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Biomedical subjects

J A Tonnaer

Publications and source records attributed to J A Tonnaer.

At least 19 recordsLinked to original sources
PubMed1992

Genomic organization, coding sequence and functional expression of human 5-HT2 and 5-HT1A receptor genes.

The family of serotonin receptors consists of at least eight distinct subtypes, divided into four classes based on their pharmacological and functional characteristics. Here we report the cloning and expression in Swiss 3T3 cells of the human 5-HT2 and 5-HT1A receptor subtypes. Both genes encode functional receptors for 5-HT, that differ considerably in genomic structure, primary amino acid sequence, pharmacology and signal transduction. The 5-HT1A receptor transfectants displayed a single high affinity site for the agonist [3H](+/-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr ([3H]8-OH-DPAT) and a pharmacological profile specific for the 5-HT1A receptor. In these transfectants, 5-HT mediated a dose-dependent inhibition of forskolin-stimulated cAMP levels. Cells expressing the 5-HT2 receptor exhibited high affinity binding for the antagonist [3H]ketanserin with a 5-HT2 receptor specific pharmacological profile. In these cells 5-HT activated phospholipase C in a dose-dependent manner. The 5-HT2 receptor displayed a genomic organization quite different from the 5-HT1A, 5-HT1B and 5-HT1D receptor subtypes. While these receptors are encoded by one single exon, the 5-HT2 receptor is encoded by three exons separated by two introns. The latter finding adds and additional molecular criterion for receptor classification.

3T3 Cells↗
PubMed1992

Enhancement of regeneration by Org 2766 after nerve crush depends on the type of neural injury.

The neurotrophic effects of the adrenocorticotropin (ACTH)-(4-9) analog Org 2766 (Met(O2)-Glu-His-Phe-D-Lys-Phe) were studied in rats recovering from a sciatic nerve crush. Org 2766 (10 micrograms/rat s.c., every 48 h) increased the number of myelinated axons reinnervating a previously denervated sciatic nerve by 32% (P less than 0.01), as assessed 13 days after crush lesioning, and facilitated recovery of sensorimotor functioning by 14% (P = 0.05), as measured by foot withdrawal after stimulation of the footsole with hot air. However, these facilitating effects were only seen if the nerve was lesioned using forceps with grooved jaws and not if forceps were used with cross-hatched jaws. Endoneural tubes and Schwann cells of the sciatic nerve appeared to be better preserved after crushing with grooved rather than cross-hatched jaws. Our data indicate that the regeneration-enhancing effects of Org 2766 are dependent on the type of injury applied to the endoneurium and endoneural tubes of the sciatic nerve and suggest that endoneural tissue may mediate the neurotrophic properties of Org 2766.

Adrenocorticotropic Hormone↗
PubMed1992

Cerebral glucose utilization during conditioned sexual arousal.

Local cerebral glucose utilization was investigated in male rats during conditioned sexual arousal. Increased glucose utilization was found in three amygdaloid nuclei after exposure to a stimulus associated with exposure to a sexually active female. No changes were observed in areas known to be of crucial importance for the expression of consummatory aspects of sexual behavior. These results corroborate and extend previous results showing a dissociation between the expression of appetitive and consummatory aspects of sexual behavior at a neural level.

Amygdala↗
PubMed1992

Characterization of the inhibitory effect of adrenocorticotropin/melanocyte-stimulating hormone-like peptides on the binding of dopamine receptor ligands to the dopamine D2 receptor in vitro.

