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ABSTRACT: The endocannabinoid system is composed of cannabinoid receptors, their endogenous ligands, the endocannabinoids, and the enzymes
that produce and inactivate them. Endocannabinoids are a new family of lipid mediators, which includes amides, esters, and
ethers of long-chain polyunsaturated fatty acids. Endocannabinoids engage the cell surface receptors that are targeted by
Δ9-tetrahydrocannabinol (Δ9-THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The pathways leading to the synthesis and release of endocannabinoids from neuronal
and nonneuronal cells are still rather uncertain. Instead, they are synthesized on demand through cleavage of membrane precursors
and are involved in various short-range signaling processes. In the brain, they combine with CB1 cannabinoid receptors (CB1Rs)
on axon terminals to regulate ion channel activity and neurotransmitter release. The endocannabinoid system is shown to be
involved in an increasing number of pathological conditions. Their ability to modulate synaptic efficacy has a wide range
of functional consequences and provides unique therapeutic possibilities. In this chapter, we aim to provide recent progress
in our understanding of the endocannabinoid system in the brain. First, the structure, anatomical distribution, and signal
transduction mechanism of cannabinoid receptors are described. The synthetic pathways of endocannabinoids are discussed, along
with the putative mechanisms of their release, uptake, and degradation. Finally, the possible role of the endocannabinoid
system in the central nervous system is discussed in relation to neurotransmitter release, synaptic plasticity, and the therapeutic
role in various disease conditions including alcohol abuse.
02/2008: pages 343-384;
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ABSTRACT: Magnesium sulfate (MgSO(4)) is widely used for the treatment and prevention of convulsions associated with preeclampsia. The aim of this study was to determine whether it alters the dose of bupivacaine required to produce convulsions in awake pregnant rats.
Twelve pregnant rats were pretreated with an intravenous infusion of either MgSO(4) or saline. Following 2 h of the pretreatment, bupivacaine was concomitantly infused in all animals until the onset of convulsions. Mean arterial pressure (MAP) and heart rate (HR) were monitored throughout. Serial arterial samples were obtained during the infusion. At the onset of convulsions, fetuses were delivered and maternal and fetal blood, as well as various tissue samples, were obtained. All samples were assayed for bupivacaine and magnesium concentrations.
Maternal MAP and HR decreased significantly shortly after the initiation of MgSO(4), while saline did not affect these measurements. Baseline concentrations of magnesium in plasma were similar in both MgSO(4) and saline groups; magnesium increased significantly during the infusion of MgSO(4). The dose (mean+/-SD) of bupivacaine required to produce convulsions in the animals receiving MgSO(4) was significantly larger (10.2+/-1.9 mg/kg) than that in the saline group (5.9+/-1.0 mg/kg) (P<0.05). As a consequence, bupivacaine concentrations in the brain and liver at the onset of convulsions were greater in animals receiving MgSO(4) (16.0+/-8.4 and 18.2+/-4.3 microg/g wet weight, respectively) than in those given saline (12.1+/-2.2 and 9.9+/-2.0 microg/g wet weight, respectively). Fetal bupivacaine concentrations at the onset of convulsions in the MgSO(4) group were also higher than those in saline group. However, the rate of placental transfer of this drug was similar between MgSO(4) and saline animals.
This study demonstrates that the clinically used concentration of magnesium sulfate increased the threshold of bupivacaine-induced convulsions in awake rats.
International Journal of Obstetric Anesthesia 02/2005; 14(1):32-6. · 1.39 Impact Factor
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ABSTRACT: Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB(1) receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) receptor density (B(max)) was observed in DS (644.6+/-48.8 fmol/mg protein) compared with matched controls (493.3+/-52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14+/-0.08 vs control; 1.12+/-0.10 nM). Higher density of CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.
