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J Traber

Publications and source records attributed to J Traber.

At least 55 records · Page 3Linked to original sources
PubMed1987

The interoceptive discriminative stimuli induced by the novel putative anxiolytic TVX Q 7821: behavioral evidence for the specific involvement of serotonin 5-HT1A receptors.

TVX Q 7821 is active in several behavioral models of anxiety in animals and has a high selective affinity for brain serotonin 5-HT1A receptors in binding assays. In order to determine if interaction with 5-HT1A receptors is important for some of the behavioral effects of this compound, 11 rats were trained to reliably discriminate the interoceptive stimuli induced by TVX Q 7821 (10 mg/kg, IP) from those of saline. Following discrimination acquisition, TVX Q 7821 administration resulted in drug-appropriate responding with an ED50 of 1.5 mg/kg, as did other substances with high affinity for the 5-HT1A receptor: 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, ED50 = 0.16 mg/kg), 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, ED50 = 2.5 mg/kg), and buspirone (ED50 = 5.4 mg/kg). Anxiolytics not acting via the 5-HT1A receptor, like diazepam and pentobarbital, did not induce full TVX Q 7821-appropriate responses. In addition, non-selective 5-HT agonists and antagonists such as bufotenin, quipazine, and methysergide, as well as substances with high affinity for the 5-HT1B receptor (m-trifluoromethylphenylpiperazine, TFMPP; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate, RU 24969) did not substitute for TVX Q 7821. These data support a selective 5-HT1A mechanism of action in vivo for TVX Q 7821 and indicate the suitability of TVX Q 7821 for the investigation of behavioral correlates of the 5-HT1A receptor.

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

Detailed projection patterns of septal and diagonal band efferents to the hippocampus in the rat with emphasis on innervation of CA1 and dentate gyrus.

The detailed patterns of afferentation to the ammon's horn and dentate gyrus of the hippocampus in the rat were investigated employing the anterograde tracer Phaseolus vulgaris leuco-agglutinin (PHA-L) after punctate iontophoretic injections in the medial septum (MS) and vertical limb of the diagonal band of Broca (VDB). The topographically ordered innervation pattern was different in the regio superior (or CA1) vs. the regio inferior (or CA3) and in the dorsal vs. ventral aspects of ammon's horn and dentate gyrus. The CA1 pyramidal and dentate granule cell layers in the dorsal hippocampus received afferent input almost exclusively from the VDB, whereas those cell layers in ventral hippocampus were supplied from both VDB and MS. The PHA-L labeled projecting fibers could be differentiated into two distinct fiber systems. One class of thick and coarse axons (tentatively called type I fibers) carried fewer but larger terminal boutons and were found to infiltrate the entire stratum oriens, dentate hilus, all layers of the regio inferior and the CA1 str. moleculare. A second, delicate thin (type II) fiber system provided with numerous and passant varicosities showed a much more restricted laminar innervation pattern and appeared to originate from areas in MS-VDB which are rich in AChE-positive neurons. The densest type II fiber networks could be observed in the CA1 subpyramidal and dentate supragranular zones, in the CA1 stratum lacunosum-moleculare and in the dentate middle third molecular layer. This laminar type II innervation pattern showed a remarkable coincidence with the reported distribution of cholinergic marker enzymes. The topographic and spatial organization of the projections described above will be discussed in relation to their possible functional significance.

Acetylcholinesterase↗
PubMed1986

Effects of N-ethylmaleimide on muscarinic acetylcholine receptor subtype autoradiography and inositide response in rat brain.

Chemical modification of brain muscarinic acetylcholine receptors (mAChr) with N-ethylmaleimide (NEM) has been employed to investigate mAChr-subtype distribution and mediation of the inositide response. 3H-Pirenzepine and 3H-oxotremorine-M were used to autoradiographically localize the M1- and M2-AChr subtypes, respectively, in brain slices. M1- and M2-AChr distribution were observed to be distinct from each other. The presence of 1 mM NEM selectively reduced the labeling of M2-, but not of M1-AChr. These data support the notion that NEM converts the high-affinity M2-AChr to a lower affinity state, without affecting the affinity of the M1-AChr. Also, regional analysis indicated that the M1- and M2-AChr subtypes were not interconvertible by NEM. NEM at 30 microM enhanced the carbamylcholine stimulated labeling of phosphatidic acid from 32Pi in nerve endings from rat forebrain, suggesting that the low affinity M2-AChr may mediate at least a part of the inositide response to cholinergic stimulation.