Adrenocorticotropin (ACTH)-(1-24) decreased the binding of the dopamine D2 agonist [3H]N-n-propylnorapomorphine [3H](NPA) to the dopamine D2 receptor in rat striatal membranes in vitro. The association and dissociation of [3H]NPA to the dopamine D2 receptor was inhibited by ACTH-(1-24), suggesting an apparent competitive interaction between ACTH-(1-24) and the binding of [3H]NPA. ACTH-(1-24) was able to inhibit the binding of the dopamine D2 receptor antagonist [3H]spiperone to the dopamine D2 receptor, both in the high- and the low-affinity state. These observations suggest a G-protein-independent mechanism of action. The inhibitory effect of ACTH-(1-24) and ACTH-(7-16)-NH2 was diminished after the addition of polylysine chains, presumably via a blockade of the attachment sites for ACTH-(1-24) on the dopamine D2 receptor. The effect of ACTH-(1-24) on membrane fluidity and on the inhibition of the binding of [3H]NPA to the dopamine D2 receptor appeared to be unrelated because lowering the incubation temperature from 25 degrees C to 4 degrees C, which causes a strong decrease of membrane fluidity, did not diminish the effect of ACTH-(1-24) on the binding of [3H]NPA to the dopamine D2 receptor. Furthermore, in both young and old rats, whose membranes are reported to differ in lipid composition and membrane fluidity, ACTH-(1-24) inhibited the binding of [3H]NPA to the dopamine D2 receptor to nearly the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1991

The effect of the potential antipsychotic ORG 5222 on local cerebral glucose utilization in freely moving rats.

The effects of administration of different doses of the potential antipsychotic Org 5222 (0.01 and 0.1 mg/kg i.v.) upon local cerebral glucose utilization (LCGU) in 102 anatomically discrete brain regions of freely moving male Wistar rats were studied with the quantitative autoradiographic [14C]2-deoxyglucose technique. Glucose utilization was significantly changed after treatment with 0.01 and 0.1 mg/kg i.v. Org 5222 in two and four brain areas, respectively. Treatment with 0.01 mg/kg Org 5222 significantly reduced LCGU in the basal thalamus (the ventral posterior medial (VPM) and lateral (VPL) nuclei). After administration of 0.1 mg/kg Org 5222, significant reductions were seen in the basal thalamus (VPL and VPM) and the medio dorsal thalamic nuclei. A highly significant elevation in LCGU was observed in the lateral nucleus of the habenula. The results show that Org 5222 selectively reduced LCGU in thalamic structures and had no or minimal effect on limbic, cortical and nigrostriatal structures, suggesting that Org 5222 may have antipsychotic potential, without inducing cognitive and extrapyramidal side-effects.

Animals↗
PubMed1991

cGMP formation and phosphoinositide turnover in rat brain slices are mediated by pharmacologically distinct muscarinic acetylcholine receptors.

The cGMP response and the accumulation of inositol monophosphate (IP) induced by carbachol were compared in slices of different rat brain structures. Basal cGMP and the responses of cGMP to carbachol appeared dependent on the concentration of added Ca2+, suggesting that distinct Ca(2+)-mediated and Ca(2+)-sensitive muscarinic receptor-mediated mechanisms stimulate guanylate cyclase. Regional responses of cGMP to carbachol or to direct stimulation of guanylate cyclase with sodium nitroprusside were markedly distinct, indicating that a major proportion of guanylate cyclase in the cortex, an intermediate proportion in other forebrain regions, and only a minor proportion in the brainstem is sensitive to muscarinic receptor stimulation. The regional patterns of IP and cGMP responses to carbachol were different in the forebrain. Maximal IP accumulation was found in the cortex, whereas cGMP responses were highest in the hippocampus. Moreover, IP and cGMP formation in the hippocampus were differently antagonized by atropine, 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP), the M2-receptor subtype-preferring antagonist AF-DX 116 and the M1-selective antagonist pirenzepine. These data support the notion that the IP formation induced by carbachol in the forebrain predominantly is mediated by muscarinic receptors of the M1 subtype, and indicate the involvement of muscarinic receptors of the M3 subtype in the carbachol-induced cGMP formation.

Animals↗
PubMed1991

ACTH/MSH-like peptides inhibit the binding of dopaminergic ligands to the dopamine D2 receptor in vitro.

