Search PubMed⌕ Search

Biomedical subjects

F Sulser

Publications and source records attributed to F Sulser.

At least 55 records · Page 3Linked to original sources
PubMed1982

Role of serotonergic input in the regulation of the beta-adrenergic receptor-coupled adenylate cyclase system.

The action of desipramine on the norepinephrine-sensitive adenylate cyclase system and the density of beta-adrenergic receptors in rat cortex was studied after selective lesioning of serotonergic neurons with 5,7-dihydroxytryptamine. In animals with lesions desipramine failed to reduce the density of beta-adrenoceptors but decreased the response of adenosine 3',5'-monophosphate to isoproterenol and norepinephrine to the same degree as in animals without lesions. The results demonstrate a functional linkage between serotonergic and noradrenergic systems in the rat cortex, with beta-adrenergic receptors and neurohormonal sensitivity of the adenosine 3',5'-monophosphate-generating system being under separate regulatory control.

Adenylyl Cyclases↗
PubMed1982

Oxaprotiline: induction of central noradrenergic subsensitivity of its (+)-enantiomer.

The effects of the tetracyclic antidepressant oxaprotiline and its two optically active enantiomers on the norepinephrine (NE) receptor coupled adenylate cyclase system were determined in slices of the rat cerebral cortex. While oxaprotiline does not change the response of the cyclic AMP generating system to NE after a single dose, chronic administration of the drug for 3 to 14 days down-regulates the receptor system. The noradrenergic subsensitivity is linked to a reduction in the Bmax value of beta-adrenergic receptors as assessed by (3H)-dihydroalprenolol binding without changes in the Kd value. The action of oxaprotiline on the NE receptor coupled adenylate cyclase system resides entirely in the (+)-enantiomer which is a potent inhibitor of the neuronal uptake of NE. The (-)-enantiomer of oxaprotiline which is a weak inhibitor of NE reuptake, failed, even in high doses, to modify the noradrenergic receptor system. Though not excluding co-regulatory factors in addition to NE, the studies support the view that an enhanced and persistent NE receptor interaction is one of the prerequisites for the in vivo down-regulation of central noradrenergic receptor function. The results also suggest that the therapeutic activity of oxaprotiline may reside in its (+)-enantiomer.

Animals↗
PubMed1982

Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain.

10-(4-Methylpiperazino)dibenz[b,f]oxepins were prepared and evaluated as potential antipsychotic agents using specific clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine] binding sites in rat forebrain that are noncholinergic and nondopaminergic in nature and from which [3H]clozapine is displaced by known antipsychotic agents. [3H]Clozapine binding in the presence of atropine represents nonmuscarinic binding, while binding in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding. The relative affinity for dopamine binding sites was determined by displacement of [3H]spiroperidol from binding sites in rat caudate nuclei. Thus, clozapine, its 2-chloro isomer, its dechloro analogue, and their 5H-dibenzo[a,d]cycloheptene and dibenz[b,f]oxepine analogues have about the same relative affinity for the nonmuscarinic clozapine binding sites. At the spiroperidol (dopaminergic) sites, both the nature of the tricyclic system and the presence of a chlorine atom on the tricyclic system have a substantial effect on the binding affinity. Within each series, shift or a chlorine atom from the position distal to the piperazino group to the proximal position increases the binding affinity by a factor of about nine, but removal of the chlorine atom substantially decreases the binding affinity. Nevertheless, 10-(4-methylpiperazino)dibenz[b,f]oxepin has a threefold greater affinity for the dopaminergic binding sites than does clozapine itself.

Animals↗
PubMed1982

Role of neuronal signal input in the down-regulation of central noradrenergic receptor function by antidepressant drugs.

Rats with unilateral lesions of the locus coeruleus were used to study the role of norepinephrine (NE) signal input in the down-regulation by antidepressants of the noradrenergic cyclic AMP-generating system in the cortex. Chronic administration of both desipramine (blockade of NE reuptake) and iprindole (no blockade of NE reuptake) reduced the cyclic AMP response to NE on the nonlesioned side, but had little or no effect on the lesioned side. The results indicate that NE signal input and thus the formation of the NE-receptor complex are prerequisites for inducing noradrenergic subsensitivity.

Animals↗
PubMed1981

The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin.

The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the Bmax value of beta-adrenergic binding sites without appreciable changes in the Kd values, as assessed by specific 3H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of beta-adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of beta-adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).

Adenylyl Cyclases↗
PubMed1981

Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain.

