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Biomedical subjects

W Z Potter

Publications and source records attributed to W Z Potter.

At least 19 recordsLinked to original sources
PubMed1996

Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder.

Central dopaminergic activity has been assumed to play a role in the efficacy of stimulant drugs in attention deficit/hyperactivity disorder (ADHD), although supporting evidence has been scant. This study examined baseline cerebrospinal fluid (CSF) of boys with ADHD in relation to response to three different stimulant drugs. Forty five boys with DSM-III-R-diagnosed ADHD had a lumbar puncture before double-blind trials of methylphenidate, dextroamphetamine, and placebo. Sixteen also received pemoline as part of a subsequent open trial. Stepwise linear regressions determined significant predictors of drug response. Our prior report of a positive significant correlation between CSF homovanillic acid (HVA) and ratings of hyperactivity on placebo was replicated in a new sample of 20 boys. After baseline symptom severity, CSF HVA was the best predictor of stimulant drug response, with significant independent contribution to four of the ten measures of hyperactivity that changed significantly with medication. Higher HVA predicted better drug response, and lower HVA was associated with worsening on some measures. This supports the mediating role of central dopaminergic activity in stimulant drug efficacy in childhood hyperactivity.

Attention Deficit Disorder with Hyperactivity↗
PubMed1996

G-protein level quantification in platelets and leukocytes from patients with panic disorder.

The objective of our study was to investigate if there are abnormalities in signal transducing G proteins in patients with panic disorder. We utilized selective antibodies to quantitate the levels of the G protein alpha subunits that regulate adenylyl cyclase activity (G alpha s and G alpha i2) and phosphoinositide turnover (G alpha q/11) in platelet membranes (and leukocyte membranes for G alpha s), and also carried out pertussis toxin (PT) catalyzed [32P]ADP-ribosylation in platelet membranes from a group of 13 untreated panic disorder patients, 10 untreated social phobia patients, and 12 healthy subjects. There were no significant differences among the three groups in the immunolabeling of G alpha s in platelets or leukocytes, or in the immunolabeling of G alpha i1/2, G alpha q/11, or PT-catalyzed [32P]ADP-ribosylation in platelets. Within the constraints imposed by using peripheral blood cells to reflect brain composition, our results do not provide support for G protein abnormalities in patients with panic disorder. These results contrast with those obtained using identical methodology in bipolar affective disorder, where elevated G alpha s in leukocytes has been reported (Manji et al. 1995).

Adenosine Diphosphate Ribose↗
PubMed1996

Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells.

Valproic acid (VPA) is an anticonvulsant drug with demonstrated efficacy in the treatment of mania. In the present study, we found that chronic exposure of rat C6 glioma cells to VPA induces a coordinate decrease in multiple components of the beta-adrenergic receptor- (beta-AR) coupled cyclic adenosine 3'-5'monophosphate (cAMP) generating system. Chronic VPA decreased the number of beta-ARs in a time- and concentration-dependent manner; the decrease of beta-ARs was largely beta 1-AR selective and affected beta-ARs in both the high- and low-affinity states. Chronic VPA also significantly attenuated receptor- and postreceptor-stimulated cAMP production, [3H]forskolin binding sites, immunolabeling of G alpha s 45, and cholera toxin catalyzed ADP-ribosylation of G alpha s 52 and 45. Although the precise underlying mechanisms remain to be elucidated, such profound long-term changes in the functioning of this key signaling pathway may help explain the antimanic effects of chronic VPA treatment and are worthy of further study.

Adenylyl Cyclases↗
PubMed1996

Modulation of protein kinase C isozymes and substrates by lithium: the role of myo-inositol.

