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R Schreiber

Publications and source records attributed to R Schreiber.

At least 127 records · Page 7Linked to original sources
PubMed1995

A drug discrimination analysis of the actions of novel serotonin1A receptor ligands in the rat using the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin.

In the present study, using a two-lever drug discrimination procedure, we characterized the effects of a series of chemically-diverse, novel 5-HT1A receptor agonists and antagonists in rats trained to discriminate the serotonin (5-HT)1A receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (0.31 mg/kg, i.p.) from saline. In analogy to the 5-HT1A receptor agonists, ipsapirone (a pyrimidinylpiperazine) and flesinoxan (a benzodioxane), the arylpiperazine derivatives, WY-48,723 and WY-50,324, as well as the methoxynaphtylpiperazines, S 14506 and S 14671, substituted 100% for the discriminative stimulus (DS) effects of 8-OH-DPAT, with the latter two displaying remarkable potency [50 effective doses (ED50s): 1.25, 0.34, 0.05, 0.69, 0.009 and 0.006 mg/kg, s.c., respectively]. In contrast, an additional pyrimidinylpiperazine, zalospirone, failed to fully mimick the training drug (maximal effect: 40%) even at a dose markedly disrupting response rates (2.5 mg/kg, s.c.). The potency of agonists in generalizing to 8-OH-DPAT correlated significantly (P < .05) with their affinity at rat hippocampal 5-HT1A receptors in vitro (r = .78), and with their potency to induce hypothermia in the rat (r = .96). S 15535 and S 15931, novel benzodioxopiperazines possessing mixed 5-HT1A autoreceptor agonist/postsynaptic 5-HT1A receptor antagonist properties, antagonized (approximately 75%) the discriminative stimulus (DS) properties of 8-OH-DPAT (ED50s: 6.9 and 0.97 mg/kg, s.c., respectively), although their structural analogue, S 14489, reduced by only 50% the action of 8-OH-DPAT. The 5-HT1A receptor antagonists, (+/-)-pindolol (-70%; ED50: 0.65 mg/kg, s.c.), (-)-alprenolol (-67%; ED50: 7.1) and NAN-190 (-80%; ED50: 1.5), all blocked the 8-OH-DPAT DS. Likewise, several novel antagonists at 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors; the benzoisothiazolpiperazine, SDZ 216-525 (-83%; ED50: 0.64), the aryloxyalkylamine, (-)-tertatolol (-83%; ED50: 7.7) and the methoxyphenylpiperazine, (+)-WAY 100,135 (-80%; ED50: 17.0), antagonized the 8-OH-DPAT cue. Antagonist potency correlated significantly with affinity at 5-HT1A receptors (r = .83) and potency for antagonism of 8-OH-DPAT-induced hypothermia (r = .83). Antagonists showed only variable and not significant (P > .05) generalization rates (13-50%) when tested alone.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists.

In this study, the involvement of serotonergic and dopaminergic receptors in the modulation of the head-twitch (HTW) response to the 5-hydroxytryptamine (5-HT)2A/5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, was characterized in rats using novel and selective ligands at 5-HT2A, 5-HT2C, D1, D2 and 5-HT1A receptors. HTW were dose-dependently inhibited by the 5-HT2A/2C antagonists, ritanserin, metergoline, mesulergine, mianserin, ICI 169,369 and LY 58,537, by the preferential 5-HT2A antagonist, ketanserin and by the novel, selective 5-HT2A antagonist, SR 46349B. A further selective 5-HT2A antagonist, MDL 100,907, very potently abolished HTW (ED50 = 0.005 mg/kg). The order of relative potency correlated highly with their affinity at 5-HT2A (r = 0.83) but not 5-HT2C receptors (r = 0.06). In addition, the novel, selective 5-HT2C antagonist, SB 200,646A, failed to abolish HTW and the 5-HT2C agonists/5-HT2A antagonists, 1-(3-chlorophenyl)piperazine and 1-(3-trifluoromethylphenyl)piperazine, blocked, rather than elicited, HTW. The D1 antagonists, SCH 23390, NNC 112, NNC 756, SCH 39166 and A 69024, in this order of relative potency that correlated with their affinity at D1 receptors (r = 0.98), blocked HTW. The D2 antagonists, raclopride, eticlopride and haloperidol also blocked HTW. The 5-HT1A agonists, S 14671, S 14506, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, ipsapirone and (+)-flesinoxan, abolished HTW. The action of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by (-)-tertatolol (ID50 = 4.5 mg/kg), a novel 5-HT1A receptor antagonist. Similarly, (-)-tertatolol attenuated the action of S 14506 and abolished that of S 14671, buspirone and ipsapirone. A role of postsynaptic 5-HT1A receptors in the action of 5-HT1A agonists was suggested by the finding that parachlorophenylalanine (3 x 300 mg/kg, i.p.), which depleted cerebral pools of 5-HT, did not modify the activity of ipsapirone. The present data demonstrate that 5-HT2A receptors mediate HTW in rats and that both D1 and D2 receptors as well as (postsynaptic) 5-HT1A receptors play a role in their expression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat?

