Biomedical subjects

S Hjorth

Publications and source records attributed to S Hjorth.

At least 55 records · Page 3Linked to original sources

PubMed1993

Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study.

The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT1A) and (-)-penbutolol (5-HT1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (-)-penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (-)-penbutolol (1 microM; via the dialysis perfusion medium), but not by (-)-penbutolol (1 microM) alone. These findings provide evidence that 5-HT, in particular 5-HT1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.

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

PubMed1993

The growth hormone (GH)-binding protein cloned from human IM-9 lymphocytes modulates the down-regulation of GH receptors by 22- and 20-kilodalton human GH in IM-9 lymphocytes and the biological effects of the hormone in Nb2 lymphoma cells.

The cDNA coding for the 246-amino acid long N-terminal extracellular portion of the human (h) GH receptor, corresponding to the circulating GH-binding protein (hGHBP), was cloned by polymerase chain reaction from human IM-9 lymphocytes. The cDNA sequence was identical to that reported for human liver and placenta and demonstrated alternative splicing of exon 3. The protein with the exon 3-encoded domain was expressed and secreted in glycosylated form from baby hamster kidney (BHK) cells, purified to homogeneity, and sequenced; the amino acid sequence was identical to that predicted from liver cDNA. The cloned hGHBP competed in a dose-dependent fashion for binding of 125I-labeled 22-kilodalton (kDa) hGH, and at higher concentrations for binding of 125I-labeled 20-kDa hGH, to IM-9 lymphocytes. hGHBP decreased the association rate of [125I]hGH to the cells without decreasing the dissociation rate. hGHBP blocked the down-regulation of GH receptor in IM-9 cells by both 22- and 20-kDa hGH. hGHBP also blocked the binding of [125I]hGH to PRL receptors on Nb2 lymphoma cells and the effect of the hormone on thymidine incorporation. Binding of both 22- and 20-kDa hGH to the binding protein was demonstrated directly by immunoprecipitation with monoclonal antibody 263. The present work thus establishes the identity of the IM-9 human GHBP from those of liver and placenta, and demonstrates its ability to bind both 22- and 20-kDa hGH with good affinity and to block their biological actions mediated though both somatogenic and lactogenic receptors. The modulation of receptor down-regulation by the BP may be a relevant facet of its physiological role.

Amino Acid Sequence↗

PubMed1993

In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol.

Recently, we found that the beta 1/beta 2 adrenoceptor blocking agent (-)penbutolol prevents behavioral and biochemical actions of the specific serotonin (5-HT)1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. The putative 5-HT1 receptor antagonist profile of (-)penbutolol was further explored in the present study, using in vivo microdialysis methods to assess its effects on central 5-HT release. (+)Penbutolol and (-)pindolol were included for comparison purposes. In contrast to (-)pindolol (8.0 mg/kg s.c.), administration of (-)penbutolol (2.0 or 8.0 mg/kg s.c.) increased hippocampal 5-HT output. The (-)penbutolol-induced 5-HT response was dose-related, stereoselective and Ca(++)-dependent. In addition, the 5-HT response to (-)penbutolol was abolished by omitting the 5-HT reuptake blocker citalopram from the perfusion medium, suggesting the need for endogenous 5-HT tone. Local (-)penbutolol (1 microM) perfusion increased the 5-HT output per se, and also blocked 5-HT release suppression caused by the 5-HT1B receptor agonist CP-93,129. Furthermore, (-)penbutolol, but not its (+)antipode, prevented the decrease of 5-HT release induced by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. By comparison, the 5-HT1 receptor inactive beta adrenoceptor blockers metoprolol (beta 1) and ICI 118,551 (beta 2), given alone or in combination, did not increase 5-HT output and were ineffective in antagonizing the (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin response. The data indicate that (-)penbutolol possesses 5-HT1A and 5-HT1B autoreceptor antagonist properties, and may be a useful tool in studies of central 5-HT receptor-mediated function.

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

PubMed1992

(-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses.

