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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
PubMed1998

Laryngeal abductor reinnervation with a phrenic nerve transfer after a 9-month delay.

BACKGROUND: Successful restoration of laryngeal abductor function, using the phrenic nerve, has been described in the cat model in the acute phase. However, in clinical practice there is usually a considerable delay between injury to the RLN and presentation for treatment. Delayed reinnervation therefore would be more suitable in clinical practice. OBJECTIVE: To test the feasibility of delayed selective abductor reinnervation following transection of the recurrent laryngeal nerve (RLN). MATERIALS AND METHODS: In 12 cats, the right RLN was severed. Nine months later, the phrenic nerve was anastomosed to the distal RLN stump with all its branches directed toward the posterior cricoarytenoid muscle. For 10 weeks after the reconstruction, electromyography and videolaryngoscopy were performed weekly. Finally, histological analysis of the RLN was performed. RESULTS: Evaluation was possible in 11 cats. Reinnervation of the right posterior cricoarytenoid muscle with the phrenic nerve occurred in 10 cats following nerve anastomosis, but results of videolaryngoscopy showed adequate to good abduction in only 4 cats. The main limiting factor was reduced mobility of the cricoarytenoid joint. Evidence of spontaneous subclinical reinnervation after the delay was observed in 7 cats but apparently did not impede the surgical reinnervation. CONCLUSIONS: Delayed selective laryngeal abductor reinnervation was feasible, but function recovery was less successful than if performed immediately. Future investigations should concentrate on early determinants of spontaneous restoration of function to allow early selection of patients who are eligible for reinnervation surgery.

Anastomosis, Surgical↗
PubMed1997

Selective laryngeal reinnervation with separate phrenic and ansa cervicalis nerve transfers.

OBJECTIVE: To perform selective reinnervation of the laryngeal abductor and adductor muscle groups after injury to the recurrent laryngeal nerve, recovering laryngeal function without impairment by synkinesis. DESIGN: Ten cats underwent the surgical procedure. To reinnervate the posterior cricoarytenoid muscle (abductor), a phrenic nerve graft was anastomosed to the main trunk of the recurrent laryngeal nerve. The adductor branch was severed, and the proximal stump was buried in the posterior cricoarytenoid muscle. The sternohyoid branch of the ansa cervicalis was anastomosed to the distal stump to reinnervate the adductor muscle group. After a period of 10 weeks, the laryngeal function was evaluated with videolaryngoscopy and electromyography of the posterior circoarytenoid and vocalis muscles. RESULTS: Of the 10 cats, 9 could be evaluated. Laryngeal abductor function was comparable with the unaffected side in the 9 cats. During respiratory distress conditions, a minor compromise of the maximal abduction was observed in 5 cats. Phonation was not tested, but spontaneous adduction during expiration was seen in all cats. Reflex closure on ipsilateral, supraglottic, tactile mucosal stimulation was seen in only 2 cats. In each cat, evidence of nerve regeneration and reinnervation of both muscle groups was established with electromyography, electrical stimulation, and histological examination. CONCLUSIONS: Using this selective reinnervation procedure, good laryngeal function can be achieved in the cat model, which may be applicable in humans. By reinnervation of the vocalis muscle, muscle tonus is achieved, which is expected to improve voice quality. Using this procedure, however, no active reflex closure may be expected.

Animals↗
PubMed1996

Laryngeal abductor function after recurrent laryngeal nerve injury in cats.

OBJECTIVE: To determine the influence of severity of neural injury of t he recurrent laryngeal nerve on recovery of laryngeal abductor function and the importance of synkinesis. DESIGN: The recovery of laryngeal abductor function was studied in 30 cats after crushing (second-degree injury) or transection followed by neurorrhaphy (fifth-degree injury) of the recurrent laryngeal nerve, with a reinnervation period of 10 weeks. MAIN OUTCOME MEASURES: Recovery of laryngeal abductor function was evaluated by videolaryngoscopy of spontaneous laryngeal abduction during respiration and electromyography of the posterior cricoarytenoid and vocalis muscles. Neural lesions were applied unilaterally, and recovery of laryngeal function was compared with the contralateral unimpaired hemilarynx. Reinnervation was confirmed by histologic examination. RESULTS: After the recurrent laryngeal nerve was crushed, laryngeal abductor function was similar to normal after a 10-week reinnervation period in 19 of the 20 cats; after neurorrhaphy, no notable recovery of laryngeal abduction resulted in any of 10 cats. Electromyographic recordings disclosed synkinesis after neurorrhaphy and recovery of normal activity patterns after crush injuries. CONCLUSIONS: Severity of neural injury to the recurrent laryngeal nerve influences the recovery of laryngeal abductor function. Damage to the endoneurium leads to misdirection of regenerating axons, inappropriate reinnervation, and synkinesis. No effective laryngeal function can then be expected.

Animals↗
PubMed1995

Melanocortin analogue Org2766 binds to rat Schwann cells, upregulates NGF low-affinity receptor p75, and releases neurotrophic activity.

