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M Dierssen

Publications and source records attributed to M Dierssen.

51 records · Page 3Linked to original sources
PubMed1997

Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome.

Mice with segmental trisomy 16 (Ts65Dn) which have triplication of a region of mouse chromosome 16 homologous to the Down syndrome critical region in human chromosome 21, are used as a model for Down syndrome. Functioning of the central beta-noradrenergic transmission was studied in Ts65Dn mice. Binding analysis in cerebral cortex revealed no change in the number of beta-adrenoceptors and a slight reduction of affinity. The beta-adrenoceptor transduction was assessed by analyzing cAMP formation in the cerebral cortex, hippocampus and cerebellar cortex under basal conditions and after stimulation with isoprenaline and forskolin. Basal production of cAMP was significantly reduced in hippocampus and cerebellar cortex of Ts65Dn mice compared to control, but not in cerebellum. After phosphodiesterase inhibition, net increments in cAMP accumulation were similar in both groups of mice. Stimulation of cAMP production by isoprenaline (10 microM) and forskolin (10 microM) was much higher in hippocampus than in cerebral cortex of either group. In both areas, but not in cerebellum, the stimulatory responses were consistently and significantly smaller in Ts65Dn than in control mice. Concentration-response curves for isoprenaline and forskolin were generated in the cerebral cortex. Emax responses were lower in trisomic than in control mice; however, in Ts65Dn mice the slope of the response curve to isoprenaline was markedly depressed whereas that to forskolin was similar to control. It is concluded that Ts65Dn mice show severe deficiencies in the synaptic transmission of the central beta-noradrenergic system, which are selective for specific brain areas.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Impaired cyclic AMP production in the hippocampus of a Down syndrome murine model.

Behavioral and learning disturbances have been found in mice with partial trisomy 16, a new model for Down syndrome. Basal production of cyclic AMP in the hippocampus of trisomic mice was shown to be impaired. In addition, the responses of adenylyl cyclase to the stimulation of beta-adrenoceptors with isoprenaline and of the catalytic subunit with forskolin were both severely depressed.

1-Methyl-3-isobutylxanthine↗
PubMed1995

A behavioral assessment of Ts65Dn mice: a putative Down syndrome model.

Mice which are trisomic for only the human chromosome (Chr) 21-homologous segment of mouse Chr 16 (segmental trisomy), including a portion of the Down syndrome region of human Chr 21, have recently been developed. Since these segmentally trisomic mice, designated Ts(17(16))65Dn, survive to adulthood, they may represent a mouse model for the study of Down syndrome. A partial characterization of their behavioral phenotype was undertaken by evaluating the sensorimotor reflexes, exploration, locomotor activity, emotionality and spatial learning in 16 male Ts65Dn mice (TS) and 16 control (CO) littermates. No sensorimotor deficits appeared in TS compared to CO mice. By contrast, head-dipping behaviour in the hold board was increased in TS mice with respect to the CO group, showing a higher repetition rate of previously explored holes. Crossings in the open field and total arm entries in the plus maze were higher in TS than in the CO group during the dark phase of the light-dark (LD) cycle under red light, but not during the light phase of the LD cycle under white light. Entries into the open arms of the plus maze were increased overall in TS mice when compared to CO mice, but no differences were found in time spent in the open arms. TS mice showed impaired place learning in the Morris water maze, whereas they were able to reach the same performance as CO animals in cued learning. Thus, absence of sensorimotor deficits, increased exploration, hyperactivity under certain experimental conditions and a moderate impairment of spatial learning were the principal characteristics observed in TS mice compared to their CO littermates.

Animals↗
PubMed1995

Early environmental stimulation produces long-lasting changes on beta-adrenoceptor transduction system.

Long-term behavioral and biochemical effects of exposure to differential early stimulation (postnatal handling and/or enriched environment) were studied in 18- to 20-month-old Sprague-Dawley rats. Postnatal handling treatment was given between 1 and 22 postnatal days. In the enriched environment procedure, the pups were maintained under enriched conditions from weaning until postnatal Day 100. At 18 months of age animals were tested for working memory in an object recognition test, based on the differential exploration of familiar and new objects. Animals reared in the enriched environment performed better in the working memory test than did control or postnatally handled rats. No interaction was observed between postnatal handling and environmental enrichment on cognitive parameters. At 20 months of age, the animals were sacrificed and cyclic AMP formation was determined under basal conditions and after activation of beta-adrenoceptors in cerebral cortex and hippocampus. Both postnatal handling and its combination with exposure to enriched environment significantly increased basal cyclic AMP accumulation in cerebral cortex, but not in the hippocampus. Environmental enrichment was able to induce a long-lasting modification in the responsiveness of the beta-adrenergic neurotransmitter system as reflected by a decreased cyclic AMP accumulation after beta-adrenoceptor activation by means of isoprenaline, in either anatomical structure. It is suggested that manipulations of the environment early in life leading to a reduction in age-related memory deficits produce subtle but long-lasting modifications of noradrenergic transmission.

Animals↗
PubMed1995

Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine.

The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.