Lithium is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes, but despite extensive research, the molecular mechanisms underlying its therapeutic actions have not been fully elucidated. Signal transduction pathways are in a pivotal position in the central nervous system, able to affect the functional balance between neurotransmitter systems and have clearly been demonstrated to be targets of lithium's actions. We investigate the hypothesis that the action of chronic lithium on PKC isozymes and substrates may be secondary to its potent effect in inhibiting the recycling of inositol. Rats received lithium for 3 weeks and also myo-inositol or saline twice daily via intracerebroventricular (ICV) injections. There was a significant interaction between chronic lithium and myo-inositol administration, with the chronic ICV administration of myo-inositol attenuating lithium's effects on PKC alpha, PKC epsilon, and on pertussis toxin-catalyzed [32P]ADP-ribosylation. These results suggest that the effects of chronic lithium on signal transduction pathways may stem initially from its inhibition of inositol-1-phosphatase. Given the critical role of PKC isozymes and G proteins in modulating intracellular cross-talk between neurotransmitter systems and thereby the integrative functions of the CNS, future studies using other inhibitors of inositol monophosphatases are warranted, and offer the hope for the development of more potent and more rapidly acting mood-stabilizing drugs.

Animals↗
PubMed1996

Attenuation of cyclic AMP production by carbamazepine.

The anticonvulsant carbamazepine is an effective treatment both for epilepsy and for bipolar affective disorder, but the molecular mechanism(s) underlying its therapeutic effects have not been identified. We have found that carbamazepine exerts significant inhibitory effects on the cyclic AMP (cAMP) generating system. Within the clinical therapeutic range (approximately 50 microM), carbamazepine inhibited both basal and forskolin-stimulated cAMP production, without having any significant effects on phosphodiesterase activity. Carbamazepine also exerted its inhibitory effects on the cAMP generating system in pertussis toxin-treated cells, suggesting that the action of carbamazepine was likely mediated through an inhibitory guanine nucleotide binding protein-independent mechanism. A forskolin affinity purification column was used to purify adenylyl cyclases from rat cerebral cortex, and we found that carbamazepine inhibited both basal and forskolin-stimulated activity of purified adenylyl cyclase. We also investigated the effects of carbamazepine on the levels of the transcription factor, cAMP response element binding protein in the phosphorylated (active) state, and found that carbamazepine significantly inhibited forskolin-induced phosphorylation of the cAMP response element binding protein. The data indicate that carbamazepine inhibits adenylyl cyclase activity as well as the downstream effects of activation of adenylyl cyclase.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine.

BACKGROUND: We investigated whether antagonism of alpha 2 adrenergic receptors would augment treatment response in schizophrenia, by administering idazoxan, an alpha 2 antagonist drug, to treatment-resistant patients on typical neuroleptics. METHOD: Seventeen hospitalised treatment-resistant patients with DSM-III-R schizophrenia or schizoaffective disorder were studied on typical neuroleptic treatment, on treatment with idazoxan plus typical neuroleptic, and after discontinuation of idazoxan, in fixed, non-random order, and under double-blind, placebo-controlled conditions. RESULTS: The addition of idazoxan to fluphenazine treatment resulted in significant reductions of global psychosis and total, positive and negative symptoms on the Brief Psychiatric Rating Scale, compared to neuroleptic treatment alone. Symptom improvement significantly correlated with idazoxan-induced changes in indices of noradrenergic function. In a subgroup of patients, idazoxan plus typical neuroleptic treatment compared favourably with clozapine treatment, when both were compared to typical neuroleptic treatment alone. CONCLUSIONS: The antagonism of alpha 2 receptors augmented therapeutic response to typical neuroleptic treatment in treatment-resistant patients with schizophrenia. This antagonism may contribute to clozapine's superior antipsychotic effects.

Adrenergic alpha-Antagonists↗
PubMed1996

Adrenoceptors and serotonin receptor function: relevance to antidepressant mechanisms of action.