Analogues of clozapine, some prepared by a novel, shorter synthesis than those described previously, were evaluated as potential antipsychotic agents using clozapine binding sites in rat forebrain that are nonmuscarinic and nondopaminergic in nature and from which [3H]clozapine is displaced by known antipsychotic agents. The binding of clozapine to muscarinic sites is inhibited in the presence of atropine. Displacement of [3H]clozapine by an analogue of clozapine in the presence of atropine represents nonmuscarinic binding, while displacement in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding. The relative affinity of the analogues for dopamine binding sites was determined by their ability to displace [3H]spiroperidol from binding sites in rat caudate nuclei. To the extent which binding affinity for nonmuscarinic clozapine sites in rat forebrain reflects the antipsychotic potential of a particular drug, dibenzo-5H-cycloheptene analogues of clozapine are as effective as clozapine itself. Strong binding to nonmuscarinic clozapine sites is not dependent on the presence of a chlorine atom on th tricyclic system. One or both of the nitrogen atoms in the dibenzo-5H-[1,4]diazepine ring of clozapine appear to be necessary for the strong inhibition of clozapine binding to spiroperidol sites in rat caudate nuclei. Anticholinergic activity is substantially higher for clozapine and its dibenz[1,4]oxazepine analogue than for its benzo-5H-cycloheptene analogue.

Animals↗
PubMed1980

Development of and recovery from subsensitivity of the noradrenergic cyclic AMP generating system in brain. Effect of amphetamine following inhibition of its aromatic hydroxylation by iprindole.

Amphetamine given intraperitoneally (10 mg/kg b.i.d.) for 2 days did not alter either the basal level of cyclic AMP or the neurohormonal response of the cylcic AMP generating system to noradrenaline (NA). The same doses of amphetamine caused a significant reduction in the responsiveness to NA and the beta-adrenergic agonist isoprenaline following the inhibition of the aromatic hydroxylation by iprindole. The EC50 values (concentration of NA which causes half maximal cyclic AMP stimulation) were not significantly changed: 9.5 micro M (controls) and 11 micro M (iprindole + amphetamine). Following discontinuation of the drugs, the recovery from adrenergic subsensitivity to NA was complete within 1 week in the limbic forebrain while the adrenergic responsiveness in the cortex was still only 65% of its control value 3 weeks following discontinuation of the drugs. The subsensitivity in both limbic forebrain and cortex was linked to a decreased Bmax value of specific 3H-dihydroalprenolol binding without changes in the Kd values. The different rates of recovery from noradrenergic subsensitivity in limbic forebrain and cortex following withdrawal of the drugs were reflected in the density of beta-adrenergic receptors in the two brain regions. Since inhibition of the aromatic hydroxylation of amphetamine markedly prolongs the half life of the drug and prevents the accumulation of p-hydroxynorephedrine (a potential NA antagonist), the results support the view that homospecific down-regulation of the NA receptor coupled adenylate cyclase system in brain depends on a sustained and unhindered NA receptor interaction.

Adenylyl Cyclases↗
PubMed1979

Subsensitivity of the norepinephrine receptor-coupled adenylate cyclase system in brain: effects of nisoxetine versus fluoxetine.

Chronic administration of the norepinephrine (NE) reuptake inhibitor nisoxetine reduced the sensitivity of the NE receptor-coupled adenylate cyclase system in rat cortex. This subsensitivity, unlike that caused by desipramine (DMI), was not related to a reduction in specific beta-adrenergic receptor binding. The specific serotonin reuptake inhibitor fluoxetine had no effect on either neurohormonal sensitivity or 3H-dihydroalprenolol binding.

Adenylyl Cyclases↗
PubMed1979

Norepinephrine stimulated cyclic AMP accumulation in rat limbic forebrain slices: partial mediation by a subpopulation of receptors with neither alpha nor beta characteristics.

Both isoproterenol and norepinephrine (NE) increase cyclic AMP in slices of the rat limbic forebrain and the responses are enhanced in the presence of the phosphodiesterase inhibitor RO 20-1724. However, even in the presence of RO 20-1724, no accumulation of cyclic AMP was observed after the addition of dopamine, serotonin or the alpha-agonists methoxamine and phenylephrine. This suggests that these agents do not activate adenylate cyclase in this preparation or that their respective receptors--unlike the beta-receptor--are not coupled to adenylate cyclase. Isoproterenol, which has a high affinity for this adenylate cyclase system but only 20-30% of the maximal activity of NE, does not interfere with the agonist activity of NE. Moreover, the effect of isoproterenol is not additive with that of NE thus suggesting that isoproterenol is acting on a subpopulation of NE receptors. The results indicate that two populations of NE receptors coupled to adenylate cyclase are present in slices of rat limbic forebrain: one which has beta-characteristics and the other with neither alpha- nor beta-characteristics based on agonist studies.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