPAT SL binding sites was strikingly different from that of HL sites, but similar to that of serotoninergic terminals identified by their capacity to take up [3H]5-HT. The selective lesion by 5,7-dihydroxytryptamine of serotoninergic projections induced a marked loss of [3H]8-OH-DPAT SL binding sites in the striatum and the cerebral cortex, indicating that these sites were located presynaptically. In contrast, [3H]5-HT binding sites remained unchanged in lesioned rats, which confirmed further their exclusive postsynaptic location in brain.

5,7-Dihydroxytryptamine↗
PubMed1986

In vivo release of endogenous amino acids from the rat striatum: further evidence for a role of glutamate and aspartate in corticostriatal neurotransmission.

By means of the push-pull cannula method, the outflow of endogenous amino acids was studied in the striatum of halothane-anesthetized rats. Addition of K+ ions (30 mM for 4 min) to the superfusion fluid increased the release of aspartate (+116%), glutamate (+217%), taurine (+109%), and gamma-aminobutyric acid (GABA) (+429%) whereas a prolonged decrease in the outflow of glutamine (-28%) and a delayed reduction in the efflux of tyrosine (-25%) were observed. In the absence of Ca2+, the K+-induced release of aspartate, glutamate, and GABA was blocked whereas the K+-induced release of taurine was still present. Under these conditions, the decrease in glutamine efflux was reduced and that of tyrosine was abolished. Local application of tetrodotoxin (5 microM) decreased only the outflow of glutamate (-25%). One week following lesion of the ipsilateral sensorimotor cortex the spontaneous outflow of glutamine and of tyrosine was enhanced. Despite the lack of change in their spontaneous outflow, the K+-evoked release of aspartate and glutamate was less pronounced in lesioned than in control animals, whereas the K+-evoked changes in GABA and glutamine efflux were not modified. Our data indicate that the push-pull cannula method is a reliable approach for the study of the in vivo release of endogenous amino acids. In addition, they provide further evidence for a role for glutamate and aspartate as neurotransmitters of corticostriatal neurons.

Amino Acids↗
PubMed1986

Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats.

The distribution of the 2 main types (A and B) of 5-HT1 binding sites in the rat brain was studied by light-microscopic quantitative autoradiography. The 5-HT1A sites were identified using 3H-8-hydroxy-2-(N-dipropylamino)tetralin (3H-8-OH-DPAT) or 3H-5-HT as the ligand. In the latter case, it was shown that 3H-5-HT binding to 5-HT1A sites corresponded to that displaceable by 0.1 microM 8-OH-DPAT or 1 microM spiperone. The "non-5-HT1A" sites labeled by 3H-5-HT in the presence of 0.1 microM 8-OH-DPAT corresponded mainly to 5-HT1B sites. 5-HT1A binding was notably high in limbic regions (dentate gyrus, CA1 and CA3 hippocampal regions, lateral septum, frontal cortex), whereas 5-HT1B binding was particularly concentrated in extrapyramidal areas (caudate nucleus, globus pallidus, substantia nigra). Except in the latter regions, where only one class of 5-HT1 sites was found, both 5-HT1A and 5-HT1B sites existed in all areas examined. The selective degeneration of serotoninergic neurons produced by an intracerebral injection of 5,7-dihydroxytryptamine was associated only with a significant loss of 5-HT1A binding to the dorsal raphe nucleus (-60%) and of 5-HT1B binding to the substantia nigra (-37%). These results are discussed in relation to the possible identity of 5-HT1A and/or 5-HT1B sites with the presynaptic 5-HT autoreceptors controlling nerve impulse flow and neurotransmitter release in serotoninergic neurons.

5,7-Dihydroxytryptamine↗
PubMed1985

Spontaneous and evoked release of methionine-enkephalin-like material from the rat spinal cord in vivo.