ACTH-(1-24) decreased the binding of the dopamine D2 receptor agonist, [3H]N-propylnorapomorphine ([3H]NPA), to rat striatal membranes in a concentration-dependent manner, with a Ki of 5 x 10(-7) M. Saturation curves for [3H]NPA binding in the presence of increasing concentrations of ACTH-(1-24) were performed. Scatchard analysis in the presence of ACTH-(1-24) revealed an increased dissociation constant (Kd), while the binding capacity (Bmax) was not affected by the peptide, suggesting an apparent competitive interaction between ACTH-(1-24) and [3H]NPA. ACTH-(1-24) also reduced the binding of the dopamine D2 receptor antagonist [3H]spiperone to striatal membranes, with a Ki of 10(-6) M. Much higher concentrations of ACTH-(1-24), up to 10(-4) M, were needed for the displacement of appropriate radiolabelled ligands from dopamine D1 receptors, serotonin 5-HT1A, serotonin 5-HT1B, muscarinic M1 acetylcholine and histamine H1 receptors. ACTH-(1-24) also inhibited the binding of [3H]spiperone to dopamine D2 receptors in membranes of the pituitary gland, the septum and the substantia nigra. ACTH-(1-39) and most ACTH fragments and analogs were less potent than ACTH-(1-24) in displacing [3H]NPA from the dopamine D2 receptor in striatal membranes. In general there was a relationship between displacing potency and chain length. ACTH-(7-16)-NH2 and benzyloxycarbonyl-ACTH-(8-16)-NH2, however, were more potent than ACTH-(1-24) in reducing the binding of [3H]NPA to dopamine D2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Ultrastructure of aberrant serotonin-immunoreactive fibers in the caudate putamen complex of the aged rat.

Degeneration of neurons in the central nervous system is associated with morphological changes. Previous observations made at the light microscopical level indicated degeneration of serotonin-immunoreactive (IR) fibers in the aged rat brain. In this study, a comparison at the ultrastructural level was made between serotonin-IR normal thin and aberrant swollen varicose fibers in the caudate-putamen complex of the aged rat. Ultrastructural features such as the size and content of the thin varicose fibers resembled those in the caudate-putamen complex of the young rat as reported by others. The aberrant profiles were swollen, reaching a size of 6 microns. Their vesicles varied in size and were no longer uniformly round. Moreover, distorted mitochondria and membrane-filled vacuolelike structures were a common feature of the aberrant profiles. These changes are indicative of a degenerative process and give further evidence that, whereas many serotonergic fibers are preserved at high age, other serotonergic fibers are degenerating in the caudate-putamen complex of the aged rat.

Aging↗
PubMed1991

Morphological, neurochemical, and behavioral studies on serotonergic denervation and graft-induced reinnervation of the rat hippocampus.

A procedure was developed to conduct simultaneously immunocytochemical and neurochemical studies on the serotonergic system in adjacent 300-micron-thick slices of rat hippocampus. This procedure was applied to correlate morphological (innervation pattern and density), neurochemical (5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake and release) and behavioral (spatial learning) effects of neurotoxin-induced denervation and reinnervation by grafting fetal mesencephalic raphe cells. Intracerebroventricular injections of a low dose of 5,7-dihydroxytryptamine caused a discrete serotonergic denervation of the hippocampus. Eleven months after lesioning, 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake capacity were decreased by 50-60%. By this time, the residual fibers displayed an enhanced vulnerability towards K(+)-induced depolarization. Grafting of a fetal raphe cell suspension resulted in a reinnervation of the host hippocampus. The pattern of reinnervation was comparable to control innervation and the density was supranormal at the level of the graft. As observed semiquantitatively, the innervation density decreased with distance from the core of the graft. Neurochemical studies showed that the fibers were capable of synthesizing, metabolizing and releasing 5-hydroxytryptamine. The turnover of 5-hydroxytryptamine in both the denervated and the reinnervated hippocampus was comparable to that in control tissue. Previous behavioral testing of the denervated and of the denervated and implanted animals did not reveal any effect on spatial learning, either in an individual or in a social test paradigm. The latter data substantiate the notion that interference with the hippocampal serotonergic innervation does not hamper adequate spatial learning.