Animals↗
PubMed1986

Muscarinic cholinergic enhancement of inositide turnover in cerebral nerve endings is not mediated by calcium uptake.

Muscarinic cholinergic stimulation of rat cerebral nerve endings incubated with 32Pi causes an enhancement of the labeling of phosphatidic acid (PA) and phosphatidylinositol (PI). The involvement of Ca2+ in the stimulation of PA and PI labeling by carbamylcholine (CCh) was investigated. Enhancement of Ca2+-influx with veratridine and the Ca2+-ionophore A23187 caused a vast decrease of the labeling of the polyphosphoinositides, which was not accompanied by an enhancement of the labeling of PA and PI. The dihydropyridine Ca2+-agonist BAY K8644 did not affect phospholipid labeling. A23187, veratridine and BAY K 8644 did not enhance stimulation of the labeling of PA and PI by CCh. When Ca2+ was omitted from the incubation, A23187 caused an enhancement of basal and CCh-stimulated labeling of PA and PI, possibly indicating a particular feature of A23187 unrelated to its iontophoretic properties. The Ca2+-channel antagonists nimodipine, verapamil and flunarizine were virtually without effect on basal and CCh-stimulated labeling of PI and PA. These data support the notion that the muscarinic cholinergic inositide response is not mediated or controlled by Ca2+-flux.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections.

The autoradiographic distributions of receptors with high affinity for [3H]oxotremorine-M (the M2 receptor) and [3H]pirenzepine (the M1 receptor) were studied in the rat brain. M1 receptors were seen in highest density only in telencephalic structures: cerebral cortex (layers I-II), hippocampus, dentate gyrus, medial and basolateral amygdala, nucleus accumbens and caudate/putamen. M2 receptors were detected throughout the brain, with highest levels observed in cerebral cortical layers III and V, forebrain cholinergic nuclei, caudate/putamen, various thalamic areas, inferior and superior colliculus, interpeduncular and pontine nuclei, brainstem cholinergic nuclei and cervical spinal cord regions. M2 receptors were found to be good markers for cholinergic cell groups and the majority of cholinergic projection areas, whereas M1 receptors were only found in a large sub-group of telencephalic cholinergic projection areas, and the pattern of distribution of receptors in these areas differed from that of M2 receptors. Scatchard analysis of [3H]oxotremorine-M binding to inferior collicular slices revealed one site with a dissociation constant (Kd) of 1.9 nM and a receptor density (Bmax) of 1.4 pmol/mg protein. Our data support the hypothesis that M1 and M2 receptors are physically distinct sub-types of the muscarinic acetylcholine receptor.

Acetylcholinesterase↗
PubMed1986

Ontogenesis of serotonin (5-HT) binding sites in the choroid plexus of the rat brain.

The increase in density of 5-HT1c receptors in the choroid plexus of the third and lateral ventricles was analyzed in rats between the 1st and 90th postnatal days. An increase was found between the 3rd day and the 4th to 5th week, at which time adult values are attained. The development of the 5-HT1c receptors clearly differs from that of 5-HT1 receptors in other brain regions. The density in the choroid plexus is about 20% higher in the third ventricle than in the lateral ventricles.

Animals↗
PubMed1986

Quantitative autoradiography of transmitter binding sites with an image analyzer.

A computerized image processing system for quantitative receptor autoradiography on tritium-sensitive film is described. The method implements an image analyzer (IBAS 1 + 2) for the acquisition of an image which is evaluated with respect to the regional distribution of binding site densities by a small computer which is connected to a digitizer. Several methodological problems must be considered when using tritium-labelled compounds and an image analyzer. The use of tissue standards and shading procedures, the improvement of signal-to-noise ratio, the calibration of the system which establishes the non-linear relation between grey values and concentration of radioactivity, the contrast enhancement and the quenching problem are discussed. This method permits a quick and precise quantitative analysis of binding site distribution in receptor autoradiography.

Animals↗
PubMed1985

Autoradiographic identification and topographical analyses of high affinity serotonin receptor subtypes as a target for the novel putative anxiolytic TVX Q 7821.