Molecular Psychiatry 03/2004; 9(2):184-90. · 13.67 Impact Factor
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ABSTRACT: Post-traumatic stress disorder (PTSD) is often comorbid with major depressive episodes (MDEs) and both conditions carry a higher rate of suicidal behavior. Hypothalamic-pituitary-adrenal (HPA) axis and serotonin abnormalities are associated with both conditions and suicidal behavior, but their inter-relation is not known. We determined cortisol response to placebo or fenfluramine in MDE, MDE and PTSD (MDE+PTSD), and healthy volunteers (HVs) and examined the relation of cortisol responses to suicidal behavior. A total of 58 medication-free patients with MDE (13 had MDE+PTSD) and 24 HVs were studied. They received placebo on the first day and fenfluramine on the second day. Cortisol levels were drawn before challenge and for 5 h thereafter. The MDE+PTSD group had the lowest plasma cortisol, the MDE group had the highest, and HVs had intermediate levels. There were no group differences in cortisol response to fenfluramine. Suicidal behavior, sex, and childhood history of abuse were not predictors of baseline or postchallenge plasma cortisol. Cortisol levels increased with age. This study finds elevated cortisol levels in MDE and is the first report of lower cortisol levels in MDE+PTSD. The findings underscore the impact of comorbidity of PTSD with MDE and highlight the importance of considering comorbidity in psychobiology.
Neuropsychopharmacology 04/2003; 28(3):591-8. · 7.99 Impact Factor
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ABSTRACT: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression.
The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects.
No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)".
This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.
Biological Psychiatry 10/2001; 50(5):313-22. · 8.28 Impact Factor
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ABSTRACT: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT.
To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse.
Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode.
Two university-based hospitals and 1 private psychiatric hospital.
Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study.
Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28).
Relapse of major depressive episode, compared among the 3 continuation groups.
Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse.
Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.
JAMA The Journal of the American Medical Association 04/2001; 285(10):1299-307. · 30.03 Impact Factor
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ABSTRACT: We investigated a possible mechanism of action for the antidepressant response to light-phase advances of the circadian clock-by measuring the onset of melatonin secretion before and after light treatment in the morning or evening.
Plasma melatonin was sampled in 42 patients with seasonal affective disorder, in the evening or overnight while depressed and after 10 to 14 days of light therapy (10 000 lux for 30 minutes) when symptoms were reassessed.
Morning light produced phase advances of the melatonin rhythm, while evening light produced delays, the magnitude depending on the interval between melatonin onset and light exposure, or circadian time (morning, 7.5 to 11 hours; evening, 1.5 to 3 hours). Delays were larger the later the evening light (r = 0.40), while advances were larger the earlier the morning light (r = 0.50). Although depression ratings were similar with light at either time of day, response to morning light increased with the size of phase advances up to 2.7 hours (r = 0.44) regardless of baseline phase position, while there was no such correlation for evening light. In an expanded sample (N = 80) with the sleep midpoint used as a reference anchor for circadian time, early morning light exposure was superior to late morning and to evening exposure.
The antidepressant effect of light is potentiated by early-morning administration in circadian time, optimally about 8.5 hours after melatonin onset or 2.5 hours after the sleep midpoint.
Archives of General Psychiatry 02/2001; 58(1):69-75. · 12.02 Impact Factor
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ABSTRACT: In an earlier study, we reported that chronic ethanol (EtOH) stimulates the formation of anandamide in human SK-N-SH cells. In the present study, we investigated the effect of chronic EtOH on the formation of yet another cannabinoid receptor (CB1) agonist, 2-arachidonylglycerol (2-AG), in cerebellar granule neurons (CGNs). The formation of 2-[(3)H]AG without any stimulation was more pronounced in the older cultures than in younger cultures. Exposure of CGNs to EtOH led to a significant increase in the level of 2-[(3)H]AG (P<0.05). Incubation with the anandamidehydrolase inhibitor phenylmethylsulfonyl fluoride and EtOH did result in an additive increase in 2-[(3)H]AG, but did not with E-6-(bromomethylene)tetrahydro-3-(1-naphthelenyl)-2H-pyran-2-one. The formation of 2-[(3)H]AG was enhanced by ionomycin in both the control and EtOH-exposed CGNs, and the ionomycin-stimulated 2-[(3)H]AG synthesis was inhibited by the intracellular chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Further, glutamate increased the formation of 2-[(3)H]AG only in control CGNs. MK-801 inhibited the EtOH-induced 2-[(3)H]AG synthesis, suggesting the participation of intracellular Ca(2+) in EtOH-induced 2-[(3)H]AG synthesis. The dopamine receptor (D2) agonist did not modify the 2-AG synthesis in either the control or EtOH-exposed CGNs. However, the D2 receptor antagonist inhibited the EtOH-induced formation of 2-[(3)H]AG. The EtOH-induced 2-[(3)H]AG formation was inhibited by SR141716A and pertussis toxin, suggesting the CB1 receptor- and Gi/o-protein-mediated regulation of 2-AG. The observed increase in 2-AG level in CGNs is possibly a mechanism for neuronal adaptation to the continuous presence of EtOH. These findings indicate that some of the pharmacological actions of EtOH may involve alterations in the endocannabinoid signaling system.