Previous studies have shown that injection of 5-hydroxytryptamine (serotonin) receptor agonists in the dorsal raphe nucleus (DRN) to stimulate somatodendritic 5-HT1A autoreceptors or in the hippocampus to stimulate postsynaptic 5-HT1A receptors, induces anxiolytic-like effects in the rat. The mechanisms triggered by the latter treatment were investigated by measuring both the electrical activity of serotonergic DRN neurons and the anxiolytic response in rats receiving injections with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone into the dorsal hippocampus. Anxiety-related behavior was estimated by recording the time of ultrasonic vocalization (USV) due to electric foot shocks under standardized conditions. Intrahippocampal application of 8-OH-DPAT or ipsapirone produced a dose-dependent inhibition of the firing of serotonergic DRN neurons and of the shock-induced USV response. However, the range of efficient doses of 8-OH-DPAT via the intrahippocampal route (1-10 micrograms/rat) was larger than that using the i.v. route of injection (0.15-2.5 micrograms/rat). Furthermore, maximal inhibition of the firing of DRN serotonergic neurons occurred earlier when 8-OH-DPAT was injected i.v. (within 1-2 min) than when it was injected into the dorsal hippocampus (within 5 min). Interestingly, the injection of 8-OH-DPAT into the striatum, where 5-HT1A receptors are hardly detectable, or a lateral ventricle, also yielded dose-dependent reduction in both the firing rate of serotonergic DRN neurons and the USV response. Finally, local lesion with ibotenic acid to eliminate postsynaptic 5-HT1A receptors did not alter the inhibitory effects of intrahippocampal application of 8-OH-DPAT on the firing of serotonergic DRN neurons and the USV response. These data indicated that postsynaptic 5-HT1A receptors were not responsible for the inhibitory effects of 8-OH-DPAT and ipsapirone injected in forebrain areas on the electrical activity of serotonergic neurons and the USV response in rats. As shown by the autoradiographic labeling by [3H]8-OH-DPAT at distance from its injection site in the dorsal hippocampus, the diffusion of 5-HT1A receptor agonists (from injected areas in the forebrain to the DRN where they directly inhibit the electrical activity of serotonergic neurons) more likely accounted for their anxiolytic-like effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

The potent activity of the 5-HT1A receptor agonists, S 14506 and S 14671, in the rat forced swim test is blocked by novel 5-HT1A receptor antagonists.

The high efficacy methoxynaphtylpiperazine 5-HT1A receptor agonists, S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)piper azine) and S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl]piperazin e), potently reduced the duration of immobility in the forced swimming test in rats [minimal effective dose (MED): 0.01 mg/kg, s.c., in each case]; in contrast, the prototypic 5-HT1A receptor agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide], was much less potent (MED: 0.63 mg/kg). The action of S 14671 (0.16 mg/kg) was completely blocked by the potent 5-HT1A receptor antagonist, SDZ 216-525 (4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2- yl)butyl]-1-piperazinyl)1H-indole-2-carboxylate) (0.63 mg/kg) and by the novel, selective 5-HT1A receptor antagonist, (+)-WAY 100,135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)piperazinylphenyl propanamide): the effect of the latter was expressed dose dependently (Inhibitory Dose50: 35 mg/kg). Similarly, in the presence of (+)-WAY 100,135, S 14506 (0.63 mg/kg) failed to reduce immobility. Pretreatment with parachlorophenylalanine (3 x 300 mg/kg per day, i.p.), which profoundly depleted cerebral pools of 5-HT, modified neither baseline immobility nor the actions of S 14506 and S 14671. It is concluded that S 14506 and S 14671 possess exceptionally potent activity in the forced swimming test and that their actions reflect the activation of postsynaptic 5-HT1A receptors.