In vivo perfusion of the subarachnoid space with an artificial cerebrospinal fluid (CSF) in paralyzed halothane-anesthetized rats allowed the collection of methionine-enkephalin (Met-Enk)-like material (MELM) released from the spinal cord. Bio-Gel P2 chromatography and high-performance liquid chromatography showed that 65% of this material corresponded to authentic Met-Enk. Under resting conditions, about 1 pg of MELM per minute was regularly released for at least 3 h; for Met-Enk, this value corresponded to a fractional rate constant of 0.002% (i.e. tissue content of the pentapeptide which was released per minute from the whole spinal cord). Perfusion with K+-enriched (40-60 mM) CSF resulted in a marked enhancement (+ 150-200%) of spinal MELM release. Similarly, calibrated pinches of the muzzle and i.p. administration of acetic acid, two strong noxious stimuli in awake animals, induced a significant increase (+ 75-150%) in spinal MELM release. In contrast, pinches applied to the tail did not enhance but instead slightly reduced (-35%) MELM release from the rat spinal cord. These data suggest that mechanisms other than segmental controls could be involved in the activation of spinal enkephalinergic neurons by some nociceptive stimuli.

Animals↗
PubMed1985

Irreversible blockade of central 5-HT binding sites by 8-methoxy-2'-chloro-PAT.

We have synthesized 8-methoxy-2-(N-2'-chloropropyl, N-propyl) aminotetralin (8-methoxy-2'-chloro-PAT), an alkylating agent derived from the potent 5-HT agonist, 8-hydroxy-2-(N,N-dipropyl)-aminotetralin (PAT). As expected for an irreversible ligand, the blockade of 3H-PAT or 3H-5-HT binding to post-synaptic 5-HT1 (A and B) sites in rat hippocampal membranes pretreated with 8-methoxy-2'-chloro-PAT could not be prevented by extensive washing of membranes. Prior occupancy of 5-HT1 sites by 5-HT or PAT prevented any subsequent irreversible blockade by the alkylating agent. Similar irreversible blockade by 8-methoxy-2'-chloro-PAT was found on 3H-PAT binding to striatal membranes suggesting that presynaptic 5-HT binding sites (see Gozlan et al., Nature, Lond. 305, 140, 1983) were sensitive also to the alkylating agent. In contrast, the modifying agent N-ethylmaleimide (NEM) reduced markedly 3H-PAT binding to postsynaptic hippocampal 5-HT1 sites, but did not alter 3H-PAT binding to striatal presynaptic 5-HT sites. Although 8-methoxy-2'-chloro-PAT bound irreversibly to different classes of 5-HT binding sites (5-HT1A, 5-HT1B, presynaptic sites), it can be considered a selective alkylating agent, since it exerted no action on 3H-spiperone binding to 5-HT2 sites, 3H-muscimol binding to GABA sites, or 3H-flunitrazepam binding to benzodiazepine sites.

2-Naphthylamine↗
PubMed1985

Irreversible blockade of beta-adrenergic receptors with a bromoacetyl derivative of pindolol.

A potent irreversible beta-adrenergic derivative of pindolol possessing a chemically reactive group (Br-AAM-pindolol) was synthesized. This compound devoid of agonist properties, competed for all (3H)-dihydroalprenolol (3H-DHA) binding sites in C6 glioma cell and rat cerebellum membranes. Pretreatment of C6 glioma cell membranes with Br-AAM-pindolol and subsequent washing resulted in a time- and dose-dependent blockade of beta-adrenergic receptors. A 50% blockade was achieved in the presence of 1.6 nM Br-AAM-pindolol. This blockade occurs specifically at the beta-adrenergic receptor level, as: 1) it induced a decrease of maximal isoproterenol stimulated adenylate cyclase activity with no modification of basal and sodium fluoride stimulated activity and 2) decreases of (3H)-DHA binding and stimulation of adenylate cyclase activity by the agonist were suppressed in the presence of isoproterenol, a beta-adrenergic agonist. Furthermore, Br-AAM-pindolol treatment did not affect (3H)-diazepam binding in C6 glioma cell membranes. Pretreatment of C6 glioma cells with Br-AAM-pindolol also reduced the response of adenylate cyclase to isoproterenol and the number of beta-adrenergic receptors. The blockade of beta-adrenergic receptors of C6 glioma cells by Br-AAM-pindolol was non-competitive, whereas the blockade obtained with AM-pindolol, a derivative of pindolol devoid of alkylating properties, was competitive. The irreversible blockade of beta-adrenergic receptors by Br-AAM-pindolol in rat erythrocyte membranes was substantiated by the demonstration that no recovery of beta-adrenergic receptors occurred during long term incubation of the membranes (48 h) following Br-AAM-pindolol treatment and subsequent washing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1985

Characteristics of tyrosine hydroxylase activation by K+-induced depolarization and/or forskolin in rat striatal slices.

