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Biomedical subjects

F Sulser

Publications and source records attributed to F Sulser.

At least 37 records · Page 2Linked to original sources
PubMed1987

The serotonin/noradrenaline-link in brain. I. The role of noradrenaline and serotonin in the regulation of density and function of beta adrenoceptors and its alteration by desipramine.

The present studies were undertaken to assess the role of noradrenaline (NA) and serotonin (5HT) in the regulation of the NA receptor coupled adenylate cyclase system and its alteration by desipramine (DMI) in brain structures with or without noradrenergic neuronal projections. In contrast to cortex and limbic forebrain, where chronic DMI administration caused subsensitivity of the NA sensitive adenylate cyclase linked to a down-regulation of beta adrenoceptors, the drug failed to alter the NA receptor coupled adenylate cyclase system in the striatum. Selective lesions of serotonergic axons with 5,7-dihydroxytryptamine caused a significant increase in the density of beta adrenoceptors in cortex, limbic forebrain and striatum and prevented the down-regulation by DMI of beta adrenoceptors in cortex and limbic forebrain while the responsiveness of the NA sensitive adenylate cyclase was reduced to the same extent as in sham-lesioned control animals. The discrepancy between beta adrenoceptor number and NA responsiveness following lesions of 5HT axons was particularly profound in the striatum. The analysis of high- and low-affinity components of agonist binding demonstrated that the increase in striatal beta adrenoceptors is due to a marked increase in receptors with low affinity while the number of receptors with high affinity is unchanged. The results lend further support to the view that the synaptic availability of NA is a prerequisite for the induction of subsensitivity of the NA sensitive adenylate cyclase and for the down-regulation of its beta adrenoceptor population by DMI and that 5HT plays a pivotal role in both the regulation of the number and the function of central beta adrenoceptors.

5,7-Dihydroxytryptamine↗
PubMed1987

Serotonin-norepinephrine receptor interactions in the brain: implications for the pharmacology and pathophysiology of affective disorders.

When chronically administered, most clinically effective antidepressant treatments (pharmacotherapy and ECT) reduce the sensitivity of the norepinephrine-sensitive adenylate cyclase in brain which, in turn, is associated with a down-regulation of the beta-adrenoceptor subpopulation. Because this norepinephrine receptor system is linked to an amplifier system, small changes in the number of receptors or in the accumulation of the second messenger cyclic AMP will be amplified. Results of the studies discussed in this paper demonstrate that an intact serotonergic neuronal input is required for the proper functioning of beta-adrenoceptors and for the down-regulation of the density of these receptors by antidepressant treatments. Under conditions of impaired serotonergic activity, beta-adrenoceptors display profound decreases in agonist but not in antagonist affinity. The changes are reminiscent of "uncoupled" receptors. While beta-adrenoceptors are coupled in a stimulatory fashion to adenylate cyclase, resulting in the formation of the second messenger cyclic AMP, serotonin (5-HT) receptors are linked to phosphatidylinositol hydrolysis (5-HT2 receptors in cortex, 5-HT1C receptors in choroid plexus) generating two second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. The final common pathway of aminergic receptor activation seems to be protein-kinase-mediated protein phosphorylation leading to changes in cellular activity. Evidence is presented suggesting that the delayed down-regulation of the linked 5-HT/norepinephrine beta-adrenoceptor system by antidepressant treatment reflects a therapeutically relevant biochemical action and prompts the generation of the "5-HT/norepinephrine link hypothesis" of affective disorders.

Adenylyl Cyclases↗
PubMed1986

S-adenosyl-L-methionine modulates phosphatidylethanolamine methyltransferase response to isoproterenol in brain.

The effect of l-isoproterenol on S-adenosyl-L-methionine (Adomet)-mediated phospholipid methylation in rat brain cortex was examined. Under conditions which favor the activity of methyltransferase I (i.e. low Adomet), formation of phosphatidyl-N-methylethanolamine was inhibited by l-isoproterenol. On the other hand, methyltransferase II activity (i.e. high Adomet) was stimulated by l-isoproterenol. The results suggest that Adomet may play a regulatory role in the response of phospholipid methyltransferases to catecholamines in brain.

Animals↗
PubMed1986

Update on neuroreceptor mechanisms and their implication for the pharmacotherapy of affective disorders.