Brain 5-HT1A and 5-HT1B receptors are important targets for drug-induced modulation of 5-HT function in vivo. However, very few compounds are available that are effective antagonists at 5-HT1 receptors, thus hampering the progress of fundamental as well as clinical research in this area. The present study assessed the usefulness of the beta-adrenolytic agent (-)-penbutolol (and its (+)-counterpart) as a 5-HT1A receptor-blocking agent. The compound was found to counteract, in a stereospecific fashion, not only the behavioural and hypothermic but also the in vivo 5-HT synthesis/turnover-reducing effects of the specific 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). These findings indicate that (-)-penbutolol is an antagonist at both postsynaptic receptors and somatodendritic autoreceptors of the 5-HT1A subtype. Thus, (-)-penbutolol represents a useful addition to the array of pharmacological tools available for the study of central 5-HT1 receptor-mediated functions.

5-Hydroxytryptophan↗

PubMed1992

Alpha 2-adrenoceptor modulation of rat ventral hippocampal 5-hydroxytryptamine release in vivo.

The putative existence of a functional alpha 2-adrenoceptor-mediated modulation of 5-HT release in vivo from serotonergic neuronal terminals in the ventral hippocampus was investigated using intracerebral microdialysis in chloral hydrate-anaesthetised rats. The alpha 2-adrenoceptor agonist clonidine (0.01-0.3 mg/kg, SC) dose-dependently decreased the 5-HT output. The response to clonidine was antagonized by systemic or local administration of the alpha 2-adrenoceptor antagonist idazoxan (0.1 mg/kg, SC, or 10 mumol/l, via the dialysis perfusion medium). Similarly, the 5-HT release-suppressing response to the thiazole alpha 2-adrenoceptor agonist jingsongling (0.1 mg/kg, SC) was blocked by idazoxan (0.1 mg/kg, SC). The mixed beta-adrenoceptor/5-HT1 receptor antagonist pindolol (8.0 mg/kg, SC) did not affect the clonidine-induced reduction of 5-HT release. Tyrosine hydroxylase inhibition by means of alpha-methyl-para-tyrosine (alpha-MT; 250 mg/kg, IP) caused a drastic reduction (greater than 80%) in dialysate 3,4-dihydroxyphenyl acetic acid (DOPAC) output but did not affect the 5-HT output per se over 3 h post-injection. Nor did the alpha-MT pretreatment prevent, but instead significantly enhanced, the 5-HT release-suppressing effect of clonidine. The results demonstrate that the release of 5-HT from serotonergic nerve terminals in rat ventral hippocampus in vivo is modulated by alpha 2-adrenoceptors, probably both by heteroreceptors on the axon terminals of the serotonergic neurones and by other alpha 2-adrenoceptor sites situated pre- and/or postsynaptic to the noradrenergic terminals. Our results also suggest that while functionally operative, these sites may receive little physiological tone, at least in chloral hydrate-anaesthetised rats.

Adrenergic alpha-Antagonists↗

PubMed1992

The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo.

The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066 B and RU 24969, the 5-HT1A/1B antagonist (+/-)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43694, the unselective 5-HT receptor antagonist methiothepin, and carbidopa + L-5-hydroxytryptophan (L-5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethyl-phenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%-220% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Dopaminergic neurotransmission in somatodendritic and terminal areas of the rat brain: susceptibility to modulation by D1 and D2 receptors and to axotomy.

We have investigated the influence of D1 and D2 dopamine receptor active drugs on dopamine (DA) release in substantia nigra (SN), striatum and limbic forebrain in intact and in hemisected rats in vivo. DA release was indirectly assessed as 3-methoxytyramine (3-MT) accumulation following monoamine oxidase inhibition by pargyline. Hemisection per se had no effect on the 3-MT accumulation in the SN. Neither, had SCH 23390, SK & F 28393, or cis-flupentixol any effect in the SN in intact animals or in the lesioned side in hemisected animals. SCH 23390 slightly increased the 3-MT accumulation both in the striatum and limbic forebrain, indicating a stimulatory action on DA release, but SK & F 38393 had no effect in these brain regions. A difference between the striatum and the limbic forebrain was that the effects of SCH 23390, and cis-FPX were almost abolished following hemisection in the limbic forebrain, but only partially reduced in the striatum. In summary, our data give further support for the concept that neither D1 nor D2 dopamine receptors have any pronounced influence on the DA release in the SN. The data also indicate operational differences in the feedback regulation of limbic versus striatal dopaminergic transmission.

