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Biomedical subjects

M E Newman

Publications and source records attributed to M E Newman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Acute or chronic lithium does not affect agonist-stimulated inositol trisphosphate formation in rat brain in vivo.

Rats were given lithium either acutely by s.c. injection (4 m eq kg-1) or chronically by including 0.2% LiCl in their diet for 3 weeks. Microdialysis probes were inserted into the cortex or hippocampus, using re-usable guides, and perfused with artificial CSF. Fractions were collected beginning 18 h after the end of treatment and were analysed for inositol trisphosphate (IP3). Neither acute nor chronic treatment affected basal levels of IP3 or stimulation of IP3 formation by either carbachol or noradrenaline in the hippocampus. Similarly, neither basal nor carbachol-stimulated IP3 levels in rat cortex were affected by acute Li administration. It would appear that the reductions in these parameters previously reported by other workers using brain slices were due to inositol depletion occurring at the stage of brain slice preparation. The inositol depletion hypothesis for the mechanism of action of lithium does not therefore appear to be supported by in vivo evidence.

Animals↗
PubMed1996

3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.

A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.

Amphetamine↗
PubMed1996

Inositol phosphate formation in mice prenatally exposed to drugs: relation to muscarinic receptors and postreceptor effects.

Mice were exposed to phenobarbital or heroin [diacetylmorphine (DAM)] prenatally by feeding the mother phenobarbital on gestation day 9-18; DAM was injected into the mother on gestation days 9-18. At the age of 50 days, mice exposed to phenobarbital or DAM prenatally were examined for long-term biochemical changes in the postsynaptic septohippocampal system as measured by alterations in formation of the second messenger inositol phosphate (i.p.). A significant increase in i.p. formation in response to carbachol was found after prenatal exposure to DAM. An increase in i.p. formation in response to 20 mM KCl alone or in the additional presence of 10 mM carbachol or 1mM physostigmine was found after prenatal exposure to phenobarbital or DAM. In addition, a significant increase in IP formation in response to sodium fluoride was found after prenatal exposure to phenobarbital or DAM. It is suggested that an increase in G-protein activation and in the second messenger formation accompanies the early drug-induced upregulation of the muscarinic receptors found in our previous studies.

Animals↗
PubMed1995

Alterations in hippocampal hemicholinium-3 binding and related behavioural and biochemical changes after prenatal phenobarbitone exposure.

Previous studies demonstrated postsynaptic septohippocampal cholinergic alterations after early exposure to phenobarbital. The present study was designed to ascertain possible corresponding presynaptic alterations while confirming the known behavioral deficits and extending previous findings on postsynaptic cholinergic alterations. Pregnant heterogeneous mice received milled mouse food containing 3 g/kg phenobarbital on gestation days 9-18. At age 50 days, [3H]hemicholinium-3 binding, which labels the presynaptic transporter for high affinity choline uptake, was increased in treated mice by 100% (P < 0.001). This change was not accompanied by a change in the affinity of the transporter to the ligand. Another group of offspring was tested for hippocampus-related behaviors. Consistent with our previous studies in the Morris maze, treated animals took longer to reach the platform in the place test as compared to control, and swam fewer times over the missing platform location in the spatial probe test. In the eight-arm maze, the treated offspring needed more entries than control to visit all the arms. In the spontaneous alternation test, the treated mice showed fewer alternations than controls. Biochemically, as in our previous results, prenatal phenobarbital exposure resulted in an increase in the degree of stimulation of inositol phosphate formation by carbachol (P < 0.05), an action presumed to occur at postsynaptic muscarinic receptors. While the present results show that the effect of a combination of raised K+ in the presence of physostigmine and carbachol was significantly greater in barbiturate-treated mice (P < 0.05), the action of K+ in the presence of physostigmine, but without carbachol, was not affected by the phenobarbital treatment. The results point to the uniqueness of outcome of early insults where alterations along nerve conduction cascades do not necessarily follow the common rules in that upregulation could simultaneously occur both pre- and post synaptically.

Animals↗
PubMed1994

Serotonin inhibition of adenylate cyclase in human platelet membranes; relation to 5-HT-1A receptor-mediated activity.