Binding of the stable melanocortin(4-9) analogue, Org2766 [Met(O2)-Glu-His-Phe-D-Lys-Phe] to cultured rat sciatic nerve Schwann cells was demonstrated using a biotinylated derivative in semiquantitative histochemical and CELISA assays. Org2766 bound to Schwann cells, but not to fibroblasts, and was displaced maximally by unlabeled Org2766, alpha-MSH and ACTH(1-24). Displacement of Org2766 from the binding sites was considerably reduced by N- and C-truncation of the peptide. Specific binding of Org2766 was also demonstrated in the immortal rat Schwann cell line SCL4.1/F7 and was more pronounced in cells displaying a differentiated morphology. Org2766 and alpha-MSH increased cyclic AMP content of Schwann cells but neither stimulated DNA synthesis when applied alone. However, in the presence of a priming (subthreshold) concentration of the mitogen, cholera toxin, Org2766 and alpha-MSH caused a delayed increase in DNA synthesis. Org2766 did not modulate the expression of several differentiation-related Schwann cell markers. However, Org2766 increased immunoreactivity for p75 low-affinity NGF receptor on Schwann cells and evoked the release of neurotrophic factor(s) that synergized with NGF in stimulating neurite outgrowth in rat DRG neurons. The results indicate that Schwann cells are a primary target for the action of Org2766 and provide evidence for an indirect mechanism by which melanocortins might stimulate neurite sprouting in regenerating peripheral nerve axons.

Adrenocorticotropic Hormone↗
PubMed1993

Topography and characteristics of specific binding sites for non-opioid gamma-type endorphins in the rat brain as studied by autoradiography with [35S]Met-desenkephalin-gamma-endorphin.

An in vitro autoradiographic study was performed to characterize specific rat brain binding sites for non-opioid neuroleptic-like gamma-type endorphins, using [35S]Met-des-enkephalin-gamma-endorphin ([35S]Met-DE gamma E; [35]S-beta-endorphins(5-17)) with high specific activity as radioligand. The binding sites appeared to be confined to rat forebrain regions, e.g., orbital cortex, frontal cortex, cingulate cortex, piriform cortex, nucleus accumbens, amygdala, mediodorsal nucleus of the thalamus and arcuate and periventricular nuclei of the hypothalamus. These regions are part of the mesocorticolimbic feedback circuit. Densitometric analysis of the autoradiographs revealed that the density of the binding sites was highest in the mediodorsal nucleus of the thalamus and the amygdala. Concentration-dependent displacement of [35S]Met-DE gamma E (500 pM) with DE gamma E yielded an IC50 of 0.6 nM whereas DE alpha E (beta-endorphin(6-16)) had an IC50 of 210 nM. Various endorphins, sharing the gamma-endorphin C terminus, displaced [35S]Met-DE gamma E to the same extent as non-labelled DE gamma E (at 10(-6) M) whereas non-endorphin peptides did not show displacing capacity. Possible relationships of the binding sites with opioid receptors were investigated. DAMGO (mu) and DPDPE (delta) displaced [35S]Met-DE gamma E to some extent at 10(-6) M whereas U69,593 (kappa) was inactive, suggesting that the binding sites for gamma-type endorphins may resemble mu- and delta-opioid receptors in some aspects. Similarly, relationships with dopamine receptors were investigated. Haloperidol partially displaced [35S]Met-DE gamma E whereas sulpiride, SKF38,393 and 3-PPP at 10(-6) M did not induce significant displacement. Thus, binding sites are distinct from dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1993

Selective laryngeal abductor reinnervation in cats using a phrenic nerve transfer and ORG 2766.

Reinnervation of the recurrent laryngeal nerve following nerve injury often leads to laryngeal synkinesis. Selective reinnervation of adductor and abductor muscles might be able to avoid synkinesis. This study presents the results of selective abductor reinnervation in cats, using a phrenic nerve transfer to the recurrent laryngeal nerve and directing all reinnervating axons toward the abductor muscle. Simultaneously, a blind, placebo-controlled, pilot study was performed to evaluate the capacity of ORG 2766, administered subcutaneously (25 micrograms/kg per 48 hours), to facilitate reinnervation by stimulation of axon sprouting. Reinnervation surgery was performed in 10 cats. Postoperative evaluation included videolaryngoscopy, electromyography, histological examination, and quantification of reinnervating axons. Nine cats could be evaluated, of which eight demonstrated electromyographic and laryngoscopic activity as soon as 6 weeks following surgery. The one cat showing no abduction was found to have an inadequate nerve anastomosis and was marked as a surgical failure. After 10 weeks, near-normal or more than normal abduction was seen in the eight cats, and histological proof of reinnervation was obtained in seven of them; one cat could not be evaluated histologically owing to unsuccessful fixation. Although no conclusive evidence was obtained concerning the effect of ORG 2766, the tendencies found warrant further experiments with this compound on laryngeal reinnervation.

Adrenocorticotropic Hormone↗
PubMed1993

Muscarinic receptor regulation and 2nd messenger responses in rat neocortex cultures.

Primary cultures of dissociated cerebral cortex cells were used to characterize the muscarinic acetylcholinergic receptors (mAChR) present and to study receptor down-regulation and receptor mediated 2nd messenger responses induced by muscarinic agonists. Binding of the hydrophilic antagonist [3H]N-methyl scopolamine ([3H]NMS) to the cultured cells was saturated after one hour at 4 degrees C with a Kd of 93 pM and a Bmax of 958 fmol/mg protein. Competition binding studies with several antagonists and agonists indicated that the mAChR present in the culture were of a mixed M1/M3 subtype. The number of muscarinic receptors at the cell surface decreased by 60% after one hour pre-incubation of the cultures with 10 microM carbachol or oxotremorine. After down-regulation with carbachol affinity for pirenzepine was decreased, while low affinity sites for 4-DAMP were lost, indicating that especially M1 subtypes are sensitive to this type of regulation. Carbachol and oxotremorine-M induced a 2-3 fold increase in phosphatidyl inositide (PI) turnover, which was blocked with high affinity by both pirenzepine and 4-DAMP. Down-regulation of the mAChR and stimulation of PI-turnover by agonists with different potency and intrinsic activity appeared highly correlated. These data suggest that activation of the PI second-messenger system is involved in the desensitization and down-regulation of the muscarinic acetylcholine receptor.

Animals↗
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↗