Biomedical subjects

T Dennis

Publications and source records attributed to T Dennis.

At least 19 recordsLinked to original sources

PubMed1995

Antidepressants reverse the olfactory bulbectomy-induced decreases in splenic peripheral-type benzodiazepine receptors in rats.

The present study investigated the effects of 21-day administration of clorgyline (1 mg/kg/day), desipramine (10 mg/kg/day) or paroxetine (10 mg/kg/day) on peripheral-type benzodiazepine receptors in rat peripheral tissues following bilateral olfactory bulbectomy. Thymus and spleen weights decreased as a result of bulbectomy. Subsequent antidepressant drug administration had no further effects on the weights of thymus glands but increased those of spleens. In thymus glands, higher densities of peripheral-type benzodiazepine receptors were observed in medulla than in cortex; no significant variations were observed following bulbectomy or antidepressant drug administration. In spleen, higher densities were observed in white pulp than in red pulp. The bulbectomy-induced decreases in binding densities observed in both regions were reversed following administration of antidepressants. Adrenal peripheral-type benzodiazepine receptors were not altered by bulbectomy or subsequent treatment with clorgyline or desipramine while paroxetine upregulated these receptors. No changes in kidney peripheral-type benzodiazepine receptors were observed. The present study confirms that cell lines of the rat immune system possess high densities of peripheral-type benzodiazepine receptor binding sites and further support the contention that, following olfactory bulbectomy, rats may present an antidepressant-reversible immunitary dysfunction.

Animals↗

PubMed1995

Effect of acute and prolonged tianeptine administration on the 5-HT transporter: electrophysiological, biochemical and radioligand binding studies in the rat brain.

In the present study, in vivo extracellular unitary recordings, in vitro [3H]5-HT uptake and [3H]cyanoimipramine binding assays were used to assess the effect of acute and prolonged administration of the putative antidepressant tianeptine, on the 5-hydroxytryptamine (5-HT) transporter. Microiontophoretic application of tianeptine onto dorsal hippocampus CA3 pyramidal neurons, as well as its intravenous administration (2 mg/kg), increased their firing frequency. Following intracerebroventricular administration of 5,7-dihydroxytryptamine, the activation induced by the microiontophoretic application of tianeptine remained unchanged, thus suggesting that the 5-HT carrier is not involved in this effect. Furthermore, in spite of its activating effect on CA3 pyramidal neuron firing frequency, the intravenous administration of tianeptine did not alter the time of recovery of these neurons from microiontophoretic applications of 5-HT, an index of 5-HT uptake activity. In keeping with this observation, the acute administration of tianeptine did not change the effectiveness of the 5-HT reuptake blocker paroxetine (1 mg/kg, i.v.) in prolonging the suppressant effect of microiontophoretically-applied 5-HT. However, in rats that had received tianeptine for 14 days (20 mg/kg/day, s.c.), the recovery time from the suppressant effect of microiontophoretic applications of 5-HT was reduced by 40% and the effectiveness of paroxetine (1 mg/kg, i.v.) was decreased. These effects were no longer observed following a 48 h washout period. In a second series of experiments, the ability of tianeptine to interfere with the uptake blocking capacity of paroxetine was assessed in vitro, using hippocampal slices obtained from rats that had been treated with tianeptine for 14 days (20 mg/kg/day, s.c.; by minipump).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Antidepressant-induced modulation of GABAA receptors and beta-adrenoceptors but not GABAB receptors in the frontal cortex of olfactory bulbectomised rats.

The effects of prolonged administration of antidepressant drugs, belonging to three different classes, on high-affinity GABAA receptor, GABAB receptor and beta-adrenoceptor binding parameters were determined in the frontal cortex of olfactory bulbectomised rats. Clorgyline (1 mg/kg/day), paroxetine (10 mg/kg/day) or desipramine (10 mg/kg/day) were administered for 21 days via subcutaneous osmotic minipumps implanted in the scapular region 7 days after bulbectomy. Cortical GABAA receptor densities, defined with [3H]gamma-aminobutyric acid ([3H]GABA), were significantly increased following bulbectomy. This effect on Bmax values was reversed by all three antidepressant drugs. GABAB receptor densities decreased slightly after bulbectomy. Chronic antidepressant administration had no effect on GABAB receptor binding parameters. Olfactory bulbectomy did not induce any changes in cortical beta-adrenoceptor binding parameters determined with [3H]CGP-12177 ((-)-4-(3-t- butylamino-2-hydroxypropxy)- [5,7-3H]benzimidazol-2-one). However, prolonged administration of all three antidepressant drugs induced a downregulation of beta-adrenoceptors. The results of the present study confirm the involvement of cortical GABAA rather than GABAB receptors in the olfactory bulbectomy animal model of human depression. Moreover, the data further support the hypothesis that a decrease in function of the GABAA receptor complex could play a role in the therapeutic effects of antidepressant treatments.