TVX Q 7821 is a putative non-benzodiazepine anxiolytic which has a high affinity to 5-HT1 receptors. In this study some of the binding characteristics of the radiolabeled drug using rat brain cryostat sections and the autoradiographic localization of binding sites using the LKB-Ultrofilm technique have been investigated. Parallel experiments have been performed using [3H]serotonin ( [3H]5-HT). Both [3H]TVX Q 7821 and [3H]5-HT bound specifically and in a saturable manner to tissue sections, the Kd values being 6.8 and 3.7 nmol/l, respectively. Quantitative autoradiography using computer-assisted image analysis revealed a mean inhibition by TVX Q 7821 of [3H]5-HT binding of 56% in many brain areas. The inhibition ranged from 80% in the hippocampus and entorhinal area to practically none in the substantia nigra and the dorsal subiculum. Color coded autoradiograms obtained either with [3H]5-HT or [3H]TVX Q 7821 showed a nearly identical pattern of labeling with high receptor densities in the hippocampus, the entorhinal area, the septum, the interpeduncular nucleus and the dorsal raphe. However, in some brain areas striking differences in the intensity of labeling were found. [3H]5-HT but not [3H]TVX Q 7821 bound strongly in the substantia nigra, the dorsal subiculum and the globus pallidus. It is proposed that TVX Q 7821 binds to a subtype of 5-HT1 receptor (the so-called 5-HT1A sites as recently proposed). Thus, the putative anxiolytic TVX Q 7821 may provide a means for the study of the functional role of 5-HT1 receptors.

Animals↗
PubMed1985

The pattern of cortical projections from the intermediate parts of the magnocellular nucleus basalis in the rat demonstrated by tracing with Phaseolus vulgaris-leucoagglutinin.

The pattern and distribution of the cortical projections from intermediate parts of the cholinergic basal magnocellular nucleus were studied by anterogradely transported Phaseolus vulgaris-leucoagglutinin. This immunocytochemical tracing technique reveals the detailed morphology and distribution of efferents from this intermediate area in the nucleus basalis to the various areas and layers of cortex and amygdala. Major projections with a relatively high density of terminal boutons were found in layers I, II and VI of the frontal cortex, in layers V and VI of parietal and temporal areas, in the entire perirhinal and entorhinal cortices, and in the basolateral nucleus of the amygdaloid body. From the nucleus basalis area studied, few if any projections could be demonstrated to cingulate and occipital cortical regions.

Acetylcholinesterase↗
PubMed1985

The ontogenetic development of serotonin (5-HT1) receptors in various cortical regions of the rat brain.

The distribution of serotonin (5-HT1) receptors in various cortical regions of the rat brain has been examined during ontogenesis by quantitative autoradiography. An increase in binding site density between the first postnatal day and adult age was observed and could be approximated by a sigmoid shaped (logistic) growth curve. A marked heterochrony in the increase of binding site density is found in the 13 analyzed cortical regions. Binding sites develop earlier in neocortex than in allocortical areas. Fifty percent of the binding site density of adult age is reached in the motor cortex at the 9th postnatal day, followed by the primary somatosensory cortex one day later, by the medial prefrontal cortex on the 12th day, by the fascia dentata on the 14th day and by the CA 1-region on the 20th day. A detailed analysis of the frontal, medial prefrontal and hippocampal regions also shows a heterochrony within these regions. Adult values of binding site densities are also reached at different ages in the various cortical regions. The highest receptor densities were observed in the dorsal subiculum, the lowest in the primary somatosensory cortex.

Aging↗
PubMed1985

Binding of the putative anxiolytic TVX Q 7821 to hippocampal 5-hydroxytryptamine (5-HT) recognition sites.

The abilities of the putative non-benzodiazepine anxiolytic compound TVX Q 7821 in comparison to 5-HT and the 5-HT2 receptor antagonist ketanserin to displace 3H-5-HT from its binding sites in various regions of calf brain were studied. Binding affinities and capacities for 3H-5-HT were determined using membranes from different calf brain regions. Competition experiments with radiolabelled 3H-ketanserin using rat prefrontal cortex membranes were also performed. High affinity 3H-5-HT binding was found in all calf brain areas examined, with the hippocampus having the highest density of binding sites. TVX Q 7821 was a potent displacer (Ki-value 10 nmol/l) of 3H-5-HT binding in hippocampal membranes but not in membranes from other brain regions. No high affinity binding of TVX Q 7821 was found to the 5-HT receptors labelled with 3H-ketanserin. It is concluded, that TVX Q 7821 may bind preferentially to a special subtype of the 5-HT1 recognition site. Furthermore the results suggest that these sites may be involved in the mechanism of the anxiolytic action of TVX Q 7821.