Unlike "acceptors" (binding sites), receptors for neurohormones display the dual function of recognition and biologic response via coupling to effector systems that generate second messengers or to ion channels that modify the passage of specific ions. The demonstration that membrane receptors for norepinephrine are coupled in a stimulatory (beta 1, beta 2) or inhibitory (alpha 2) way via nucleotide regulatory proteins to adenylate cyclase, thus increasing or decreasing the formation of the second messenger cyclic AMP, is discussed. Serotonin receptors are linked to phosphatidylinositol hydrolysis generating two second messengers, diacylglycerol and inositol triphosphate. Pharmacologically, serotonin (5-HT) receptors that are linked to phosphatidylinositol hydrolysis are of the 5-HT2 type in the cerebral cortex and of the 5-HT1c type in the choroid plexus. The final common pathway of signal transduction appears to be the protein-kinase-mediated phosphorylation of cellular proteins. Glucocorticoid receptors have been found to be located in the cytoplasma or nuclei of aminergic cell bodies and may exert their effects by modifying the genomic expression of the respective neurons. The two aminergic receptor systems are biomolecularly linked, with glucocorticoids exerting a modulatory role. The implications of central receptor research for the pharmacotherapy and the pathophysiology of affective disorders are reviewed.

Animals↗
PubMed1984

A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action parachlorophenylalanine by 5-hydroxytroptophan.

An acute reduction in the synaptic availability of serotonin (5HT) by p-chlorophenylalanine (PCPA) nullifies the decrease in the density of cortical beta adrenoceptors caused by desipramine (DMI) but does not appreciably alter the attenuation of the norepinephrine (NE) sensitive adenylate cyclase. The analysis of competition-binding curves of [3H]-dihydroalprenolol shows that the affinity of the agonist (-)-isoproterenol for cortical beta adrenoceptors is profoundly reduced following PCPA. This reduction in agonist affinity is enhanced by DMI. Resupplying 5HT by by-passing tryptophan hydroxylase inhibition, by administering 5-hydroxytryptophan, converts a DMI non-responsive to a DMI responsive beta adrenoceptor population and shifts the markedly decreased agonist affinity towards the affinity values found in control preparations. The results demonstrate the pivotal role of 5HT in the regulation of the density and agonist affinity characteristics of cortical beta adrenoceptors and contribute to the scientific basis of the 'serotonin-norepinephrine link hypothesis' of affective disorders.

5-Hydroxytryptophan↗
PubMed1984

Regulation and function of noradrenaline receptor systems in brain. Psychopharmacological aspects.

Central beta-adrenoceptors are coupled to adenylate cyclase in a stimulatory manner. However, there is only circumstantial evidence that alpha 2-adrenoceptors in brain are coupled to adenylate cyclase in an inhibitory manner. The desensitization of the beta-adrenoceptor system induced by antidepressants seems to be a common action of clinically effective antidepressants. alpha 2-Adrenoceptor subsensitivity, if it occurs following administration of some antidepressants, contributes to the development of down-regulation of beta-adrenoceptors. The occupancy of adrenoceptors by noradrenaline (NA) is a prerequisite for both desensitization of the system and the reduction in the number of beta-adrenoceptors while serotonin (5-HT) is co-required with NA for the regulation of the density of beta-adrenoceptors. The decrease in the number of beta-adrenoceptors induced by antidepressants is rapidly reversible following inhibition of 5-HT synthesis by p-chlorophenylalanine. Since beta-adrenoceptor-coupled adenylate cyclase systems function as kinetic amplification systems, small changes in the NA signal transfer are amplified or deamplified respectively. beta-Adrenoceptors may also subserve a critical role in neuronal membranes by determining the sensitivity of other membrane receptor systems.

Animals↗
PubMed1984

Desensitization by antidepressants of central norepinephrine receptor systems coupled to adenylate cyclase.

The experimental results discussed in this paper provide evidence that antidepressant-induced attenuation of the NE receptor-coupled adenylate cyclase system in brain and the down-regulation of its beta adrenoceptor subpopulation result in a net deamplification of the NE signal. The desensitization of the NE receptor system requires an unhindered occupancy of the receptor by the agonist NE. Following adrenalectomy, the non-beta population of NE receptors coupled to adenylate cyclase shows an enhanced response to NE without changes in the activity of adenylate cyclase or phosphodiesterase. This supersensitivity to NE can be prevented by corticosterone. The synaptic availability of 5HT is co-required for the down-regulation by DMI-like drugs of the density of beta adrenoceptors. Moreover, beta adrenoceptors from tissue deprived of serotonergic neuronal input display a marked decrease in agonist affinity as determined from competition binding of (-)-isoproterenol for [3H]dihydroalprenolol. Using NE as an agonist, competition binding curves with membrane preparations from cortical tissue lacking 5HT input show low affinity binding of the receptor for NE that cannot be further modified by guanine nucleotides. The reduction in beta adrenoceptor agonist affinity following reduction of the synaptic availability of 5HT is accentuated by chronic administration of DMI or zimelidine. The new experimental data on the biomolecular linkage between serotonergic and noradrenergic neurons, expressed functionally at the level of NE receptors, provide the scientific basis for a "serotonin-norepinephrine link hypothesis" of affective disorders. The pursuit of studies on the molecular mechanisms of the action of steroid hormones on central NE receptor systems and on mechanisms underlying the functional 5HT-NE linkage and its modification by antidepressants should generate a deeper understanding of neuronal signal processing in brain.