Adrenergic beta-Antagonists↗

PubMed1992

Quantitative autoradiographic distribution of calcitonin gene-related peptide (hCGRP alpha) binding sites in the rat and monkey spinal cord.

Calcitonin gene-related peptide (CGRP) has been implicated in various spinal functions on the basis of its presence in the substantia gelatinosa and motoneurons and the biological effects induced by intrathecal CGRP injections. We investigated here the comparative distribution of [125I]hCGRP alpha binding sites in various segments of the rat and monkey spinal cord. The immunocytochemical localization of CGRP-like material in rat spinal cord was also evaluated for comparison. In the rat spinal cord, high densities of [125I]hCGRP alpha binding sites were observed in lamina I, in a U-shaped band that included lamina X and the medial parts of laminae III-IV and in the intermediolateral and intermediomedial nuclei. The substantia gelatinosa (lamina II) contained relatively lower, but still significant, densities of [125I]hCGRP alpha binding sites, while the ventral horn showed low amounts of specific labeling. CGRP-like immunoreactive fibers, on the other hand, were heavily concentrated in laminae I-II and in the reticulated portion of lamina V of the dorsal horn. Immunoreactivity to CGRP antiserum was also noted in fibers around the central canal and in a number of motoneurons of the ventral horn. In the monkey spinal cord, [125I]hCGRP alpha binding sites were present in lamina I in a U-shaped band that included lamina X and the medial portions of laminae V-VI. Relatively low levels of [125I]hCGRP alpha binding were detected in laminae II to IV of the dorsal horn, while the ventral horn was more enriched with specific [125I]hCGRP alpha binding sites. Thus, it appears that the autoradiographic distribution of [125I]hCGRP alpha sites is species dependent in the spinal cord. Additionally, some differences are observed between the localization of [125I]hCGRP alpha binding sites and immunoreactive material in the rat spinal cord. These differences may be relevant to the purported roles of CGRP-like peptides in spinal functions such as nociception, control of sympathetic output, and motor control.

Animals↗

PubMed1992

A comparison of knowledge of medical students and practicing primary care physicians about cardiovascular risk assessment and intervention.

BACKGROUND: Heart attack and stroke are still prevalent causes of death and disability in the U.S. adult population (1, 2). Studies (3-9) have shown that modification of hypertension, smoking, and hypercholesterolemia can reduce risks for atherosclerosis and subsequent cardiovascular events. Therefore, it is important that physicians be skilled in assessing and modifying patients' overall cardiovascular risk. This study compares acquired knowledge of second-year medical students about cardiovascular risk assessment with knowledge in a selected group of practicing primary care physicians, who are members of the medical school's clinical faculty, using a new experimental testing technique called the tailored response test (TRT). METHODS: Students performed a structured cardiovascular risk intervention on a patient in primary care clinics. Their acquired knowledge was then tested using the TRT, which contained 43 discrete judgments about a clinical case. Test scores of students and faculty were compared. RESULTS: Both students and faculty demonstrated knowledge about the most important risk factors, appropriate screening tools, and interventions. However, the selected physicians did not demonstrate knowledge of certain important risk assessment and intervention recommendations, based on national standards. Only 38% of faculty and 27% of students were aware that a "fasting" serum cholesterol is not needed for screening, 30% of faculty believed that if cholesterol was over 300 they would "probably prescribe medicine" before other intervention strategies were tried, and 32% of faculty and 30% of students would order a screening chest X-ray, which is incorrect in the case history. CONCLUSIONS: The TRT, in contrast to self-report surveys, demonstrates that important cardiovascular risk assessment and intervention knowledge, with implications for cost effectiveness in health care delivery, has not penetrated to a selected group of physicians who are members of the medical school's clinical faculty and therefore serve as role models for medical students. This is disturbing, in light of current emphases on cost effectiveness in health care. Greater undergraduate curricula and CME emphasis on cardiovascular preventive practice is needed, such that almost 100% of students and faculty demonstrate knowledge, and practice, of preventive medicine according to national standards. In turn, groups developing national standards are enjoined to design and implement effective approaches for disseminating these recommendations.

Cardiovascular Diseases↗

PubMed1991

Calcitonin gene-related peptide (hCGRP alpha) binding sites in the nucleus accumbens. Atypical structural requirements and marked phylogenic differences.