Biochimica et Biophysica Acta 12/2000; 1535(1):78-86. · 4.66 Impact Factor
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ABSTRACT: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans.
In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM.
Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023).
The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.
Biological Psychiatry 11/2000; 48(7):627-40. · 8.28 Impact Factor
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ABSTRACT: This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats.
All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry.
The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 h after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart.
These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable. Whether this slow elimination of 3'-hydroxybupivacaine causes any adverse effects on the fetus-newborn needs to be explored.
Anesthesiology 11/2000; 93(4):1069-74. · 5.36 Impact Factor
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A Abi-Dargham,
J Rodenhiser,
D Printz,
Y Zea-Ponce,
R Gil,
L S Kegeles,
R Weiss, T B Cooper,
J J Mann,
R L Van Heertum,
J M Gorman,
M Laruelle
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ABSTRACT: The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D(2) receptor. We measured in vivo occupancy of striatal D(2) receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D(2) receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (19% +/- 11%) compared with control subjects (9% +/- 7%, P = 0.003). The increased occupancy of D(2) receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D(2) receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.
Proceedings of the National Academy of Sciences 08/2000; 97(14):8104-9. · 9.68 Impact Factor
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ABSTRACT: The metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have been considered pharmacologically inactive when administered systemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of cocaine and its metabolites when administered systemically to awake rats fitted with catheters for long-term monitoring.
Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce sequential behavioral alterations and central nervous system and cardiovascular toxic effects. Arterial blood pressure and heart rate were monitored continuously. Plasma and tissue samples were analyzed for all compounds by capillary gas chromatography-mass spectrometry.
The dose of norcocaine necessary to produce toxic effects was smaller than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic manifestations at infusion rates that produced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl ester, respectively, were necessary to produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at doses 100 times greater than cocaine.
These results indicate that benzoylecgonine and ecgonine methyl ester are not as toxic as cocaine, norcocaine, or cocaethylene when administered intravenously to pharmacologically naive rats.
Anesthesiology 07/1999; 90(6):1684-90. · 5.36 Impact Factor
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ABSTRACT: Gender differences may significantly influence the toxicity of cocaine in mammals. In this study, the influence of gender on the toxicity of norcocaine, a pharmacologically active metabolite of cocaine, was compared with its parent compound in adult male and female rats. In addition, the plasma and tissue norcocaine concentrations were evaluated after the administration of norcocaine and cocaine. Norcocaine or cocaine was administered intravenously at a rate of 2 mg/kg/min until circulatory collapse. Arterial blood samples as well as heart, liver, and brain tissues were obtained at circulatory collapse for the measurement of concentrations of norcocaine as well as cocaine and its major metabolites. There were no gender-related differences in the doses of norcocaine required to produce circulatory collapse; however, there were significant gender-related differences in the norcocaine tissue-to-plasma concentration ratios (T:P ratios). After the administration of norcocaine, T:P ratios for heart, liver, and brain tissue were significantly greater in males. Furthermore, after cocaine administration, the hepatic norcocaine T:P ratio was approximately 3-fold greater in the male rats than in the female rats. In contrast, female rats had a greater percentage of norcocaine in the plasma at circulatory collapse after acute cocaine administration. Although no gender differences in the lethality of norcocaine were observed, it remains to be seen whether the gender differences in the distribution and uptake of norcocaine play a role in the hepatotoxicity of the drug, particularly after chronic exposure.
