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D H Manier

Publications and source records attributed to D H Manier.

32 records · Page 2Linked to original sources
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↗
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

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↗
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↗