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Biomedical subjects

H K Manji

Publications and source records attributed to H K Manji.

At least 73 records · Page 4Linked to original sources
PubMed1994

In vivo evidence that nonneuronal beta-adrenoceptors as well as dopamine receptors contribute to cyclic AMP efflux in rat striatum.

We applied in vivo microdialysis to assess the effects of dopaminergic and beta-adrenergic receptor stimulation on cyclic AMP efflux in rat striatum under chloral hydrate anesthesia. Dopamine (up to 1 mM) infused for 20 min through the probe did not increase cyclic AMP, whereas both the selective dopamine D1 agonist SKF 38393 and D2 antagonist sulpiride produced modest increases. It is interesting that the beta-adrenoceptor agonist isoproterenol produced a marked increase (204.7% of basal level at 1 mM) which was antagonized by the beta-adrenoceptor antagonist propranolol. Pretreatment with a glial selective metabolic inhibitor, fluorocitrate (1 mM), by a 5-h infusion through the probe attenuated basal cyclic AMP efflux by 30.3% and significantly blocked the response to isoproterenol. By contrast, striatal injection of a neurotoxin, kainic acid (2.5 micrograms), 2 days before the dialysis experiment did not affect basal cyclic AMP or the response to isoproterenol, but blocked the response to SKF 38393. These data demonstrate the beta-adrenoceptors as well as dopamine receptors contribute to cyclic AMP efflux in rat striatum in vivo. They also suggest that basal and beta-adrenoceptor-stimulated cyclic AMP efflux are substantially dependent on intact glial cells.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro.

Valproic acid (VPA) is a fatty acid antiepileptic with demonstrated antimanic properties, but the molecular mechanism or mechanisms underlying its therapeutic efficacy remain to be elucidated. In view of the increasing evidence demonstrating effects of the first-line antimanic drug, lithium, on protein kinase C (PKC), we investigated the effects of VPA on various aspects of this enzyme. Chronic exposure (6-7 days) of rat C6 glioma cells to "therapeutic" concentrations (0.6 mM) of VPA resulted in decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases in the levels of PKC alpha and epsilon (but not delta or zeta) in both the membrane and cytosolic fractions after chronic VPA exposure; VPA added to reaction mixtures did not alter PKC activity or 3H-phorbol ester binding. Together, these data suggest that chronic VPA indirectly lowers the levels of specific isozymes of PKC in C6 cells. Given the pivotal role of PKC in regulating neuronal signal transduction and modulating intracellular cross-talk between neurotransmitter systems, the specific decreases in PKC alpha and epsilon may play a role in the antimanic effects of VPA.

Animals↗
PubMed1994

Comparative tolerability profiles of the newer versus older antidepressants.

Although the standard tricyclic antidepressants (TCAs) are generally effective in the treatment of depression, they can cause several troublesome adverse effects. Chief among these are their anticholinergic actions, which range from annoying dryness of the mouth and constipation to potentially dangerous urinary retention and confusion or delirium in the ill and elderly. Cardiovascular effects of TCAs include orthostatic hypotension, tachycardia and cardiac conduction slowing. Many TCAs are sedating and promote weight gain. Also problematic is the potential lethality of TCAs in overdose. The continual introduction of a host of new antidepressants over the past 15 years has provided an opportunity to improve the benefit-risk ratio for many patients by reducing medication-related toxicity. Selective serotonin reuptake inhibitors (SSRIs) and amfebutamone (bupropion), among others, are examples of effective antidepressants free of tricyclic-like anticholinergic, cardiovascular, sedating and appetite/weight-increasing effects. However, the new-generation drugs also present adverse effects of their own, including gastrointestinal distress, agitation and drug-drug interactions in the case of the SSRIs, and the risk of seizures or psychosis in amfebutamone recipients. Monoamine oxidase (MAO) inhibitors have also been refined; reversible inhibitors of MAO-type A afford protection against the usually feared hypertensive reaction to indirect sympathomimetic substances. The availability of new-generation antidepressants thus increases the likelihood of clinical response with a reduction in unwanted toxicity.

Antidepressive Agents↗
PubMed1994

Catecholamines in depression: an update.