5,7-Dihydroxytryptamine↗
PubMed1990

Aging and regenerative capacity of the rat serotonergic system. A morphological, neurochemical and behavioral analysis after transplantation of fetal raphe cells.

Morphological dissimilarities between the brains of young (3 months) and aged (28 months and older) rats were demonstrated using serotonin-immunocytochemistry. A degeneration of the serotonergic system, noted as a decreased innervation and the appearance of enlarged or swollen varicosities, was observed particularly in the frontoparietal cortex, and the neostriatum of the aged rat brain. No direct relationship between this aberrant morphology and decrease in density of serotonin-innervation was found as we demonstrated a decline in fiber density without the appearance of aberrant serotonergic fibers in the hippocampus. HPLC analysis revealed that serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in the frontoparietal cortex, hippocampus and raphe area were increased in the aged rat, while the 5-HT level in the caudate-putamen complex was not different from the young adult rat. The ratio 5-HIAA/5-HT, indicative of 5-HT turnover, appeared increased in the frontoparietal cortex, sensoric part, the caudate-putamen and the raphe area, while this ration in the frontoparietal cortex, motoric part and the hippocampus was not altered in the aged rat. Behavioral screening revealed a decrease spatial performance of aged males in a Morris Water-Maze task. To investigate whether the age of the host recipient was of influence on the regenerative capacity, a fetal raphe cell suspension of embryonic day E 15 was implanted in the caudate-putamen of young adult as well as aged rats. Neither differences in survival of the serotonergic cells nor in fiber outgrowth between both groups appeared five weeks after transplantation. Subsequently, transplantation of raphe cells in the hippocampus of young adult rats, after lesioning the hippocampal serotonergic innervation with 5,7-DHT, was performed to compare behavioral, morphological and neurochemical effects of the implants. It appeared that 11 months after transplantation the serotonergic innervation of the previously denervated hippocampus was greatly restored. There was a striking resemblance between the immunohistochemical and neurochemical data with respect to the increase in the amount of newly formed serotonergic fibers, the increase in uptake of [3H]-5-HT and in 5-HT and 5-HIAA levels. Also the behavior of lesioned and lesioned + transplanted males was rather similar to controls. In the behavioral tests we were mainly interested in hippocampal functioning, therefore orientation was of our prime interest. The other behavioral tests were only to confirm that the possible changes were linked to hypothalamic or extra-hypothalamic functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1990

Neurochemical studies with the potential antipsychotic compound trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate.

trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (Org 5222) has dopamine D2 antagonistic and negligible anticholinergic properties of the classical neuroleptic haloperidol. In addition it combines the strong antiserotonergic and antihistaminergic properties of chlorpromazine and clozapine with the potent dopamine D-1 antagonistic properties of Sch 23390 (R-(+)-delta-chloro-2,3,4,5-tetrahydro-3-methyl-5- phenyl-1H-3-benazepin-7-ol(Z)-2-buteneoate). This in conjunction to its behavioural properties, warrants clinical testing in psychotic patients.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

The neuropeptide, Org 5878 (desenkephalin-gamma-endorphin, DE gamma E), affects local cerebral glucose utilization in freely moving rats.