Animals↗
PubMed1994

Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the 'atypical' antipsychotics, clozapine and risperidone.

In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose50 (ED50) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidine-methanol) very potently (ED50 = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED50 values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.

Amphetamines↗
PubMed1994

Effects of aniso-osmolarity and hydroperoxides on intracellular pH in isolated rat hepatocytes as assessed by (2',7')-bis(carboxyethyl)-5(6)-carboxyfluorescein and fluorescein isothiocyanate-dextran fluorescence.

Freshly isolated rat hepatocytes were plated for 4-6 h and either loaded with (2',7)-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) or allowed to endocytose fluorescein isothiocyanate (FITC)-coupled dextran in order to study the effects of aniso-osmotic exposure and oxidative stress on cytosolic (pHcyt) and apparent vesicular pH (pHves) by single-cell fluorescence recordings. In the presence of normo-osmotic (305 mosmol/l) medium pHcyt was 7.23 +/- 0.03 (n = 108), whereas an apparent pH of 6.07 +/- 0.02 (n = 156) was found in the vesicular compartment accessible to endocytosed FITC-dextran. Substitution of 60 mM NaCl against 120 mM raffinose had no effect on pHcyt or apparent pHves, whereas addition of NH4Cl increased both pHcyt and apparent pHves. Hypo-osmotic cell swelling lowered pHcyt, whereas simultaneously apparent pHves increased. These effects were rapidly reversible upon re-institution of normo-osmotic media. Similarly, an increase of apparent pHves was observed when cell swelling was induced by Ba2+, glutamine or histidine. Conversely, hyperosmotic cell shrinkage due to addition of NaCl or raffinose led to a cytosolic alkalinization and a vesicular acidification. Both, H2O2 (0.2 mmol/l) and t-butyl-hydroperoxide (0.2 mmol/l) were without effect on pHcyt, but lowered apparent pHves by about 0.2 pH units. Ba2+ (1 mmol/l) diminished the acidifying effect of the hydroperoxides by about 50%. Pretreatment of the cells with colchicine, but not with lumicolchicine, largely abolished the effects of aniso-osmolarity and hydroperoxides on pHves. The data suggest that hepatocellular hydration affects the proton gradients built up across the membranes of endocytotic FITC-dextran-accessible compartments in a microtubule-dependent way. They further suggest that hydroperoxides induce vesicular acidification in a colchicine- and Ba(2+)-sensitive way. Because hydroperoxides induce Ba(2+)-sensitive cell shrinkage [Hallbrucker, Ritter, Lang, Gerok and Häussinger (1992) Eur. J. Biochem. 211, 449-458], the results are compatible with the view that hydroperoxide-induced cell shrinkage mediates vesicular acidification. It is concluded that modulation of vesicular pH by the hepatocellular hydration state may play a role in triggering some metabolic changes in response to cell swelling/shrinkage.

Ammonium Chloride↗
PubMed1994

Involvement of microtubules in the link between cell volume and pH of acidic cellular compartments in rat and human hepatocytes.

Cell swelling is shown to induce an increase in acridine orange fluorescence intensity, an effect pointing to the alkalinization of acidic vesicles. Since autophagic hepatic proteolysis is accomplished by pH-sensitive proteinases within acidic lysosomes, this effect may contribute to the well-known inhibitory effect of cell swelling on proteolysis. In the present study, the role of microtubules in volume-dependent alterations of pH in acidic vesicles of rat and human hepatocytes was studied. Colcemid and colchicine were used to depolymerize microtubules and vesicular pH was monitored using two different fluorescent dyes, fluorescein isothiocyanate conjugated-dextran and acridine orange. Colcemid and colchicine, but not the inactive stereoisomer gamma-lumicolchicine, blunted the increase of pH during osmotic cell swelling. The alkalinization of acidic vesicles by NH4Cl was not significantly modified by colcemid or colchicine, indicating that the vesicles were still sensitive to alkalinizing procedures other than cell swelling. Further, colchicine, but not gamma-lumicolchicine, inhibited the antiproteolytic action of osmotic cell swelling. The present observations point to an involvement of the microtubule network in the link of cell volume, lysosomal pH, and proteolysis.

