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Biomedical subjects

M E Newman

Publications and source records attributed to M E Newman.

At least 19 recordsLinked to original sources
PubMed1999

Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo.

Venlafaxine is a dual serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake inhibitor which has been claimed to have an onset of antidepressant action which is faster than for other comparable drugs. The effects of venlafaxine on brain 5-HT levels in vivo have not yet been examined. Acute administration of venlafaxine to rats by i.p. injection resulted in dose-dependent increases in cortical and hippocampal 5-HT levels, as measured by in vivo microdialysis, over the range 5-20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.) for 4 weeks did not change basal 5-HT levels in either brain area. The effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg s.c.) to reduce 5-HT levels was unaffected by chronic venlafaxine at this dose, indicating that there was no change in sensitivity of presynaptic 5-HT1A autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Low doses of ipsapirone increase growth hormone but not oxytocin secretion in normal male and female subjects.

OBJECTIVE: The present study investigated whether administration of a 5-HT1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects. METHODS: Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19-74 years and 16 females, 22-69 years) using a randomized, double blind design. RESULTS: Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups. CONCLUSIONS: The effects of gender and age on the degree of stimulation of GH secretion by 5-HT1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects.

Adult↗
PubMed1999

5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.

Adrenocorticotropic Hormone↗
PubMed1999

Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity.

Augmentation of tricyclic antidepressant (TCA) treatment with triiodothyronine (T3) has been shown to potentiate the therapeutic effect of TCA drugs in depressed patients. We have attempted to elucidate the mechanism of this potentiation by determining the effects of T3 alone and together with a TCA on serotonin (5-HT) levels in living rats, using in vivo microdialysis. A single s.c. injection of T3 at 0.1 mg/kg had no effect on 5-HT levels in frontal cortex or hippocampus. Chronic administration of clomipramine (10 mg/kg i.p. daily for 4 weeks) to rats resulted in increased basal 5-HT levels in the frontal cortex. Administration of T3 daily for 7 days at 0.1 mg/kg s.c. also resulted in elevated 5-HT levels, whereas in rats administered both clomipramine and T3, cortical 5-HT levels were significantly elevated compared with the levels in rats that had received only one treatment. Basal levels in hippocampus were unaffected by these treatments. Subcutaneous injection of the 5-HT-1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.2 mg/kg) resulted in a decrease in 5-HT levels in both cortex and hippocampus. In frontal cortex of animals that had received T3 or a combination of clomipramine and T3, the extent of the decrease was significantly reduced compared to that seen in control animals. The extent of the decrease in hippocampus was not affected by any of the treatments. Subcutaneous injection of the 5-HT-1b/1d antagonist GR 127935 (5 mg/kg) resulted in an increase in 5-HT levels in both brain areas. The extent of the increase was not affected by any of the treatments in either brain area. It is concluded that the action of T3 in potentiating the clinical response to TCA drugs may be due to its effect on 5-HT levels in the frontal cortex, which is due to desensitization of the presynaptic 5-HT-1a autoreceptors.

Animals↗
PubMed1998

Role of serotonin in the amygdala in hypothalamo-pituitary-adrenocortical responses.

In view of the fact that the amygdala (AMG) and hypothalamic serotonin (5-HT) have an excitatory effect on the hypothalamo-pituitary-adrenal (HPA) axis, we have investigated the role of 5-HT in the AMG on this response. In intact freely moving rats, a mildly stressing short photic stimulation caused depletion of median eminence CRH-41, due to its release into the portal circulation and a rise in serum ACTH and corticosterone levels. This effect was significantly inhibited in rats in which 5-HT was depleted in the AMG following local 5,7-dihydroxytryptamine administration, which did not affect hypothalamic 5-HT content. Also, local pretreatment with ketanserin (a 5-HT2 receptor antagonist) in the AMG had the same inhibitory effect on the HPA axis response. These results indicate that AMG 5-HT has an important role in the activation of the HPA axis following neural stimulation and that 5-HT2 receptors are involved.

5,7-Dihydroxytryptamine↗
PubMed1998

Neurochemical mechanisms of action of ECS: evidence from in vivo studies.