Journal of Laboratory and Clinical Medicine 07/1999; 133(6):590-6. · 2.62 Impact Factor
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ABSTRACT: A procedure was developed for the determination of memantine in plasma using liquid chromatography with fluorescence detection. Following a liquid-liquid extraction from 1 ml of plasma containing the internal standard amantadine, the extract was derivatized at room temperature with dansyl chloride, and the highly fluorescent derivatives were chromatographed with a reversed-phase C18 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated memantine and amantadine were eluted in less than 13 min with no interference from endogenous material. The calibration curve was linear over the concentration range of 3-400 ng/ml with inter- and intra-assay imprecision (C.V.) of less than 10%. The limit of quantitation was 3 ng/ml, and no major antidepressant, neuroleptic or their respective metabolites interfered with the quantitation of memantine. This method could also be applied to the quantitation of amantadine.
Journal of chromatography. B, Biomedical sciences and applications 07/1999; 729(1-2):217-24.
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ABSTRACT: The aim of this project was to examine the disposition of maternally administered cocaethylene in the fetus.
Pregnant rats with long-term catheter placement received an intravenous infusion of cocaethylene during a period of 30 minutes. At either the completion of the infusion or 6 hours after the infusion the fetuses were delivered by hysterotomy. Maternal and fetal blood and major tissue samples were obtained for assays of cocaethylene and its metabolites.
Cocaethylene was present in all samples obtained at the end of the infusion, but after 6 hours it was no longer detectable in the maternal and fetal systemic circulations. However, a substantial amount of cocaethylene was still present in the placenta on both the maternal and fetal sides, with the concentration on the maternal side being higher, indicating that the placenta stores cocaethylene. At the end of the infusion benzoylecgonine was found in all samples and the maternal concentrations were higher than the corresponding fetal concentrations. This order was reversed 6 hours after infusion. Extremely high concentrations of cocaethylene and benzoylecgonine were found in the amnion.
These results suggest that the placenta limits the transfer of cocaethylene to the fetus. The high affinity of this compound for extraplacental sites cannot be ignored.
American Journal of Obstetrics and Gynecology 06/1999; 180(5):1289-96. · 3.47 Impact Factor
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ABSTRACT: The goal of this study was to compare the efficacy and side effects of two doses of haloperidol and placebo in the treatment of psychosis and disruptive behaviors in patients with Alzheimer's disease.
In a 6-week random-assignment, double-blind, placebo-controlled trial (phase A), haloperidol, 2-3 mg/day (standard dose), and haloperidol, 0.50-0.75 mg/day (low dose), were compared in 71 outpatients with Alzheimer's disease. For the subsequent 6-week double-blind crossover phase (phase B), patients taking standard- or low-dose haloperidol were switched to placebo, and patients taking placebo were randomly assigned to standard- or low-dose haloperidol.
For the 60 patients who completed phase A, standard-dose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. Response rates according to three sets of criteria were greater with the standard dose (55%-60%) than the low dose (25%-35%) and placebo (25%-30%). The advantage of standard dose over low dose was replicated in phase B. In phase A, extrapyramidal signs tended to be greater with the standard dose than in the other two conditions, primarily because of a subgroup (20%) who developed moderate to severe signs. Low-dose haloperidol did not differ from placebo on any measure of efficacy or side effects.
The results indicated a favorable therapeutic profile for haloperidol in doses of 2-3 mg/day, although a subgroup developed moderate to severe extrapyramidal signs. A starting dose of 1 mg/day with gradual, upward dose titration is recommended. The narrow therapeutic window observed with haloperidol may also apply to other neuroleptics used in Alzheimer's disease patients with psychosis and disruptive behaviors.
American Journal of Psychiatry 12/1998; 155(11):1512-20. · 12.54 Impact Factor
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ABSTRACT: Animal studies suggest that vasopressin has cognitive-enhancing properties and oxytocin may have amnestic effects. A clinical report suggests that the acute increase in oxytocin-associated neurophysin predicts clinical response to electroconvulsive therapy (ECT) in depressed patients.
Medication-free patients with major depression were randomized to receive right unilateral or bilateral ECT administered with electrical stimulus intensity at either just above seizure threshold or at 150% above seizure threshold. The associations between plasma vasopressin, oxytocin, ECT treatment parameters, clinical outcome, and cognitive effects were assessed.
The sample comprised 55 patients. At the second ECT, patients receiving ECT at 150% above initial seizure threshold had significantly greater increases in plasma vasopressin than patients receiving low-dose ECT (ps < .01-.04), with no effects of electrode placement. At the second and ninth ECT treatments, the vasopressin or oxytocin surges were not associated with clinical improvement, seizure duration, time to orientation, or memory test performance. There were inverse trend-level associations between the acute surge in oxytocin levels at the ninth ECT and clinical response, contradicting a report in the literature.