Animals↗
PubMed1994

Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin.

Niemann-Pick type C is an autosomal-recessive, neurovisceral storage disorder that results from defective cholesterol esterification. Cholesterol-lowering agents have been demonstrated to decrease hepatic lipids in Niemann-Pick type C patients. The objective was to determine the effects of cholesterol-lowering agents on neurologic features and to develop a noninvasive method of monitoring clinical response. A 9-month-old boy with progressive hepatosplenomegaly and neurodevelopmental delay was studied. Water-suppressed proton magnetic resonance spectra from a supraventricular volume of central white and gray matter revealed an abnormal lipid signal. The patient was treated with cholesterol-lowering agents (i.e., cholestyramine, lovastatin). Repeat standardized neurodevelopmental assessments (Peabody and Griffith scales) at 13 and 19 months were normal and magnetic resonance spectra no longer detected the previously observed lipid resonance. Early treatment of Niemann-Pick type C patients with cholesterol-lowering agents appeared to have short-term beneficial effects. Magnetic resonance spectra provided a noninvasive means of monitoring CNS response.

Brain↗
PubMed1994

The thioredoxin system of Penicillium chrysogenum and its possible role in penicillin biosynthesis.

Penicillium chrysogenum is an important producer of penicillin antibiotics. A key step in their biosynthesis is the oxidative cyclization of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N by the enzyme isopenicillin N synthase (IPNS). bis-ACV, the oxidized disulfide form of ACV is, however, not a substrate for IPNS. We report here the characterization of a broad-range disulfide reductase from P. chrysogenum that efficiently reduces bis-ACV to the thiol monomer. When coupled in vitro with IPNS, it converts bis-ACV to isopenicillin N and may therefore play a role in penicillin biosynthesis. The disulfide reductase consists of two protein components, a 72-kDa NADPH-dependent reductase, containing two identical subunits, and a 12-kDa general disulfide reductant. The latter reduces disulfide bonds in low-molecular-weight compounds and in proteins. The genes coding for the reductase system were cloned and sequenced. Both possess introns. A comparative analysis of their predicted amino acid sequences showed that the 12-kDa protein shares 26 to 60% sequence identity with thioredoxins and that the 36-kDa protein subunit shares 44 to 49% sequence identity with the two known bacterial thioredoxin reductases. In addition, the P. chrysogenum NADPH-dependent reductase is able to accept thioredoxin as a substrate. These results establish that the P. chrysogenum broad-range disulfide reductase is a member of the thioredoxin family of oxidoreductases. This is the first example of the cloning of a eucaryotic thioredoxin reductase gene.

Amino Acid Sequence↗
PubMed1994

Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo.

De novo expression of TNF, IFN gamma, IL-3, IL-4, and IL-6 genes was initiated rapidly by treatment of mice with anti-CD3. A specific feature of this reaction was that TNF was derived exclusively from T cells. TNF was produced both as a mature soluble trimeric protein and as a 26-kD anti-TNF-reactive protein compatible with membrane-anchored TNF. Pretreatment with anti-TNF did not affect anti-CD3-triggered TNF mRNA expression in T cells. In contrast, in vivo and in vitro anti-TNF treatment upregulated anti-CD3-induced IFN gamma mRNA expression and inhibited IL-4 mRNA expression. These latter effects were not dependent on TNF neutralization: pretreatment with soluble recombinant 55-kD TNF receptor (TBPI) as an alternative TNF-neutralizing agent did not modify the anti-CD3-induced cytokine profile. These results suggest that a direct interaction between anti-TNF and T cell membrane-anchored TNF could account for the observed modulation of cytokine gene expression. The increased expression of INF gamma mRNA observed in anti-TNF-treated animals correlated with a decrease in IL-3 and IL-6 mRNA expression. Conversely, IFN gamma blockade by a neutralizing anti-IFN gamma mAb led to a substantial increase in both IL-3 and IL-6 gene expression induced by anti-CD3. Taken together, these results strongly argue for the existence, in the anti-CD3-induced cytokine cascade, of IFN gamma-dependent regulation of IL-3 production, which in turn modulates IL-6 production.