Recent advances in receptor pharmacology and in the understanding of intracellular signal-transduction systems have given rise to new theories of the mechanism of action of antidepressant drugs. The relevance of these theories to the antidepressant mechanism(s) of electroconvulsive shock (ECS) is discussed, with a view to increasing understanding of the mechanism of electroconvulsive therapy (ECT). Particular attention is given to results obtained with in vivo methods both in experimental animals and in human subjects.

Animals↗
PubMed1998

Wernicke-Korsakoff amnestic syndrome secondary to malnutrition in a patient with schizoaffective disorder.

OBJECTIVE: The authors identify a rare case of Wernicke-Korsakoff amnestic syndrome and highlight its occurrence in the absence of alcohol dependence. METHOD: A longitudinal case history of a patient with schizoaffective disorder who developed Wernicke-Korsakoff syndrome secondary to malnutrition. RESULTS: Refusal to eat based on persecutory delusions in chronic psychotic patients can cause malnutrition and result in Wernicke-Korsakoff syndrome. CONCLUSIONS: With increasing managed-care demands for outpatient treatment of chronic psychotic patients, physicians may see more cases of Wernicke-Korsakoff syndrome in psychiatric populations.

Amnesia↗
PubMed1997

A model of mass extinction.

In the last few years a number of authors have suggested that evolution may be a so-called self-organized critical phenomenon, and that critical processes might have a significant effect on the dynamics of ecosystems. In particular it has been suggested that mass extinction may arise through a purely biotic mechanism as the result of "coevolutionary avalanches". In this paper we first explore the empirical evidence which has been put forward in favor of this conclusion. The data center principally around the existence of power-law functional forms in the distribution of the sizes of extinction events and other quantities. We then propose a new mathematical model of mass extinction which does not rely on coevolutionary effects and in which extinction is caused entirely by the action of environmental stress on species. In combination with a simple model of species adaption we show that this process can account for all the observed data without the need to invoke coevolution and critical processes. The model also makes some independent predictions, such as the existence of "aftershock" extinctions in the aftermath of large mass extinction events, which should in theory be testable against the fossil record.

Animals↗
PubMed1997

Chronic electroconvulsive shock and 5-HT autoreceptor activity in rat brain: an in vivo microdialysis study.

In vivo microdialysis was used to determine the effects of chronic electroconvulsive shock (ECS), given daily for 10 days, on basal 5-HT levels in rat frontal cortex and hippocampus and on the effect of systemic administration of the 5-HT-la receptor agonist, 8-OH-DPAT (0.2 mg/kg), to reduce 5-HT levels in these areas by activation of somatodendritic autoreceptors. Neither basal 5-HT levels nor the effects of 8-OH-DPAT on 5-HT levels were altered after chronic ECS. The effect of systemic administration of the 5-HT1A and 5-HT1B antagonist, (+/-)-pindolol (10 mg/kg), to increase 5-HT levels in hippocampus, was also not affected by chronic ECS.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

In vivo cyclic AMP responses in rat brain are not modified by chronic electroconvulsive shock.

In vivo microdialysis was used to determine the effects of chronic electroconvulsive shock (ECS), given daily for 10 days, on the cyclic AMP (cAMP) responses to noradrenaline (NA) and to forskolin in the cortex of freely-moving conscious rats. Microdialysis probes were inserted on the final day of ECS administration, and cAMP responses measured the following day. Chronic ECS did not modify the responses to either NA or forskolin. These results differ markedly from those previously obtained with incubated slices of rat brain. It is concluded that care is needed in interpreting results obtained by either ex vivo or in vitro methods.

Adrenergic alpha-Agonists↗
PubMed1996

A model for evolution and extinction.

We present a model for evolution and extinction in large ecosystems. The model incorporates the effects of interactions between species and the influences of abiotic environmental factors. We study the properties of the model by approximate analytic solution and also by numerical simulation, and use it to make predictions about the distribution of extinctions and species lifetimes that we would expect to see in real ecosystems. It should be possible to test these predictions against the fossil record. The model indicates that a possible mechanism for mass extinction is the coincidence of a large coevolutionary avalanche in the ecosystem with a severe environmental disturbance.

Animals↗
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↗