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

PubMed1992

Acute reserpine treatment increases rat brain serotonin synthesis via a nerve impulse-dependent mechanism.

Notwithstanding recent advances in the understanding of central serotonin (5-HT) function, important basic aspects of the control of brain 5-HT neuronal transmission remain incompletely elucidated. The present experiments addressed the putative mechanism(s) by which acute reserpine treatment stimulates cerebral 5-HT synthesis; also, such studies might shed further light on the relation between impulse flow and transmitter synthesis in central 5-HT neurons. Reserpine (5 mg/kg, i.p., 90 min before death) markedly elevated 5-HT synthesis [5-hydroxytryptophan (5-HTP) accumulation after decarboxylase inhibition by means of NSD 1015] in the limbic, striatal, and cortical rat brain parts. Hemitransection of ascending neuronal connections between the brainstem and the forebrain, performed immediately before reserpine injection, did not affect the 5-HT synthesis per se but completely prevented the drug response on the lesioned side. Similarly, systemic administration of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.1 mg/kg, s.c., 60 min before death) blocked the reserpine-induced elevation of brain 5-HT synthesis. These findings indicate that the reserpine-induced rise in axon terminal 5-HTP accumulation is dependent on intact (5-HT) neuronal impulse flow, which may or may not involve a transient impairment of somatodendritic 5-HT release and, in turn, autoreceptor tone.

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

PubMed1992

Differences in the in vitro and in vivo 5-hydroxytryptamine extraction performance among three common microdialysis membranes.

The present study summarizes the results of an in vitro and in vivo comparison of the apparent 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid dialysis performance of three types of membrane frequently used in intracerebral microdialysis experiments. The dialysis fiber types examined were a regenerated cellulose Cuprophan (GF), a proprietary polycarbonate ether (CMA), and a polyacrylonitrile/sodium methallylsulfonate copolymer (HOSPAL). The experiments unexpectedly revealed that the HOSPAL membrane-equipped probes displayed clearly aberrant 5-HT diffusion dynamics compared with GF and CMA probes, demonstrable not only in vitro, but also in in vivo experiments. In vitro, the GF and CMA membrane-equipped probes exhibited maximum relative recovery for 5-HT already in the first 20-min sample, whereas the 5-HT recovery of HOSPAL probes increased in a very slow and protracted manner over a period of a little less than 2 h. The GF and CMA probes further displayed an immediate washout of 5-HT when the probes were subsequently transferred to artificial CSF only-containing medium (no 5-HT), whereas approximately 2 h was required to yield near-total extinction of dialysate 5-HT with the standard HOSPAL probes. In vivo, the rat ventral hippocampal dialysate 5-HT output responses to K+ (100 mM) infusion, to Ca2+ omission, and to systemic 8-hydroxy-2-(di-n-propylamino)tetralin injection were all markedly retarded and blunted when HOSPAL instead of GF membrane-equipped probes were used. However, the 5-hydroxyindoleacetic acid and 3,4-dihydroxyphenylacetic acid extraction in vitro and in vivo were comparable using either of the membrane types.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Effects of sexual interactions on the in vivo rate of monoamine synthesis in forebrain regions of the male rat.

The effects of heterosexual interactions on the in vivo rate of regional brain monoamine synthesis were examined in the male rat. To this end, the animals were administered an inhibitor of cerebral aromatic L-amino acid decarboxylase, NSD-1015 (100 mg.kg-1 i.p.), and regional brain DOPA and 5-HTP accumulation, over a 15-35 min period of sexual interaction, was compared with the DOPA or 5-HTP accumulation in time-matched home cage controls. Using the DOPA and 5-HTP accumulation as an estimate for the rate of tyrosine and tryptophan hydroxylase activity, respectively, the present results demonstrate: (1) an increased demand on catecholamine synthesis in the neocortex, the amygdala and in the septal area; and (2) an increased dopamine and serotonin synthesis in the ventral striatum (excluding the olfactory tubercle), and in the dorsal striatum.