Animals↗
PubMed1993

Endogenous hydroperoxide formation, cell volume and cellular K+ balance in perfused rat liver.

Addition of benzylamine (0.5 mM) to isolated perfused rat liver led to a net release of K+ of 10.5 +/- 0.3 mumol/g, which was accompanied by a decrease in liver mass by 9.3 +/- 0.4% and a decrease of the intracellular water space by 13.7 +/- 0.6%, suggestive of hepatocellular shrinkage. Benzylamine had no effect on the perfusion pressure, and there was a close relationship between benzylamine-induced net K+ release and the accompanying decrease in liver mass. Benzylamine-induced net K+ release was sensitive to inhibition of monoamine oxidase by pargyline and increased with benzylamine flux through monoamine oxidase, suggesting its dependence on intracellular H2O2 formation. In line with this, infusion of H2O2 (but not of benzaldehyde, the other product of benzylamine metabolism) stimulated net K+ release from the liver. However, at a given H2O2 load K+ release was about 2-3-fold higher when H2O2 was generated intracellularly during the oxidation of benzylamine, as compared with exogenously delivered H2O2. Inhibition of catalase by 3-amino-1,2,4-triazole (0.2 mM) significantly increased the benzylamine-induced net K+ release as well as the benzylamine-induced release of GSSG into bile, but had no effect on benzylamine oxidation at monoamine oxidase. In the presence of Ba2+ (1 mM) or in Ca(2+)-free perfusions, the benzylamine-induced net K+ efflux was diminished by 60-70% or about 30%, respectively. This was not explained by the 20-30% decrease in flux through monoamine oxidase observed under these conditions. The results suggest that metabolic generation of H2O2 inside the liver leads to a net K+ efflux and subsequent hepatocellular shrinkage. Net K+ efflux under these conditions is enhanced when catalase is inhibited, suggesting that the rate of both intracellular H2O2 generation and degradation can modulate cellular K+ balance and cellular volume. The data support the idea that oxidative stress may affect hepatocellular functions also by lowering the hepatocellular hydration state.

Animals↗
PubMed1993

Shock-induced ultrasonic vocalization in young adult rats: a model for testing putative anti-anxiety drugs.

A putative animal model of anxiety based on shock-induced ultrasonic vocalization was pharmacologically validated in young adult rats. Suppression of shock-induced ultrasonic vocalization was obtained with diazepam, chlordiazepoxide, meprobamate and pentobarbital; the serotonin (5-HT)1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], buspirone, ipsapirone, gepirone and tandospirone; the nonselective 5-HT receptor agonists TFMPP [1-(3-trifluoromethylphenyl)piperazin], mCPP [1-(3-chlorophenyl)piperazin] and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); the NMDA antagonists PCP (phencyclidine) and MK-801; the alpha 2-adrenoceptor antagonists idazoxane, yohimbine and 1-PP (1-pyrimidinylpiperazine); and the atypical neuroleptic clozapine. The alpha 2-adrenoceptor agonist clonidine, the 5-HT2/5-HT1C antagonist ritanserin, the 5-HT3 antagonists ondansetron and ICS-205,930, and the 5-HT reuptake inhibitor fluoxetine did not, or only partially, reduce ultrasonic vocalization. Tricyclic and tetracyclic, as well as some atypical antidepressants and a monoamineoxidase (MAO) inhibitor, showed no ultrasonic vocalization reducing effects, or reduced ultrasonic vocalization only at high doses. An opiate, an antimuscarinic, (pro)convulsants and typical neuroleptics did not reduce ultrasonic vocalization. The present findings suggest that the ultrasonic vocalization model specifically measures anxiolytic effects. Because ultrasonic vocalization responding develops within five days, remains stable for at least three months and gives highly reproducible results, the test appears suitable for rapid and repeated testing of new anxiolytics in the same animals.