The mechanisms of tyrosine hydroxylase (TH) activation by depolarization or exposure of dopaminergic terminals to cyclic AMP have been compared using rat striatal slices. Tissues were incubated with veratridine or 60 mM K+ (depolarizing conditions), on the one hand, and forskolin or dibutyryl cyclic AMP, on the other. K+-(or veratridine-)induced depolarization triggered an activation of TH (+75%) that persisted in soluble extracts of incubated tissues. This effect disappeared when drugs (EGTA, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, Gallopamil) preventing Ca2+- and calmodulin-dependent processes were included in the incubating medium. In contrast, prior in vivo reserpine treatment or in vitro addition of benztropine did not affect the depolarization-induced activation of TH. In vitro studies of soluble TH extracted from depolarized tissues indicated that activation was associated with a marked increase in the enzyme Vmax but with no change in its apparent affinity for the pteridin cofactor 6-methyl-5,6,7,8-tetrahydropterin (6-MPH4) or tyrosine. Furthermore, the activated enzyme from depolarized tissues exhibited the same optimal pH (5.8) as native TH extracted from control striatal slices. In contrast, TH activation resulting from tissue incubation in the presence of forskolin or dibutyryl cyclic AMP was associated with a selective increase in the apparent affinity for 6-MPH4 and a shift in the optimal pH from 5.8 to 7.0-7.2. Clear distinction between the two activating processes was further confirmed by the facts that heparin- and cyclic AMP-dependent phosphorylation stimulated TH activity from K+-exposed (and control) tissues but not that from striatal slices incubated with forskolin (or dibutyryl cyclic AMP). In contrast, the latter enzyme but not that from depolarized tissues could be activated by Ca2+-dependent phosphorylation. These data strongly support the concept that Ca2+- but not cyclic AMP-dependent phosphorylation is responsible for TH activation in depolarized dopaminergic terminals.

Animals↗
PubMed1985

[3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to pre- and postsynaptic 5-hydroxytryptamine sites in various regions of the rat brain.

The specific binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([ 3H]8-OH-DPAT) to 5-hydroxytryptamine (5-HT)-related sites was investigated in several regions of the rat brain. Marked differences were observed in the characteristics of binding to membranes from hippocampus, striatum, and cerebral cortex. Hippocampal sites exhibited the highest affinity (KD approximately 2 nM) followed by the cerebral cortex (KD approximately 6 nM) and the striatum (KD approximately 10 nM). Ascorbic acid inhibited specific [3H]8-OH-DPAT binding in all three regions but millimolar concentrations of Ca2+, Mg2+, and Mn2+ enhanced specific binding to hippocampal membranes, whereas only Mn2+ increased it in the cerebral cortex and all three cations inhibited specific binding to striatal membranes. Guanine nucleotides (0.1 mM GDP, GTP) inhibited binding to hippocampal and cortical membranes only. As intracerebral 5,7-dihydroxytryptamine markedly decreased [3H]8-OH-DPAT binding sites in the striatum, but not in the hippocampus, the striatal sites appear to be on serotoninergic afferent fibers. In contrast, in the hippocampus the sites appear to be on postsynaptic 5-HT target cells, as local injection of kainic acid decreased their density. Both types of sites appear to be present in the cerebral cortex. The postsynaptic hippocampal [3H]8-OH-DPAT binding sites are probably identical to the 5-HT1A subsites, but the relationship between the presynaptic binding sites and the presynaptic autoreceptors controlling 5-HT release deserves further investigation.

5,7-Dihydroxytryptamine↗
PubMed1985

[The spinal enkephalinergic and serotoninergic systems in the control of transmission of nociceptive messages].