Despite extensive research, the biochemical abnormalities underlying the predisposition to and the pathogenesis of affective disorders remain to be clearly established. Efforts to study norepinephrine (NE) output and function have utilized biochemical assays, neuroendocrine challenge strategies, and measures of peripheral blood cell receptors; the cumulative database points to a dysregulation of the noradrenergic system. Depressed patients (in particular, melancholic, unipolar subjects) excrete disproportionately greater amounts of NE and its major extraneuronal metabolite, normetanephrine, than do controls. Depressed patients also show subsensitive neuroendocrine (growth hormone) and biochemical (inhibition of adenylate cyclase) responses to alpha 2-adrenergic agonists, suggesting that subsensitivity of nerve terminal alpha 2 autoreceptors may underlie the exaggerated plasma NE observed in response to various challenges in affective disorders. Future advances in brain imaging techniques and in the molecular biology of adrenergic receptor-coupled signal transduction systems offer promise for meaningful advances in our understanding of the pathophysiology of affective disorders.

Affective Disorders, Psychotic↗
PubMed1993

Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme.

We investigated the effects of lithium on alterations in the amount and distribution of protein kinase C (PKC) in discrete areas of rat brain by using [3H]phorbol 12,13-dibutyrate quantitative autoradiography as well as western blotting. Chronic administration of lithium resulted in a significant decrease in membrane-associated PKC in several hippocampal structures, most notably the subiculum and the CA1 region. In contrast, only modest changes in [3H]phorbol 12,13-dibutyrate binding were observed in the various other cortical and subcortical structures examined. Immunoblotting using monoclonal anti-PKC antibodies revealed an isozyme-specific 30% decrease in hippocampal membrane-associated PKC alpha, in the absence of any changes in the labeling of either the beta (I/II) or gamma isozymes. These changes were observed only after chronic (4 week) treatment with lithium, and not after acute (5 days) treatment, suggesting potential clinical relevance. Given the critical role of PKC in regulating neuronal signal transduction, lithium's effects on PKC in the limbic system represent an attractive molecular mechanism for its efficacy in treating both poles of manic-depressive illness. In addition, the decreased hippocampal membrane-associated PKC observed in the present study offers a possible explanation for lithium-induced memory impairment.

Animals↗
PubMed1992

Idazoxan down-regulates beta-adrenoceptors on C6 glioma cells in vitro.

Incubation of the C6 cells with 10 microM idazoxan (an alpha 2-adrenoceptor antagonist and putative antidepressant) for 5 days in vitro resulted in a 23% reduction of beta-adrenoceptor number and a 37% decrease in isoproterenol-induced cyclic AMP accumulation. In contrast, post-receptor stimulated cyclic AMP accumulation (by the use of forskolin or cholera toxin) was unaffected. The desensitization of the beta-adrenoceptor was accompanied by an increase in the KL/KH ratio for this receptor. Chronic in vitro treatment of C6 glioma cells with idazoxan did not significantly affect cholera or pertussis toxin catalyzed ribosylation of Gs and Gi/Go in these cells. Similarly, idazoxan did not alter either the basal levels of protein kinase C (PKC) alpha, or its cytoplasm to membrane translocation. These results suggest that idazoxan may have direct postsynaptic effects, the site of which may be at the level of receptor/G protein interaction.

Adrenergic alpha-Antagonists↗
PubMed1992

Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain.

Signal-transducing G proteins, heterotrimers formed of alpha, beta, and gamma subunits, are central to the coordination of receptor-effector communication. They are derived from a large gene family, and recent cloning and sequencing of cDNAs encoding the alpha subunits, which confer receptor and effector specificity on the heterotrimer, have defined four major classes, Gs, Gi, Gq, and G12, with at least 16 isotypes. The G proteins that coordinate receptor-effector activity are especially important in the central nervous system (CNS), where they serve widespread, critical roles in the regulation of neuronal function, maintain the functional balance between neurotransmitter systems, and, as such, represent attractive potential targets for antidepressant drugs. We describe an integrated series of animal and cell culture studies aimed at testing the hypothesis that alterations in G protein function may contribute the complex neuroadaptive mechanisms involved in the clinical actions of antidepressants, and demonstrate that long-term administration of a wide spectrum of antidepressant drugs regulate G alpha s, G alpha i1, G alpha i2, G alpha o, G alpha q, and G alpha 12 mRNA and protein expression in various areas of the rat brain. Additionally, we present the polymerase chain reaction-(PCR) mediated cross-species partial cDNA cloning and sequencing of rat and human G alpha o and rat G alpha 12, illustrate the regional distribution of G alpha mRNA and protein in rat brain, and provide evidence that different classes of antidepressants alter expression and/or stability of the recently identified G alpha 12 mRNA. We conclude that long-term treatment with antidepressant drugs exerts differential effects on G alpha mRNA and protein expression in rat brain, thus modifying signal transduction as an integral part of complex neuroadaptive mechanisms that may underlie their therapeutic efficacy. The development of novel drugs with G proteins as primary targets remains an attractive prospect for the future.