Animals↗
PubMed1993

The Ca2+ channel agonist Bay K 8644 induces central respiratory depression in cats, an effect blocked by naloxone.

We analyzed the respiratory effects induced by the Ca2+ channel agonist Bay K 8644 and its enantiomers, Bay R 5417 and Bay R 4407, applied to the ventral medullary surface of cats. Bay K 8644 (10 to 100 micrograms) and Bay R 5417 (50 to 200 micrograms) elicited a dose-dependent respiratory depression. Naloxone (0.1 mg/kg), but not D-naloxone, reversed these effects, indicating that an endogenous opioid mechanism was involved. Bay R 4407 (100 micrograms) was ineffective. The respiratory depressant effects induced by Bay K 8644 and its (-) enantiomer were a consequence of their agonist properties on the L-type Ca2+ channel, since (1) the activity of Bay K 8644 was stereospecific, and (2) nimodipine prevented the effect. We suggest that potent activation of Ca2+ channels or other mechanisms by high doses of Ca2+ agonists elicits the release of endogenous opioid peptides in medullary respiration-related structures.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Differential effects of physostigmine and 1,2,3,4-tetrahydro-9-aminoacridine on the beta-adrenoceptor transduction system.

The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) and physostigmine on beta-adrenoceptor-linked cyclic AMP accumulation have been analyzed in vitro in rat cortex and hippocampus. A 10-min incubation with increasing concentrations of THA reduced isoprenaline (10 microM)-stimulated cyclic AMP accumulation in a concentration-dependent manner in cortical (IC50 = 1.31 +/- 0.13 microM) and hippocampal (IC50 = 0.02 +/- 0.003 microM) structures. Conversely, physostigmine did not modify cyclic AMP synthesis in any experimental condition. The action of THA was non-competitive since it induced a non-parallel shift to the right of the concentration-response curve for isoprenaline. The differential effects of THA and physostigmine on the beta-adrenoceptor transduction system may account for the difference in their ability to restore cognitive function.

Animals↗
PubMed1993

Potentiation of acute opioid-induced respiratory depression and reversal of tolerance by the calcium antagonist nimodipine in awake rats.

The interaction between sufentanil, a mu-opioid agonist, and the Ca2+ antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstrated that chronic treatment with nimodipine together with sufentanil increases the analgesic potency of the opioid 50 fold. Therefore, we have investigated whether the opioid-induced respiratory depression is potentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10-80 micrograms/kg) consistently induced a dose-dependent respiratory depression. Pretreatment with nimodipine (200 micrograms/kg) potentiated this effect but to a lesser extent than it potentiated analgesia. After chronic administration of the opioid (2 micrograms/h, 7 days) tolerance was manifested as a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 microgram/h) administered concurrently with sufentanil for 7 days counteracted the tolerance to respiratory depression but no additional potentiation was observed. These results demonstrate that the interaction between nimodipine and sufentanil is not limited to antinociception but also extends to respiratory depression. However, compared with analgesia, the clinical relevance of a potential increase in opioid-induced respiratory depression by nimodipine may be negligible.

Animals↗
PubMed1993

Effects of age on alpha 1-adrenoceptor subtypes in the heart ventricular muscle of the rat.

The effects of ageing on alpha 1-adrenoceptor subtypes have been examined in heart ventricular muscle of young (2-3 months) and middle-aged (18 months) Sprague-Dawley rats. Radioligand binding studies with [3H]prazosin revealed an age-related loss of binding sites (Bmax 56.7 +/- 1.93 fmol (mg protein)-1 age 2 months vs 31.7 +/- 2.45 fmol (mg protein)-1 age 18 months) not followed by changes in the dissociation constant value (Kd 0.16 +/- 0.03 nM age 2 months and 0.10 +/- 0.03 nM age 18 months). Competition curves with WB 4101 showed two distinct sites with different affinities, the proportion of sites with high affinity being similar for both age groups (22.2 +/- 1.89% vs 17.8 +/- 1.96% for animals aged 2 and 18 months, respectively). Agonist displacement curves of [3H]prazosin indicate the existence of two different affinity sites for the agonist, that are maintained regardless of the ageing process (R(high) = 16.2 +/- 1.54% and R(low) = 83.8 +/- 1.89% in rats aged 2 months and R(high) = 16.3 +/- 3.23% and R(low) = 83.7 +/- 3.95% in rats aged 18 months). The fractional inactivation of alpha 1-adrenoceptors by chloroethylclonidine resulted in a loss of [3H]prazosin specific binding, and a percentage of 22.5 +/- 0.95 and 22.6 +/- 4.2 of remaining binding sites for the groups of 2 and 18 months of age, respectively. The percentage of chloroethylclonidine-insensitive [3H]prazosin binding sites was similar to those with high affinity for WB4101. The present study confirms a decline of alpha 1-adrenoceptors with increasing age and reveals that the equilibrium of the expression of the two existing subpopulations of the receptor is maintained during ageing.

Adrenergic alpha-Antagonists↗
PubMed1992

Post-train administration of 9-amino-1,2,3,4-tetrahydroacridine enhances passive avoidance retention and decreases beta-adrenoceptor-linked cyclic AMP formation in middle-aged rats.