5-Hydroxytryptophan↗

PubMed1991

The putative 5-HT1B receptor agonist CP-93,129 suppresses rat hippocampal 5-HT release in vivo: comparison with RU 24969.

We have compared the ability of the new putatively specific 5-HT1B receptor agonist CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b] pyrid-5-one) and the structurally related mixed 5-HT1A/5-HT1B receptor ligand RU 24969, to influence 5-HT release in brain in vivo, using microdialysis techniques in chloral hydrate-anaesthetised rats. CP-93,129 (3 or 10 microM, via the dialysis perfusion medium) caused a concentration-dependent and methiothepin (10 microM)-sensitive suppression of ventral hippocampal 5-HT output. The effect of RU 24969 on 5-HT output was dependent on whether or not the 5-HT reuptake blocker citalopram was present in the perfusion medium. Thus, RU 24969 (0.1 microM) induced a decrease, or an increase followed by a decrease (1 microM), in 5-HT output in the absence of citalopram, but monotonically decreased (1 microM) 5-HT release when citalopram (1 microM) was present. CP-93,129 decreased dialysate 5-HT in either condition. Our findings are consistent with the characterisation of CP-93,129 as a 5-HT1B receptor agonist, and may thus represent in vivo support for 5-HT1B autoreceptor-mediated feedback control of 5-HT release in the rat brain. The 5-HT1B selectivity of CP-93,129, and its lack of 5-HT reuptake blocking properties, suggests that the compound compares favourably with other purported 5-HT1B receptor agonists.

Animals↗

PubMed1991

Single-dose 8-OH-DPAT pretreatment does not induce tachyphylaxis to the 5-HT release-reducing effect of 5-HT1A autoreceptor agonists.

It has recently been suggested that central 5-HT1A autoreceptors are already desensitised after single-dose 5-HT1A agonist treatment. In turn, this would lead to an attenuated feedback suppression of transmitter release from 5-HT neurones, and thus to enhanced 5-HT synaptic transmission. In the present study in vivo brain microdialysis techniques were used in an attempt to test this hypothesis. The results show that single-dose pretreatment with the reference 5-HT1A receptor agonist 8-hydroxy-2-(din-propylamino)tetralin, 8-OH-DPAT, (i) did not significantly alter the baseline output of 5-HT in the rat ventral hippocampus 24 h later, and (ii) did not alter the release-reducing response to 5-HT1A agonist (8-OH-DPAT, ipsapirone or BMY 7378) challenge under the same conditions. These observations indicate that the functional responsiveness of the 5-HT release-controlling 5-HT1A autoreceptors is maintained after bolus 8-OH-DPAT pretreatment. When related to the acute 8-OH-DPAT-induced reduction in raphe 5-HT1A radioligand binding density recently reported by others, the present results are consistent with a large functional overcapacity of this 5-HT1A receptor population. The mechanism by which 5-HT1A receptor-mediated hypothermia and hyperphagia are rapidly attenuated by a previous large single dose of a 5-HT1A receptor agonist remains to be explained.

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

PubMed1991

Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis.

Recent electrophysiological studies, measurements of 5-HT synthesis and in vivo voltammetry recordings of 5-HT metabolism have suggested that serotoninergic neurones in the median raphe (MR) are less sensitive to 5-HT1A autoreceptor stimulation relative to those in the dorsal raphe (DR). To further study the putative differences in regulation between ascending 5-HT projections from the raphe nuclei we have used microdialysis to measure the release of 5-HT in ventral hippocampus, globus pallidus, dorsal hippocampus, frontal cortex, nucleus accumbens and medial septum, following systemic administration of the specific 5-HT1A agonist 8-OH-DPAT. The results show that the baseline output of 5-HT was similar in each of the areas studied. While 8-OH-DPAT decreased dialysate levels of 5-HT in all areas, the inhibition of 5-HT release seen in globus pallidus was significantly less marked compared to that observed in the other five regions. The results indicate that 5-HT1A autoreceptor-mediated control of 5-HT release is functional in all of the brain areas studied, including those receiving a preferential 5-HT innervation from the DR and MR. We find little evidence in support of the idea that brain 5-HT neuronal projections are heterogenous with respect to 5-HT1A autoreceptor regulation of 5-HT release; the globus pallidus, however representing a possible exception to this.