Hypotheses of antidepressant action which argue that even norepinephrine (NE) uptake inhibitors ultimately work through potentiation of serotonergic function are critically reviewed. Preclinical electrophysiologic data can be interpreted as evidence for enhanced serotonin (5-HT) throughput as a common mechanism of action of all antidepressants. Biochemical data in rats (e.g., microdialysis) and humans (e.g., opposite effects of ECT on 5-HIAA in cerebrospinal fluid), however, suggest that more is involved than simply enhanced 5-HT function when NE uptake inhibition is combined with 5-HT uptake inhibition. The case, however, for noradrenergic effects on 5-HT function is quite strong either with regard to stimulation of alpha 1 receptors on 5-HT cell bodies or alpha 2 heteroreceptors on 5-HT nerve endings. Even the reported ability of pindolol to potentiate the antidepressant effects of 5-HT uptake inhibitors may prove to involve noradrenergic effects and not simply antagonism of 5-HT1A receptors as currently hypothesized. The biochemically specific drugs needed to directly test these concepts are not yet available. On the other hand, compounds which combine noradrenergic and serotonergic effects (e.g., alpha 2 antagonism and 5-HT2 antagonism) that go beyond those of the classic uptake inhibitors are emerging as agents to test the clinical potential of selective manipulation of these interacting neurotransmitter systems.

Adrenergic Uptake Inhibitors↗
PubMed1995

Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.

Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.

Adrenocorticotropic Hormone↗
PubMed1995

Guanine nucleotide-binding proteins in bipolar affective disorder. Effects of long-term lithium treatment.

BACKGROUND: This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions. METHODS: We used selective antibodies to quantitate the levels of the G protein alpha subunits that regulate adenylate cyclase activity (G alpha s and G alpha i2) and phosphoinositide turnover (G alpha q/11). We also quantitated levels of pertussis toxin-catalyzed phosphate 32-labeled adenosine diphosphate ([32P]ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls. RESULTS: In both tissues, the immunolabeling of the 45-kd form of G alpha s was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of G alpha i1/2, G alpha q/11, or pertussis toxin-catalyzed [32P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G alpha q/11 and higher levels of pertussis toxin-catalyzed [32P]ADP-ribosylation, which reached significance in the platelet membranes. CONCLUSIONS: Our results are complementary to the previously reported findings of elevated G alpha s levels in postmortem brain tissue form patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin-catalyzed [32P]ADP ribosylation in the subjects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating G alpha i as a target of lithium's actions.

Adenosine Diphosphate Ribose↗
PubMed1995

Signal transduction pathways. Molecular targets for lithium's actions.

Lithium remains the most widely used treatment for bipolar disorder, and this monovalent cation represents one of psychiatry's most important treatments. Despite its demonstrated efficacy in reducing both the frequency and severity of recurrent affective episodes and decades of clinical use, the molecular mechanisms underlying its therapeutic actions have not fully been elucidated. In this report, we review the exciting recent progress in the identification of key components of signal transduction pathways (in particular, guanine nucleotide-binding proteins [G proteins], adenylyl cyclases, and protein kinase C isozymes) as targets for lithium's actions and attempt to integrate these effects with the large body of data emphasizing alterations in various neurotransmitter (particularly monoaminergic) systems. Regulation of signal transduction within critical regions of the brain by lithium affects the function of multiple neurotransmitter systems and may thus explain lithium's efficacy in protecting susceptible individuals from spontaneous, stress-induced, and drug-induced cyclic affective episodes. Recent evidence has also demonstrated significant effects of lithium on the regulation of gene expression in the central nervous system, effects that may play a major role in the long-term stabilization of mood. The identification of these intracellular targets for lithium's actions offers the potential for the development of novel, improved therapeutic agents and, in conjunction with molecular genetic approaches, may facilitate our understanding of the biological factors predisposing individuals to manic-depressive illness.

Adenylyl Cyclases↗
PubMed1995

Regional brain glucose metabolism after acute alpha 2-blockade by idazoxan.

BACKGROUND: Several classes of antidepressant drugs act on alpha 2-adrenergic receptors. Studies of patients with disorders responsive to treatment with these drugs report group differences in ex vivo measures of alpha 2-binding and in vivo responses mediated by alpha 2-receptors. Measurement of regional brain metabolic response to an alpha 2-antagonist may be a useful method for further definition of the role alpha 2-receptor regulation plays in the treatment of neuropsychiatric disorders. METHODS: Regional brain glucose metabolism was measured before and after infusion with 200 micrograms/kg idazoxan with use of 18F-fluoro-2-deoxyglucose positron emission tomography in 13 healthy men. Arterial drug concentration, behavioral responses, and cardiovascular responses were also measured. RESULTS: The absolute and normalized glucose metabolic rate significantly increased in primary visual cortex. Significant increases and decreases occurred in normalized metabolic rates in prefrontal cortical regions. Measurement of metabolic effects occurred during the peak cardiovascular response. CONCLUSIONS: Our findings are consistent with regionally specific effects of alpha 2-blockade. This method may be useful for the study of alpha 2-receptor function in humans.