The distribution of [125I]hCGRP alpha binding sites was studied in tissue sections from rat brain and, at the level of the nucleus accumbens in the brains of 6 other species. In the rat, very high levels of binding were found in the nucleus accumbens, the amygdaloid complex and mammillary body while high amounts were localized to the superficial layers of the superior colliculus, temporal cortex, cerebellum (molecular layer), frontal cortex and inferior olive. Moderate densities of [125I]hCGRP alpha binding were observed in the medial geniculate nucleus, inferior colliculus and substantia nigra. Regional competition studies in rat brain showed that salmon calcitonin was almost as effective as hCGRP alpha in competing for [125I]hCGRP alpha binding sites in the nucleus accumbens but was mostly inactive in other regions such as the mesolimbic cortex and the striatum. On the basis of their atypical sensitivity to salmon calcitonin, [125I]hCGRP alpha binding sites in the rat nucleus accumbens, which appear between postnatal days 4 and 7, do not seem to correspond to either the CGRP1 or CGRP2 receptor subtypes. Marked species differences were observed in the distribution of [125I]hCGRP alpha binding sites, especially in the nucleus accumbens. In the mouse, low densities of hCGRP alpha sites were observed in striatum and fronto-parietal cortex while low to moderate levels were found in the medial and posterior aspects of the nucleus accumbens. A similar distribution was seen in the guinea pig brain albeit of generally higher density. In the rat, very high amounts of [125I]hCGRP alpha binding were seen in the nucleus accumbens while lower levels were found in the striatum and certain cortical areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1990

Influences of marital status and parental status on the professional choices of physicians about to enter practice.

The trend toward increasing numbers of working women may alter the ways both men and women physicians structure their professional lives. The 1987 graduates of residency and fellowship programs at the University of Minnesota Medical School--Minneapolis were surveyed in June 1987 about professional plans and factors that led to their decisions. The women expected that their spouses would contribute half of their family's income, whereas the men expected that they would be largely responsible for their family's income. The married women with children planned on working fewer hours than did other physicians. Family structure may play an important role in preventing the convergence of men and women physicians' personal incomes or working hours.

Career Choice↗

PubMed1990

hCGRP8-37, a calcitonin gene-related peptide antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery.

The C-terminal fragment of human calcitonin gene-related peptide (CGRP), hCGRP8-37, fails to induce any biological activity in a variety of isolated tissues and behavioral assays even though it possesses nanomolar affinity for [125I]hCGRP alpha binding sites in the central nervous system and peripheral membrane preparations. However, hCGRP8-37 displays relatively potent, competitive antagonist properties toward the action of native hCGRP alpha in guinea pig atrial and ileal preparations and on the central nervous system-mediated inhibition of CGRP on food intake. On the contrary, in the rat vas deferens the antagonistic potency of hCGRP8-37 was much weaker and was ineffective against CGRP-induced hyperthermia after i.c.v. injection. Such evidence suggests the existence of at least two classes of CGRP receptors, the first (CGRP1) being sensitive to the antagonist properties of hCGRP8-37, whereas the second (CGRP2) is not. The use of hCGRP8-37 should greatly facilitate the characterization of the physiological roles of CGRP-like peptides, especially those which are mediated via the activation of CGRP1 receptors.

Animals↗

PubMed1989

Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand [3H]PK 14105.

The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with [3H]PK 14105. In thymus sections, [3H]PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands.

Animals↗

PubMed1989

Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity.

The radioligand binding characteristics and in vitro biological activities of human calcitonin gene-related peptide (hCGRP) homologs, analogs and fragments have been tested in a variety of preparations in order to determine the structural requirements of the calcitonin gene-related peptide (CGRP) receptor. The ligand selectivity profile observed in this study suggests that [125I] hCGRP binding sites present in rat brain and spleen are similar. The high affinity of the analogs [Cys(ACM)2.7]hCGRP and cyclo2.7 [Asp2, Lys7]hCGRP indicates that the disulfide bridge between positions 2 and 7 is not essential for the binding of the ligand to the CGRP receptor. On the other hand, the lack of affinity of various N-terminal fragments in the binding assays demonstrates the importance of amino acids 9-37 in maintaining appropriate receptor recognition. The existence of CGRP receptor subtypes is supported by data obtained in various in vitro bioassays. For example, the linear analog, [Cys(ACM)2.7]hCGRP, which retained high potency in the rat vas deferens bioassay displayed no agonistic activity in the right and left guinea pig atrial preparations. Additionally, the C-terminal fragment hCGRP 12-37 possessed some antagonist properties in atrial but not vas deferens preparations. Thus, it appears that it is possible to differentiate between CGRP receptor subtypes on the basis of differential agonistic (e.g.[Cys(ACM)2.7]hCGRP) and antagonistic (e.g., hCGRP 12-37) potencies in various isolated tissues. Moreover, the weak but significant antagonistic properties of hCGRP 12-37 may be most useful in order to design more potent CGRP receptor antagonists.