The effect of the antipsychotic peptide, Org 5878 (desenkephalin-gamma-endorphin, beta-endorphin-(6-17), on local cerebral glucose utilization was studied in freely moving male Wistar rats. Org 5878 (20 micrograms/kg, i.v.) or saline were given acutely and local cerebral glucose utilization was measured in 116 brain structures. Glucose uptake was not altered by Org 5878 in most brain areas, including areas of the nigrostriatal system, the cortex and the thalamus. However, significant reductions in glucose uptake were observed in the ventral tegmental area, the diagonal band complex, the hippocampus, the amygdala, the interpeduncular nucleus, the reticular nucleus of the thalamus and the cerebellum. These results indicate that the nigrostriatal and cortico-thalamic systems remain unaffected but the activity of the mesolimbic ventral tegmental area and of major target areas of cholinergic basal forebrain structures is selectively reduced following Org 5878 administration. It is concluded that the effect of Org 5878 on local cerebral glucose utilization is distinct from and more selective than that of antipsychotics currently used in the clinic.

Animals↗
PubMed1989

Selective fimbria lesions impair acquisition of working and reference memory of rats in a complex spatial discrimination task.

It has been reported that transections of the fimbria-fornix or lesions of the hippocampus selectively impair spatial working memory. Disruptive effects of these lesions on reference memory performance, however, have also been reported. We studied the effects of selective fimbria lesions on the acquisition of a complex spatial discrimination in the cone field. The cone field task is a place learning task that permits the simultaneous assessment of working and reference memory performance. Reproducible bilateral stereotaxic lesions were made by knife-cuts parallel to the midline. Sham lesions consisted of similar knife-cuts that were restricted to the overlying tissue. The rats were randomly started from 1 of 4 positions in order to prevent the development of a fixed food search pattern. On both memory components, fimbria-lesioned rats made about twice as many errors as the sham-lesioned and intact subjects, even after extensive training. Transection of the fimbria caused pronounced cholinergic denervation, predominantly at the more ventral part of the hippocampus, as indicated by reduced acetylcholinesterase histochemistry. Our results suggest a major role of the cholinergic innervation of the ventral hippocampus in spatial discrimination.

Acetylcholinesterase↗
PubMed1989

Binding of the neurotrophic peptide Org 2766 to rat spinal cord sections is affected by a sciatic nerve crush.

The binding of the neurotrophic peptide, [3H]Org 2766 (55 nM), to rat spinal cord sections was studied, employing quantitative autoradiography. The binding was unevenly distributed over spinal cord structures and was displaceable by non-labelled Org 2766 to a limited extent (35%). Binding could not be displaced by the opiate antagonist, naloxone, indicating that [3H]Org 2766 binding sites are distinct from opiate receptors. However, the exact nature of the binding sites remains to be elucidated. A marked left-right difference in [3H]Org 2766 binding in the dorsal horns of the spinal cord at level L2 was observed, 6 days after unilateral crush lesioning of the sciatic nerve. No such effect was found at level T10. After 28 days, when sensorimotor functioning had completely recovered, the [3H]Org 2766 binding pattern was comparable to that in sham-operated rats again. It is suggested that Org 2766 binds to axonal sprouts or glia in the dorsal horn of the spinal cord.

Adrenocorticotropic Hormone↗
PubMed1989

Similarities between aberrant serotonergic fibers in the aged and 5,7-DHT denervated young adult rat brain.

Recent morphological observations have suggested neurotransmitter specific degeneration of amongst others, the serotonergic system in the aged rat brain. However, morphological studies can only give a static picture of the events that take place over a period of several months. In the present study we used an experimental model in which degeneration of the serotonergic system in the young adult rat brain was produced on a short time scale. Morphological changes were studied 2 h and 1 or 14 days after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT). Non-specific damage and severe depletion of serotonergic fibers was observed in the immediate surroundings of the injection site, representing the effects of high local concentrations of 5,7-DHT. Sometime after injection swollen varicosities and dilated non-varicose fibers were observed. Fourteen days after the 5,7-DHT treatment cluster-like fibers appeared. It is argued that these swollen and crumpled fiber knots are slowly degenerating fibers. A comparison is made with the abnormal serotonergic fibers in the aged rat brain and it is concluded that these aged abnormal fibers represent axonal degeneration of the serotonergic system in the senescent rat brain.

5,7-Dihydroxytryptamine↗