Serotonin inhibited both basal and forskolin-stimulated adenylate cyclase activity in human platelet membranes by approx. 30%, with an EC50 of 54 nM. Addition of NaCl to the assay medium reduced the degree of inhibition. 5-carboxamidotryptamine (5-CT) behaved as a full agonist in this system (EC50 of 5.4 nM) and BMY 7378 as a partial agonist (inducing 19% inhibition); the putative 5-HT-1a receptor agonists metergoline, spiroxatrine and MDL 73005 were inactive. The 5-HT-1a receptor antagonists metitepin and NAN-190 behaved as antagonists with Kb or Ki values of 11.2 and 1.17 nM, respectively. Spiperone behaved as a partial antagonist only. Epinephrine and 5-HT produced convergent, non-additive inhibition of both basal and forskolin-stimulated cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1994

Platelet adenylate cyclase activity in Israeli victims of Iraqi Scud missile attacks with post-traumatic stress disorder.

Platelet adenylate cyclase activity was measured in 16 control subjects and 16 patients who developed post-traumatic stress disorder (PTSD) as a result of damage inflicted on their homes during the Iraqi Scud missile attacks on Israel which occurred during the 1991 Gulf War. There were no differences in basal, NaF-stimulated, PGE1-stimulated or forskolin-stimulated activity between controls and PTSD subjects. Epinephrine inhibition of forskolin-stimulated activity, an effect mediated by alpha 2 adrenergic receptors, was slightly but not significantly increased in the PTSD patients compared to the controls, while 5-HT induced inhibition, an effect mediated by putative 5-HT1a-like receptors, was unchanged. The relationship of these activities to measures of anxiety and depression in these patients is discussed.

Adenylyl Cyclases↗
PubMed1993

Prolactin response to fenfluramine and placebo challenge following maintenance pharmacotherapy withdrawal in remitted depressed patients.

Plasma prolactin (PRL) response to fenfluramine (FF) (60 mg orally) and placebo challenge was examined in eight remitted depressed patients who were withdrawn for 14 days from maintenance pharmacotherapy with clomipramine (CMI) plus lithium carbonate (Li) (n = 6) or Li alone (n = 2), 6 months after recovering from their major depressive episode. The patients had undergone identical FF challenge tests while drug free prior to commencing treatment with electroconvulsive therapy (ECT) (n = 4) or CMI supplemented with Li (n = 4) and after completing the above treatments. PRL response to FF in the remitted, drug-free state was significantly enhanced compared to the response prior to treatment (while depressed and drug-free) and not significantly different from the response following treatment with ECT (n = 4) or CMI plus Li (n = 4) 6 months before. Other work of a similar nature supports the view that enhanced serotonergically mediated hormone release in drug-withdrawn, remitted depressives, represents a long-standing change in central serotonergic responsiveness and not a continued effect of antidepressant treatment or a manifestation of medication withdrawal.

Clomipramine↗
PubMed1993

Septohippocampal cholinergic changes after destruction of the A10-septal dopaminergic pathways.

Mice were injected bilaterally into the septum with 6-hydroxydopamine and 6 weeks later the hippocampi were assayed for activity of choline acetyltransferase, muscarinic receptor binding capabilities and for formation of inositol phosphate in response to direct (carbachol) or presynaptically elicited (K+) stimulation of the postsynaptic receptors. Levels of dopamine in the septum were reduced by 70% in the lesioned animals and hippocampal choline acetyltransferase was elevated by the same amount. The Bmax of muscarinic binding was significantly reduced without changes in Kd; nevertheless, carbachol-induced stimulation of formation of inositol phosphate was unaffected. The response to K+ was markedly elevated in the 6-hydroxydopamine-treated animals. Thus, the regulatory effect of A10-septal dopaminergic pathways on the septohippocampal cholinergic innervations is both on the presynaptic and postsynaptic levels.

Animals↗
PubMed1993

5-HT-1A receptor-mediated effects of antidepressants.

1. Antidepressant (AD) drugs in general induce subsensitivity of behavioural functions associated with activation of 5-HT-1a receptors in animals. 2. Electrophysiological studies in animals in general indicate increased serotonergic transmission after AD administration, mediated partly by increased functioning of post-synaptic 5-HT-1a receptors in the hippocampus. 3. Binding studies have in general shown no change in 5-HT-1a receptor number either pre-or post-synaptically, while results of second messenger studies (inhibition of adenylate cyclase) indicate subsensitivity after AD administration. 4. Human studies also indicate subsensitivity of 5-HT-1a receptors after ADs.

Animals↗
PubMed1992

Serotonin inhibits adenylate cyclase in human platelet membranes.

Serotonin (5-HT), the non-specific 5-HT1 receptor agonist methysergide, and the 5-HT1B receptor agonist CGS 12066 dose-dependently inhibited forskolin-stimulated adenylate cyclase activity in membranes derived from human platelets. Buspirone and ipsapirone showed partial agonist activity. The effect of 5-HT to inhibit forskolin-stimulated activity was partially antagonised by spiperone, yohimbine and pindolol, with each of these compounds showing some partial agonist activity. It is concluded that human platelet membranes possess receptors for 5-HT coupled negatively to adenylate cyclase. The relationship of these receptors to other binding sites which have been shown for 5-HT on platelet membranes remains to be finally elucidated.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Platelet adenylate cyclase activity in depression and after clomipramine and lithium treatment: relation to serotonergic function.