Animals↗

PubMed1988

Imaging of human brain lesions with an omega 3 site radioligand.

The topography and magnitude of increase in peripheral type benzodiazepine binding sites (omega 3 sites) was investigated autoradiographically in the brains of patients with ischemic cerebrovascular disease, with multiple sclerosis, and with malignant glioma. 3H-PK 11195, a selective omega 3 site ligand, was employed. A manyfold increase in omega 3 site density was observed in all these disease states; this increase reflects macrophage invasion or glial proliferation or both as demonstrated by neuropathological studies carried out in parallel. There was an excellent spatial correlation between increased omega 3 site densities and extent of the lesion histologically. Specifically, an elevated density of omega 3 sites was observed in the plaques of demyelination in multiple sclerosis patients, in the periphery of infarcted zones in stroke patients, and throughout tumor in patients with grade IV astrocytomas. As our approach is applicable to both tomographic (in vivo) and autoradiographic investigations, imaging of omega 3 sites may be considered for the detection and monitoring of the natural evolution of many disorders of the human central nervous system.

Adult↗

PubMed1988

Lack of correlation between DST results and urinary MHPG in depressed inpatients.

Abnormalities of noradrenaline metabolism and of the activity of hypothalamic-pituitary adrenal axis (HPA) have been reported in depression. To study the possible relationship between these 2 parameters, urinary excretion of 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) and Dexamethasone Suppression Test (DST) were analyzed in 58 depressed patients. A positive correlation was found between the age of depressed patients and 24-h urinary excretion of MHPG. Twenty-two patients (38%) were DST non suppressors. Pre-DST plasma cortisol levels were significantly higher in non suppressors than suppressors. No difference was found however between urinary MHPG levels in suppressors and non suppressors. There was no correlation between pre-DST plasma cortisol and levels of urinary excretion of MHPG. These results do not support the hypothesis of a relationship between these 2 parameters. However, when depressed patients were separated into two groups according to urinary excretion of MHPG ("high MHPG" and "low MHPG"), the "high MHPG" group included significantly more non suppressors then the "low MHPG" one. This result is not sufficient to demonstrate of link between HPA system activity and central noradrenaline metabolism.

Adult↗

PubMed1988

Changes in the distribution of physicians in rural areas of Minnesota, 1965-85.

The purpose of this study was to assess changes in the physician-population ratio in non-SMSA Minnesota counties between 1965 and 1985 using county specific data published by the American Medical Association. The physician-population ratio actually decreased by 2 per cent for primary care physicians and by 11 per cent for family practitioners in the non-SMSA counties. The large increase in the number of physicians in Minnesota has not translated into improved access to primary care physicians in Minnesota's rural areas.

Humans↗

PubMed1988

Distribution of central omega 1 (benzodiazepine1) and omega 2 (benzodiazepine2) receptor subtypes in the monkey and human brain. An autoradiographic study with [3H]flunitrazepam and the omega 1 selective ligand [3H]zolpidem.