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

PubMed1991

Microencapsulated dopamine (DA)-induced restitution of function in 6-OHDA-denervated rat striatum in vivo: comparison between two microsphere excipients.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated-striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.

Animals↗

PubMed1990

Effects of MDL 73005EF on central pre- and postsynaptic 5-HT1A receptor function in the rat in vivo.

The effects of MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-8- azaspiro[4,5]decan-7,9-dione methyl sulphonate), a novel selective 5-HT1A receptor ligand with putative anxiolytic properties, were explored using models of central pre- and postsynaptic 5-HT1A receptor function in the male rat. MDL 73005EF dose dependently decreased the hippocampal 5-HT output measured by in vivo microdialysis in chloral hydrate-anaesthetised rats and this response was antagonised by the 5-HT1A/B receptor antagonist, pindolol. Local administration of MDL 73005EF had no effect on the hippocampal 5-HT output. MDL 73005EF failed to alter basal plasma adrenocorticotropin (ACTH) levels but, in common with pindolol, attenuated the ACTH response to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In contrast to 8-OH-DPAT, MDL 73005EF significantly increased plasma prolactin but apparently not through a 5-HT receptor-mediated mechanism. The results indicate that MDL 73005EF possesses mixed 5-HT1A receptor agonist/antagonist properties, acting as an agonist at presynaptic 5-HT1A receptors controlling 5-HT release and as an antagonist at postsynaptic 5-HT1A receptors mediating ACTH release.

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

PubMed1990

Further investigation of the in vivo pharmacological properties of the putative 5-HT1A antagonist, BMY 7378.

The present study examined the actions of the putative 5-HT1A antagonist BMY 7378 on central pre- and postsynaptic 5-HT1A function in the rat in vivo. Unlike the direct acting 5-HT1A agonist 8-hydroxy-2-(di-n-pro-pylamino)tetralin (8-OH-DPAT), BMY 7378 (0.25-5 mg/kg s.c.) did not induce the full postsynaptically mediated 5-HT behavioural syndrome (forepaw treading, head weaving, flat body posture hindlimb abduction). Indeed, the maximal 5-HT behavioural syndrome scores of BMY 7378 were about 10% of those for 8-OH-DPAT. Following pretreatment, however, BMY 7378 dose dependently (0.25-5 mg/kg s.c.) reduced to undetectable levels forepaw treading and head weaving induced by 8-OH-DPAT (0.75 mg/kg s.c.). BMY 7378 also inhibited stereotypy and locomotor activity induced by 0.5 mg/kg apomorphine although this effect was only statistically significant at the highest dose tested (5 mg/kg). In contrast to its apparent 5-HT1A antagonist properties in the behavioural experiments, BMY 7378 caused a marked and dose-dependent (0.01-1.0 mg/kg s.c.) decrease of 5-HT release in ventral hippocampus of the anaesthetized rat as detected by brain microdialysis. This effect of BMY 7378 had a similar onset and duration of action but with slightly reduced efficacy compared to that previously described for 8-OH-DPAT. As with 8-OH-DPAT, the inhibitory effect of BMY 7378 on 5-HT release was attenuated by pretreatment with the 5-HT1 receptor/beta-adrenoceptor antagonist pindolol (8 mg/kg s.c.) but not its counterpart propranolol (20 mg/kg s.c.). Pretreatment with a combination of the beta 1- and beta 2-adrenoceptor antagonists metoprolol (4 mg/kg s.c.) and ICI 118 551 (4 mg/kg s.c.), respectively, did not alter the 5-HT response to BMY 7378. From these data we conclude that BMY 7378 is a mixed agonist/antagonist at central 5-HT1A receptors.

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

PubMed1990

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue.

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Animals↗

PubMed1990

cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors. An in vivo brain microdialysis study.

The somatodendritic 5-HT1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound--8-OH-DPAT (0.3 mg/kg s.c.)--in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (-)ALK-3 and the racemic trans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (-)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK-3 (10 microM) via the perfusion medium did not affect 5-HT output. In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT1A autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