Adrenergic alpha-Antagonists↗
PubMed1995

Alterations in cyclic AMP generation and G protein subunits following transient ischemia in gerbil hippocampus.

We examined alterations in the cyclic AMP generating system and G protein subunits in gerbil hippocampus following 10 min of transient ischemia. In hippocampal slices, basal and isoproterenol- and forskolin-stimulated cyclic AMP accumulations were markedly increased at 6 and 24 h after ischemia. Interestingly, both the inhibition of forskolin-stimulated cyclic AMP and the potentiation of beta-adrenoceptor-stimulated cyclic AMP by a gamma-aminobutyric acidB receptor agonist were attenuated at these time points. Ischemia did not affect the immunolabeling of any of the G protein alpha subunits; only that of beta subunits was significantly decreased, by 28.2%, 4 days after ischemia. In contrast, pertussis toxin-catalyzed [32P]ADP ribosylation declined progressively during the late recirculation period, reaching a significant reduction (25.4%) at 6 h after ischemia. These results suggest that ischemia affects the heterotrimeric conformation (alpha beta gamma) of Gi/Go during the recirculation period, thereby leading to increased cyclic AMP production. Because cyclic AMP-dependent protein kinase A modulates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-kainate receptor channels, postischemic sensitization of the cyclic AMP generating system may contribute to neuronal degeneration in the hippocampus.

Adenosine Diphosphate Ribose↗
PubMed1995

Down-regulation of PKC alpha by lithium in vitro.

In recent years, research aimed at the elucidation of lithium's molecular mechanisms has focused on signal transduction pathways. This research has demonstrated that lithium has multiple effects on the phosphoinositide turnover signaling system. We have previously demonstrated that chronic (but not acute) in vitro exposure of HL60 cells to 1 mM lithium reduces both receptor and phorbol-ester-mediated Na+/H+ activity without affecting agonist-induced increases in intracellular Ca2+ or phosphoinositide breakdown, findings which suggest an attenuation of protein kinase C (PKC) function. The present study sought to measure the in vitro effects of lithium on PKC more directly and demonstrated that 5-day in vitro exposure of HL60 cells to either 1 mM or 10 mM lithium chloride dramatically reduces PKC alpha in both cytosolic and membrane fractions. Given the critical role of PKC in regulating neuronal signal transduction, these effects may play a major role in lithium's mood-stabilizing effects.

Autoradiography↗
PubMed1995

Bupropion: a review of its mechanism of antidepressant activity.

BACKGROUND: The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action. METHOD: A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion. RESULTS: (1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders. CONCLUSION: The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.

Animals↗
PubMed1995

Pharmacologic profile of natural products used to treat psychotic illnesses.

Natural products have a long history of being the sources for therapeutic drugs in medicine. Investigations of natural products also have the potential for enhancing our understanding about the pathophysiology and treatment of various disorders. The screening assays described here were conducted on the phytochemical and pharmacological profiles of natural products used to treat psychotic illnesses in Korean traditional medicine, which are eligibly archived in Tongeuibogam, a traditional medicinal book in Korea. Two rounds of radioligand receptor binding assays on natural products demonstrated that many plants show potent selectivity to various receptors, especially monoamine receptors presumed to be involved in mental disorders. Further studies for the pharmacologic activity of active ingredients and in vivo behavioral profiles focusing on the central nervous system (CNS) effects are currently under way with these plant extracts. These investigations may lead to the development of new psychotropic drugs with no serious side effects, a major concern for modern psychopharmacology.

Animals↗