The distribution of the central omega 1 (benzodiazepine1; BZD1) and omega 2 (BZD2) receptor subtypes has been studied autoradiographically in monkey and human brain sections using [3H]flunitrazepam (which binds indiscriminately to omega 1 and omega 2 subtypes) and [3H]zolpidem (which recognizes selectively the omega 1 subtype). Both ligands labeled an homogeneous population of binding sites (Kd values approximately equal to 1.5 nM and approximately equal to 5 nM, respectively) whose pharmacological characteristics were similar to those of central omega (BZD) receptors. Regional displacement studies in monkey brain showed that zolpidem was a more effective displacer of [3H]flunitrazepam from omega 1-than from omega 2-enriched areas. For example, it was 73-fold more potent in the cerebellum (omega 1-enriched) than in the dentate gyrus (omega 2-enriched). Zolpidem thus selectively recognizes omega 1 sites in primate brain. The autoradiographic distribution of [3H]flunitrazepam (omega 1 + omega 2) binding sites in primate brain was highly heterogeneous. Very high densities were observed in lamina IV of the neocortex (with higher densities in the occipital than in the frontal pole), the substantia innominata and molecular layer of the dentate gyrus. Intermediate densities were found in other neocortical laminae, cerebellum (molecular layer), claustrum, globus pallidus, caudate-putamen, nucleus accumbens, dentate gyrus (granular layer) and the majority of thalamic nuclei. Structures displaying low binding densities included the substantia nigra and the subthalamic nucleus. The regional distribution pattern of [3H]zolpidem binding sites was qualitatively similar to that of [3H]flunitrazepam but the relative density of the 3H-ligands differed in several brain regions. The relative density of omega 1 and omega 2 subtypes in each particular primate brain region was evaluated by measuring 1) the ratio of [3H]zolpidem to [3H]flunitrazepam binding; 2) [3H]flunitrazepam binding in the presence and in the absence of 100 nM zolpidem. With both approaches, a preferential enrichment in omega 1 sites was observed in lamina IV of sensorimotor cortical regions and in the extrapyramidal motor system (globus pallidus, ventral thalamic complex, subthalamic nucleus, substantia nigra and cerebellum). In contrast, omega 2 sites predominated in limbic areas (e.g., the dentate gyrus, amygdala, nucleus accumbens, cingulate and parahippocampal gyri) and in the anterior thalamic nucleus and caudate nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Effect of prolonged clonidine treatment and its withdrawal on noradrenaline turnover in the cerebral cortex and medulla oblongata of the spontaneously hypertensive rat.

We have investigated the effect of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.5 mg . kg-1 X 24 h-1 for 10 days) and of withdrawal of this treatment on ingestive behaviour and on the cerebral turnover of noradrenaline in the adult spontaneously hypertensive rat (SHR). Clonidine amplified the fall in food and water intakes induced by minipump implantation. Ingestive behaviour returned to normal by the 4th to the 5th day in controls and by the 7th to the 8th day in clonidine-treated SHR. Clonidine withdrawal produced an increase in water intake above pre-implantation values. Body weight fell during clonidine treatment, then recovered slightly during withdrawal. After 5 days' treatment total DOPEG levels (an index of noradrenaline turnover) were reduced in cerebral cortex and medulla oblongata. The noradrenaline metabolite levels increased following withdrawal of drug treatment, the increase being more marked and faster in onset in cerebral cortex than in medulla oblongata. Thus prolonged treatment with clonidine decreases noradrenaline turnover and withdrawal of such treatment increases turnover.

Animals↗

PubMed1987

Parkinson's disease and dementia: norepinephrine and dopamine in locus ceruleus.

Norepinephrine, 3-methoxy 4-hydroxyphenylethyleneglycol and homovanillic acid levels were similar in the locus ceruleus of 13 controls and 8 parkinsonian patients with no intellectual deterioration, but were decreased in 7 demented patients. The concentration of dopamine was similarly diminished in non-demented and demented parkinsonians, and binding of 3H-desmethylimipramine and 3H-rauwolscine was not abnormal in parkinsonians. These data indicate that norepinephrine metabolism in the locus ceruleus is subnormal only in demented parkinsonians.

Aged↗

PubMed1987

Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain.

In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.

Animals↗

PubMed1987

Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat.

The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.) does not alter norepinephrine uptake but accelerates the turnover rate of norepinephrine in the rat brain as demonstrated by the enhancement of: the alpha-methyl-p-tyrosine-induced disappearance of norepinephrine in the hypothalamus; 3,4-dihydroxyphenylacetic acid levels in noradrenergic cell body areas; the pargyline-induced accumulation of normetanephrine in the hypothalamus; and 3,4-dihydroxyphenylethyleneglycol levels in the hypothalamus, septum and spinal cord. No tolerance to the effect of fengabine on the latter biochemical parameter was observed after repeated treatment for 2 weeks at doses of 100 or 200 mg/kg i.p., b.i.d. Fengabine (100 or 200 mg/kg i.p., b.i.d.), given for 14 days, causes a desensitization of isoprenaline-stimulated adenylate cyclase in septal and cortical slices of the rat but fails to modify cortical beta, alpha-1 or alpha-2 adrenoceptor binding sites. Fengabine (up to 400 mg/kg i.p.) has no effect on rat cerebral serotonin uptake, synthesis or metabolism. Moreover, when given subacutely (100 or 200 mg/kg i.p., b.i.d. for 2 weeks), it fails to alter rat cortical serotonine receptors or [3H]imipramine binding sites. Fengabine (up to 50-100 microM) is also inactive in vitro on [3H] GABA binding to GABAA or GABAB receptors in the rat brain or on GABA transaminase activity in the mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