Animals↗
PubMed1985

3H-TVX Q 7821: identification of 5-HT1 binding sites as target for a novel putative anxiolytic.

In order to clarify the mechanism of action of the putative nonbenzodiazepine anxiolytic TVX Q 7821 [2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1, 2-benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride], binding studies with the radio labelled compound were performed. 3H-TVX Q 7821 bound rapidly, reversibly and in a saturable manner with high affinity to calf brain structures with preference for the hippocampus (KD 1.62 nmol/l; Bmax 320 fmol/ mg protein). 3H-TVX Q 7821 binding was displaced only by 5-hydroxytryptamine and its agonists and antagonists including spiperone, but was not displaced by a variety of other neurotransmitters and drugs. The 5-HT2 receptor antagonist ketanserin was a weak displacer. The hippocampal binding sites for 3H-TVX Q 7821 were pharmacologically very similar to the 5-HT1-binding sites in this region. TVX Q 7821 is likely to be an important tool in research on functional aspects of 5-HT1 binding sites.

Animals↗
PubMed1984

TVX 2706--a new phosphodiesterase inhibitor with antiinflammatory action. Biochemical characterization.

The effects of the anti-inflammatory and analgesic drug 3-ethyl-1-(3-nitrophenyl)-2,4[1H, 3H]-quinazolindione (TVX 2706) on neuronal and glial cell culture systems including neuroblastoma X glioma hybrid cells have been studied. This compound strongly enhances the increase in intracellular levels of cyclic AMP caused by appropriate effectors in all systems tested so far. EC50 values are in the submicromolar range. The effect is apparently neither due to an increased responsiveness of the hybrid cells for an effector like prostaglandin E1 nor to an increased activity of adenylate cyclase, but to an inhibition of both low and high affinity cyclic AMP phosphodiesterases. Half-maximal inhibition of enzyme activity is obtained at 10 microM TVX 2706. The drug is at least equipotent to or more potent than some other common phosphodiesterase inhibitors. Inhibition of phosphodiesterase activity is also observed in homogenates from rat polymorphonuclear leucocytes, where the low Km-enzyme is preferentially inhibited. TVX 2706 does not interfere with the calmodulin activation of phosphodiesterase. The role of phosphodiesterase inhibition as a possible mechanism of the anti-inflammatory action of TVX 2706 is discussed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Brain serotonin receptors as a target for the putative anxiolytic TVX Q 7821.

In animal behavioral tests of anxiolytic efficacy, TVX Q 7821 was active and equipotent with diazepam, but did not produce muscle relaxation or anti-convulsant effects. The high affinity, specific binding of 3H-TVX Q 7821 to calf hippocampal membranes was displaced by serotonin (5-HT) but not by diazepam. Similarly, unlabeled TVX Q 7821 displaced 3H-5-HT but not 3H-flunitrazepam binding. Since ketanserin (a putative 5-HT2 ligand) was equally weak in displacing labeled 5-HT or TVX Q 7821, TVX Q 7821 may preferentially bind to 5-HT1, receptors.

Aggression↗
PubMed1982

Actions of antidepressant and neuroleptic drugs on ACTH- and novelty-induced behavior in the rat.

The present study deals with the effects of psychoactive drugs (neuroleptics and antidepressants) on ACTH-induced excessive grooming in the rat. The neuroleptics haloperidol and clozapine and the antidepressants amitriptyline, nomifensine and mianserin all suppressed the grooming response in a dose-dependent manner. The neuroleptic sulpiride was ineffective even at high doses. Experimental evidence is presented suggesting that the suppression of peptide-induced grooming was not the result of competing behavioral activity elicited by the drug itself. Instead it is assumed that the psychoactive drugs tested affected directly the activity of the neural substrate underlying the peptide-induced behavior. In view of the complexity of the mechanisms of action of the drugs tested it is argued that this substrate may be a more complex one than the dopamine systems as suggested before.

Adrenocorticotropic Hormone↗