Adrenergic alpha-Agonists↗
PubMed1993

Neuronal circuits involved in the anxiolytic effects of the 5-HT1A receptor agonists 8-OH-DPAT ipsapirone and buspirone in the rat.

In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in non-lesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Anxiolytic effects of the 5-HT1A receptor agonist ipsapirone in the rat: neurobiological correlates.

Ipsapirone, a 5-HT1A receptor agonist, is a psychoactive compound with anxiolytic and antidepressive properties. Concerning the mechanism of action of ipsapirone, most studies point towards an interaction with the central serotonergic system. For characterization of the anxiolytic properties of ipsapirone, the ultrasonic vocalization test, a rat model based on conditioned anxiety, was used. In this test ipsapirone time and dose dependently inhibited the shock induced ultrasonic vocalization of rats after systemic application of ipsapirone, indicating its potent anxiolytic properties. To gain further insight into the mechanism underlying the anxiolytic activity of ipsapirone, the effects of this compound on the central serotonergic system of rats were characterized. Extracellular single unit recordings, measuring the firing rate of serotonergic dorsal raphe neurons in anaesthetized rats, showed that ipsapirone dose and time dependently suppressed neuronal firing. In the hippocampus, one of the projection areas of the serotonergic dorsal raphe neurons, systemic application of ipsapirone resulted in a dose- and time-dependent reduction in serotonergic neurotransmission, measured as a reduced serotonin output in microdialysis experiments with freely moving rats. The time- and dose-effect curves reflecting the anxiolytic, electrophysiological, and biochemical effects correlated well with each other for different doses of ipsapirone. It is concluded that ipsapirone exhibits its anxiolytic effects, at least partially, by stimulating presynaptic somatodendritic 5-HT1A receptors in the brain stem raphe nuclei (i.e., the dorsal raphe), resulting in attenuation of presynaptic cell firing and subsequent inhibition of serotonergic neurotransmission in the limbic system (i.e., the hippocampus).

Animals↗
PubMed1993

Ipsapirone and 8-OH-DPAT reduce ethanol preference in rats: involvement of presynaptic 5-HT1A receptors.

The selective serotonin(5-HT)1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70-90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00 P.M.-8:00 A.M.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED50: 2.4 mg/kg, SC) and ipsapirone (ED50: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (-73%) and ipsapirone (-72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 micrograms, 0.5 microliters) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (-12%, 8:00-12:00 P.M.). Only marginal effects on ingestion behavior were observed after microinjection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2 x 150 mg/kg, IP) resulted in a short lasting, marked reduction (-54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT1A receptor ligands reduce EtOH preference via stimulation of 5-HT1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

5-HT1A receptor ligands in animal models of anxiety, impulsivity and depression: multiple mechanisms of action?

1. Preclinical and clinical studies suggest that 5-HT1A receptor agonists are a new class of mixed anxiolytics/antidepressants with, possibly, impulsivity reducing properties. 2. The anxiolytic effects of 5-HT1A receptor agonists result predominantly from an interaction with presynaptic 5-HT1A receptors (resulting in a decrease of serotonergic transmission), whereas the antidepressive and, possibly, the impulse control enhancing effects, result predominantly from an interaction with postsynaptic 5-HT1A receptors. 3. These proposed mechanism(s) of action fit well with the generally held view that anxiety is the result of a hypersensitive 5-HT system; whereas impulsivity and depression is the result of a hyposensitive 5-HT system. 4. However, it appears very likely that activation of pre- and postsynaptic 5-HT1A receptors is additionally involved in the antidepressive and impulse control enhancing effects, on the one hand, and in the anxiolytic effects of these compounds, on the other hand. 5. These latter, seemingly paradoxical, findings can be explained by assuming that (1) the presynaptic mechanism reflects an anxiolytic component in the animal models of impulsivity and depression, (2) antagonism of postsynaptic 5-HT1A receptors by these compounds contributes to their anxiolytic effects, (3) postsynaptic 5-HT1A and 5-HT2 receptors have functionally opposing effects or, alternatively, that (4) downregulation of postsynaptic 5-HT2 receptors contributes to the therapeutic effects of these compounds.

Animals↗