Amino Acid Sequence↗
PubMed1992

Lithium administration modulates platelet Gi in humans.

Platelet G proteins were assessed in 7 normal volunteers before and after 14 days of lithium administration at therapeutic plasma levels. Cholera and pertussis toxin catalyzed ADP-ribosylation of platelet membrane proteins were measured by SDS-PAGE. Immunoblotting with specific antibodies was used to measure platelet membrane alpha i content. There was a statistically significant 37% increase in pertussis toxin mediated ADP-ribosylation of a 40,000 Mr protein in platelet membranes after lithium administration, but cholera toxin mediated ADP-ribosylation of a 45,000 Mr protein and alpha i immunoblotting were unchanged by lithium. Increased pertussis toxin stimulated ADP-ribosylation in the absence of changes in alpha i content could be explained by a shift in platelet Gi in favor of its undissociated, inactive form. This would be consistent with increased platelet adenylyl cyclase activity found in these same subjects after lithium.

Adenosine Diphosphate Ribose↗
PubMed1992

G proteins: implications for psychiatry.

There is mounting evidence that a family of guanosine triphosphate binding proteins (G proteins) play an obligatory role in the transduction of a vast array of extracellular, receptor-detected signals across cell membranes to intracellular effectors. The author reviews the literature dealing with G protein coupling to second messenger generation, the role of G proteins in regulating both the convergence and divergence of neurotransmitter action in the CNS, and the involvement of G proteins in a variety of clinical conditions, with an emphasis on psychiatric conditions and their treatments. G proteins from the basis of signal integration in the CNS, endowing the neuron with a large degree of functional diversity. Abnormalities in the function and/or expression of G proteins have been implicated in a variety of pathophysiologic states, and a number of currently available psychotropic drugs affect G proteins. The understanding of the mechanisms by which G proteins modulate neuronal activity may be one of the keys to understanding the functioning and the complexities of the nervous system. Given their widespread, critical roles in the regulation of neuronal function, it seems likely that G proteins are involved in the pathophysiology of various major psychiatric illnesses. The development of novel, site-specific drugs with primary G protein targets remains an exciting prospect for the future.

Brain↗
PubMed1991

Chronic exposure of C6 glioma cells to desipramine desensitizes beta-adrenoceptors, but increases KL/KH ratio.

Incubation of rat glioma C6 cells with 10 microM desipramine for five days in vitro resulted in a 31% reduction of beta-adrenoceptors and a 38% reduction in isoproterenol-stimulated cyclic AMP accumulation. In contrast, forskolin or cholera toxin-stimulated cyclic AMP was unaffected by desipramine. Surprisingly, the beta-adrenoceptor desensitization was accompanied by an increase in the ratio of dissociation constants (KL/KH) for the low and high affinity states of the beta-adrenoceptor respectively and supports the concept of a complex interaction between the receptor and Gs protein.

Animals↗
PubMed1991

The mechanisms of action of lithium. I. Effects on serotoninergic and noradrenergic systems in normal subjects.

The effects of 2 weeks of lithium carbonate administration at therapeutic plasma levels were examined in 11 normal volunteers. Serotoninergic function before and after lithium administration was assessed using low-dose intravenous clomipramine hydrochloride challenge, while urinary and plasma metabolites of norepinephrine (NE) were used to assess noradrenergic systems. Long-term lithium administration in normal subjects did not significantly or consistently enhance serotonin-mediated neuroendocrine responses but did increase measures related to neuronal release of NE. No statistically significant effects of lithium on prolactin, corticotropin, or cortisol responses to serotoninergic challenge could be detected. The probability of a type II error was assessed, and a doubling of prolactin level was unlikely to have been missed, although more modest increases (less than 75%) could have been overlooked. After 2 weeks of lithium administration, there were significant increases in 24-hour urinary excretion of NE, normetanephrine, and fractional NE release, compatible with increased neuronal release of NE and a lithium-induced subsensitivity in alpha 2-adrenergic receptor function. These changes were not statistically significant after 1 week of administration, suggesting that increased NE release is characteristic of long- rather than short-term lithium administration. Since previous reports have demonstrated enhanced prolactin responses after short- but not long-term lithium use, the present study points to temporal specificity in lithium's effects on both serotoninergic and noradrenergic function. Lithium's effects on NE release were consistent but small (a 16% increase), while its effects on serotoninergic responses were larger (a 50% increase in prolactin responses) but quite inconsistent, suggesting that neither of these systems is the primary site of action of lithium.

Adrenocorticotropic Hormone↗