The possible involvement of beta-adrenoceptor system in the effectiveness of 9-amino-1,2,3,4-tetrahydroacridine (THA) to attenuate retention deficits exhibited by middle-aged rats in a one-trial passive avoidance task has been investigated. THA (2.5 mg.kg-1), injected i.p. after training, induced a significant increase in test step-through latency (STL) in middle-aged rats. Post-training injection of THA reduced basal and isoprenaline stimulated cyclic AMP accumulation in cortex and hippocampus of every group of rats. It is suggested that the effect of THA on memory processes may involve an action on beta-adrenoceptor-linked cyclic AMP accumulation.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Acute effects of tetrahydroaminoacridine on beta-adrenoceptor-linked cyclic AMP accumulation in brain of young and middle-aged rats.

The effects of acute treatment with 1,2,3,4-tetrahydro-9-aminoacridine (THA), a 4-aminopyridine derivative clinically effective in Alzheimer's disease, on beta-adrenoceptor-linked cyclic AMP accumulation have been investigated in cortical and hippocampal structures of young and middle-aged rats. In a first series of experiments, pretreatment with 2.5 mg/kg THA decreased basal cyclic AMP accumulation. When a phosphodiesterase inhibitor was added to the preparation, THA again decreased cyclic AMP levels in young rats, but failed to significantly modify cyclic AMP accumulation in middle-aged animals. Finally, in isoprenaline-stimulated conditions, acute treatment with tacrine was able to diminish cyclic AMP accumulation in every group of rats. It is suggested that the neurochemical action of THA in mammalian brain is more complex than earlier has been anticipated and may involve an action on beta-adrenoceptors.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Ca2+ channel modulation by dihydropyridines modifies sufentanil-induced respiratory depression in cats.

We analyzed the interaction between sufentanil, a selective mu agonist, and two dihydropyridines, the Ca2+ antagonist, nimodipine, and the Ca2+ agonist, Bay K 8644, on the respiratory actions induced in the brainstem of cats. Drugs were applied topically to the ventral medullary surface. Sufentanil (0.26-26 nmol) consistently induced an immediate and dose-dependent reduction in tidal volume. Respiratory frequency was only depressed by the higher doses of the opiate. Pretreatment with nimodipine (0.19 and 0.38 mumol) potentiated the respiratory depression induced by sufentanil (0.26 nmol). The potentiation included both frequency and tidal volume. On the other hand, under the influence of Bay K 8644 (0.28 nmol), the respiratory effect of the opiate (7.8 nmol) was partially antagonized. Our results indicate that modulation of the L-type Ca2+ channels by dihydropyridines modifies sufentanil-induced respiratory depression at the controlling medullary mechanisms of breathing.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions.

The study was aimed at elucidating the possible participation of L-type Ca2+ channel in the acute analgesic effect of an opiate and the development of tolerance to this action. Sufentanil, a selective mu agonist, and two dihydropyridines, the Ca2+ antagonist nimodipine and the Ca2+ agonist Bay K 8644, were selected. The tailflick test was used to assess the nociceptive threshold. In naive rats, nimodipine (200 micrograms/kg) potentiated the analgesic effect of sufentanil reducing the ED50 from 0.26 to 0.08 microgram/kg. Similar results were observed with its (-)-enantiomer Bay N 5248, while the (+) enantiomer Bay N 5247 was ineffective. Tolerance to the opiate was induced by chronic subcutaneous administration of sufentanil with minipumps (2 micrograms/h, 7 days). In these conditions the dose-response curve to sufentanil was displaced to the right and the ED50 was increased to 1.49 micrograms/kg. In tolerant rats, nimodipine preserved its potentiating ability and prevented the displacement to the right of the sufentanil dose response-curve (ED50 = 0.48 microgram/kg). When nimodipine was pumped (1 microgram/h, 7 days) concurrently with sufentanil, the development of tolerance to the opioid was not disturbed. However, the expression of tolerance was abolished and even the effect of acutely administered sufentanil was markedly potentiated (ED50 = 0.03 microgram/kg). Similar experiments were performed with Bay K 8644. In naive rats, Bay K 8644 at a low dose (20 micrograms/kg) that behaves as a calcium agonist, antagonized the analgesic effect of sufentanil (ED50 = 0.58 microgram/kg), whereas at a high dose (200 micrograms/kg) it potentiated this action (ED50 = 0.15 microgram/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Lack of interaction between cholecystokinin and opioid systems in the central control of breathing.

The present study investigates the interaction between CCK and opioid systems on the central control of breathing by analyzing the respiratory effects of CCK-8S (0.09 nmol) and met-enkephalin (0.7 and 1.4 mumol) applied to the ventral medullary surface of cats under the influence of the opiate antagonist naloxone and the CCK antagonist proglumide. Neither naloxone nor proglumide were able to modify the respiratory effects of CCK-8S and met-enkephalin, respectively. Therefore, the hypothesis that CCK and the opioid systems might operate as parallel and antagonic forces throughout the central nervous system, is no longer tenable.

Animals↗