Adenylate cyclase activity was measured in platelet membranes from 10 healthy controls, 12 depressed patients, and the same patients after treatment with clomipramine (CMI) followed by lithium carbonate (Li) supplementation, in an attempt to determine whether any evidence for an effect on the serotonergic system could be obtained in peripheral cells. There were no differences in basal, NaF-, PGE1-, or forskolin-stimulated activity either between the control subjects and depressed patients or between activities in the patients measured before treatment, after CMI, and after CMI+Li. The degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT, an effect putatively mediated by a 5-HT1A-like receptor, was not different in the depressed patients compared to controls or affected by CMI treatment, but was significantly reduced after Li supplementation.

Adenylyl Cyclases↗
PubMed1992

Hormone responses to fenfluramine and placebo challenge in endogenous depression.

Plasma prolactin and cortisol levels after oral administration of d-l fenfluramine hydrochloride (60 mg) and placebo were examined in 24 endogenously depressed patients and 21 age- and sex-matched normal control subjects in a randomized, double-blind study. Prolactin levels were significantly increased by fenfluramine in both groups, but the response was significantly blunted in the depressed patients compared with the controls. This effect was partially dependent upon elevated baseline cortisol levels in the depressed group and was also influenced by a history of weight loss. Plasma cortisol levels were not increased by fenfluramine in either group. These findings confirm previous reports and suggest that patients with endogenous major depression are characterized by central serotonergic hyporesponsivity. The need to account for baseline effects on hormonal responses to putative serotonergic agents is supported by the findings; however, these effects appear to be less striking when endogenicity is a prominent clinical feature of the depressive syndrome. The apparently complex influence of weight loss on prolactin response to serotonergic challenge remains to be clarified as well as the role played by the bioavailability of the challenge drug and its metabolite.

Adult↗
PubMed1992

Hippocampal cholinergic alterations and related behavioral deficits after early exposure to phenobarbital.

Mice were exposed to phenobarbital (PhB) prenatally and neonatally. Prenatal exposure was accomplished by feeding the mother PhB (3 g/kg milled food) on gestation days 9-18. Neonatal exposure was accomplished by daily injections of 50 mg/kg sodium PhB directly to the pups on days 2-21. Long-term biochemical alterations in the pre- and postsynaptic septohippocampal system, as well as related behavioral deficits, were assessed in the treated animals. Significant increase in B(max) values for binding of [3H]QNB to muscarinic cholinergic receptors was obtained on both ages 22 and 50 in prenatally (40-90%, respectively, p less than 0.001) and neonatally exposed (58-89%, p less than 0.001) mice whereas Kd remained normal. Similarly, a significant increase of inositol phosphate (IP) formation in response to carbachol was found after both prenatal and neonatal exposure to PhB (p less than 0.05). No alterations in choline acetyltransferase (ChAT) activity were observed in the prenatally or neonatally treated animals. The early exposed mice showed deficits in the performance in Morris water maze, a behavior related to the septohippocampal pathway. The results suggest that early exposure to PhB induces alterations in postsynaptic components of the hippocampal cholinergic system and concomitantly to impairment in hippocampus-related behavior.

Animals↗
PubMed1992

Regulation of 5-hydroxytryptamine1A receptor function in rat hippocampus by short- and long-term administration of 5-hydroxytryptamine1A agonist and antidepressants.

Single s.c. injections of the 5-hydroxytryptamine (5-HT)1A receptor agonists buspirone at 4 mg/kg, 8-hydroxy-2-(di-n-propylamino)tetralin at 1 or 4 mg/kg or ipsapirone at 10 mg/kg did not affect 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. However, a single injection of buspirone at 8 mg/kg, and daily injections of each of the agonists for 8 days, resulted in a reduction in the degree of enzyme inhibition by 5-HT. Chronic administration of the antidepressants fluoxetine, zimelidine and maprotiline by i.p. injections at 15 mg/kg for 3 weeks also resulted in a decreased degree of enzyme inhibition. Chronic iprindole at the same dose had no effect. It is concluded that the antidepressant-like properties of 5-HT1A receptor agonists may be mediated partly by a postsynaptic action at the level of serotonergic second messenger transduction in the hippocampus.

Adenylyl Cyclases↗