Numerous anatomical, pharmacological and electrophysiological data described in the literature indicate that spinal enkephalinergic and serotoninergic systems are probably involved in the control of nociceptive inputs from the periphery to the cerebral cortex. However, reported evidence was generally indirect and did not provide a real demonstration of the physiological participation of these neurones in pain control. This led us to select appropriate experimental approaches for studying directly the activity of spinal enkephalinergic and serotoninergic systems in animals (rat, cat) submitted to noxious stimuli. Owing to two catheters introduced into the subarachnoidal space of anesthetized rats, it was possible to perfuse the whole spinal cord with an artificial cerebro-spinal fluid and thus collect the neuroactive compounds released by spinal neurones (at least those in superficial layers) under various experimental conditions. Using this technique, we observed that some (but not all) nociceptive stimuli such as intense pinching of the muzzle, intraperitoneal injection of acetic acid or noxious heat applied to the muzzle or the tail induced a significant increase in met-enkephalin release from the spinal cord (see fig. 2). Similar effects were observed following the blockade of enkephalin catabolism by thiorphan and bestatin (see fig. 1) indicating that they were not due to some alteration of peptidase activities but really involved the activation of spinal enkephalinergic systems. Since cervical cord transection suppressed the stimulatory action of noxious stimuli on spinal met-enkephalin release, it could be proposed that the mechanisms involved were not limited to the cord but depended on supraspinal structures. Bulbo-mesencephalic serotoninergic neurones projecting to the spinal cord might well correspond to such structures (or at least to some of them) since nociceptive stimuli (such as noxious heat applied to the tail) also evoked a marked increase of serotonin (5-HT) release at the spinal level (fig. 3). Such observations together with indirect evidence reported in the literature suggested therefore that the activation of spinal enkephalinergic systems triggered by noxious stimuli might result from excitatory influence due to descending serotoninergic projections. However, in vitro studies using slices of the dorsal zone of the rat lumbar cord did not reveal any stimulatory effect of 5-HT on the spontaneous or K+-evoked release of met-enkephalin (fig. 4).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Biochemical evidence for the 5-HT agonist properties of PAT (8-hydroxy-2-(di-n-propylamino)tetralin) in the rat brain.

In vitro investigations revealed that PAT (8-hydroxy-2-(n-dipropylamino)tetralin) interacted with postsynaptic 5-HT receptors in the rat brain: the drug stimulated 5-HT-sensitive adenylate cyclase in homogenates of colliculi from new-born rats (KAapp 8.6 microM) and inhibited the specific binding of [3H]5-HT to 5-HT1 sites. The PAT-induced inhibition of [3H]5-HT binding showed marked regional differences compatible with a preferential interaction of PAT (IC50 2 nM) with the 5-HT1A subclass. As previously seen with 5-HT agonists, the efficacy of PAT for displacing [3H]5-HT bound to hippocampal membranes was markedly increased by Mn2+ (1 mM) and reduced by GTP (0.1 mM). PAT also affected presynaptic 5-HT metabolism since it inhibited competitively (Ki 1.4 microM) [3H]5-HT uptake into cortical synaptosomes and reduced (in the presence of the 5-HT uptake inhibitor fluoxetine) the K+-evoked release of [3H]5-HT previously taken up or newly synthesized from [3H]tryptophan in cortical or striatal slices. This latter effect was prevented by 5-HT antagonists (methiothepin, metergoline) suggesting that it was mediated by the stimulation of presynaptic 5-HT autoreceptors by PAT. Like 5-HT, PAT counteracted the stimulatory effect of K+-induced depolarization on the synthesis of [3H]5-HT from [3H]tryptophan in cortical slices. It is concluded that PAT is a potent 5-HT agonist acting on both post- and presynaptic 5-HT receptors in the rat brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

Autoradiographic evidence for the heterogeneity of 5-HT1 sites in the rat brain.

The distribution of the binding sites of a new, potent agonist of serotonin (5-HT), 8-OH-N,N-dipropyl-2-aminotetralin (PAT), was studied in the rat brain with the quantitative autoradiographic technique utilizing tritium-sensitive LKB film. The localization of [3H]PAT binding sites was very similar to that of [3H]5-HT binding sites, except in some discrete regions (choroid plexus, striatum, area preoptica lateralis, subiculum, and substantia nigra), which exhibited very low levels of labeling with [3H]PAT and high levels with [3H]5-HT. These results indicate that 5-HT1 receptors are heterogeneous, and that [3H]PAT recognizes only a 5-HT1 subclass (called 5-HT1A).

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