Adenylyl Cyclases↗
PubMed1983

Effect of selective monoamine oxidase inhibition by clorgyline and deprenyl on the norepinephrine receptor-coupled adenylate cyclase system in rat cortex.

The consequences of selective monoamine oxidase (MAO) inhibition on the norepinephrine(NE)-sensitive adenylate cyclase system were determined in slices of rat cerebral cortex. The chronic administration of clorgyline, which selectively inhibited the activity of MAO-A, caused a significant decrease in the responsiveness of the noradrenergic cyclic AMP-generating system. The noradrenergic subsensitivity was accompanied by a significant decrease in the density of beta-adrenoceptors, as measured by 3H-dihydroalprenolol (DHA) binding, without altering the Kd value. However, selective inhibition of MAO-B by deprenyl did not alter the sensitivity of the cyclic AMP-generating system to NE or the specific DHA binding. The basal levels of cyclic AMP in the cortex were unaltered by the drugs. Since inhibition of MAO-A, but not MAO-B, increases the availability of NE, the results support the hypothesis that a persistent NE-receptor interaction is one of the prerequisites for the in vivo densitization of the NE-sensitive adenylate cyclase and the concomitant down-regulation of the number of beta-adrenoceptors in brain.

Adenylyl Cyclases↗
PubMed1983

Norepinephrine-sensitive adenylate cyclase system in rat brain: role of adrenal corticosteroids.

Two weeks after bilateral adrenalectomy, the responsiveness of the norepinephrine (NE)-sensitive adenylate cyclase system in the rat frontal cortex was increased. This effect was restricted to the non-beta-component of the system as no change was observed in the cyclic AMP response elicited by isoproterenol after bilateral adrenalectomy, thus indicating that subpopulations of cortical NE receptor systems are under separate endocrine control. The effect of adrenalectomy on the NE-sensitive adenylate cyclase system could be completely reversed by administering corticosterone for 3 days. No changes in the cyclic AMP response to NE were observed 2 weeks after bilateral medullectomy. Furthermore, an increase in the responsiveness of the system was also observed 2 weeks after hypophysectomy. These results suggest that the effects observed in the NE-sensitive adenylate cyclase system after adrenalectomy are mediated by the loss of adrenal corticosteroids. Adrenalectomy did not alter the activities of either adenylate cyclase or phosphodiesterase. No apparent changes were observed in the maximum binding or dissociation constant values of either beta or alpha adrenoceptors as assessed with [3H]alprenolol, [3H]WB-4101 and [ [3H]clonidine. Furthermore, the effects of adrenalectomy cannot be accounted for by a shift in the diurnal variation of the system as the cyclic AMP response to NE in tissue from adrenalectomized animals was higher than that in tissue from shamoperated rats throughout a 24-hr period.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Regulation of noradrenergic receptor systems in brain that are coupled to adenylate cyclase.

The current status of regulation of norepinephrine (NE) receptor systems in brain that are coupled to adenylate cyclase is briefly reviewed. The availability of NE and the formation of the NE receptor complex is one prerequisite for the regulation of both the sensitivity of the system and the density of its beta-adrenoceptor population. Serotonergic neuronal input is corequired with NE for the down-regulation of the number of beta-adrenoceptors, which in the absence of serotonergic input, show a marked decrease in agonist affinity. Steroid hormones influence either the sensitivity of the NE receptor system (adrenocorticoids) or the biological responsiveness and the density of beta-adrenoceptors (sex steroids) while preliminary data indicate that 3,5,3'-triiodothyronine can convert a "DMI resistant" to a "DMI responsive" receptor system. The complex neurohormonal and endocrine regulation of the biological responsiveness of NE receptor systems, the number of receptors and the efficacy of their coupling to adenylate cyclase appear to represent control mechanisms for the intensity of signal transfer.

Adenylyl Cyclases↗