Overall, these findings do not support the hypothesis that diencephalic seizure propagation is central to the mechanism of action of ECT.
Biological Psychiatry 10/1998; 44(7):610-6. · 8.28 Impact Factor
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ABSTRACT: The effects of chronic ethanol (EtOH) consumption on the central nervous system may be related in part to its action on biological membranes by altering various receptor functions. In the current study, we examined the effects of chronic EtOH (4 day inhalation) on cannabinoid receptors (CB1) labeled with [3H]CP55,940 in synaptic plasma membranes (SPM) isolated from mouse brain. Our results indicate the presence of a high level of CB1 receptors in controls (Bmax=12.0+/-0.3 pmol mg-1 protein) which decreased significantly (-58%) in SPM from mouse brain chronically exposed to EtOH. This effect occurs without any changes in the receptor affinity (Kd=2. 3+/-0.3 nM for control and 2.9+/-0.3 nM for EtOH group, P>0.05). Dissociation kinetic results showed a dissociation rate constant (K-1) of 0.09+/-0.01 min-1 for control and this dissociation rate constant decreased significantly in the chronic EtOH treated mice brain (0.05+/-0.01 min-1, P<0.05). The competition studies with anandamide resulted in a substantial decrease in [3H]CP55,940 binding in both the control and EtOH group, with a decrease (P<0.05) in the Ki values in the SPM of chronic EtOH exposed mice. Hill transformation analysis showed an nH close to one in control (0. 92+/-0.01). This did not change significantly after chronic EtOH (0. 95+/-0.01) administration, which indicates the existence of a single class of receptor for [3H]CP55,940 binding in SPM from control and EtOH treated mice. The observed down-regulation of CB1 receptors by chronic EtOH may indicate the involvement of cannabinoid receptors in EtOH tolerance and dependence.
Brain Research 05/1998; 793(1-2):212-8. · 2.73 Impact Factor
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ABSTRACT: The enzyme phospholipase A2 (PLA2), which catalyzes the hydrolysis of an ester bond at the sn-2 position of 1,2-sn-diacylglycerols, has been suggested to play an important role in regulating cellular functions. Although ethanol (EtOH)-induced activation of PLA2 activity was reported previously by us in mouse brain (Hungund et al., Neurochem Int 25: 321-325, 1994), its subcellular localization and biochemical properties have not been investigated. Therefore, in the present study, we examined the subcellular localization and characterization of EtOH-activated PLA2 activity in mouse brain. The results indicated that EtOH treatment decreased the specific activity of PLA2 for the first 48 hr, and then the activity increased and reached a peak level in both cytosol (1.6-fold) and membrane (1.7-fold) fractions at 96 hr of exposure. Specific activity was found to be higher in the membrane fraction than in the cytosol. Using differential density gradient centrifugation, subcellular localization of the membrane-associated PLA2 revealed that most of the EtOH-activated PLA2 specific activity was associated with the synaptic membrane (44%) followed by the nuclear membrane (13%). No significant increase in the PLA2 specific activity of mitochondrial and microsomal membranes was observed. No activity was detected in the myelin membrane. PLA2 specific activity of membranes from control and EtOH-exposed mouse brain exhibited preference for arachidonic acid over linoleic acid at the sn-2 position of glycero-3-phosphocholine (PC). No detectable PLA2 specific activity was found when PC containing oleic acid at the sn-2 position was used as a substrate. The present results also indicated that the PLA2 specific activity of membrane from control and EtOH-exposed mouse brain was insensitive to dithiothreitol, strongly stimulated by Ca2+, enhanced by glycerol, and inhibited by the cytosolic PLA2 (cPLA2) inhibitor methyl arachidonyl fluorophosphonate with an IC50 value of 3.33 microM. In summary, results suggest that the properties of EtOH-activated PLA2 activity found in mouse brain membrane fraction are similar to those of cPLA2 found in variety of cells, including mammalian brain.
Biochemical Pharmacology 02/1998; 55(4):515-21. · 4.70 Impact Factor
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ABSTRACT: Human neuroblastoma cells were exposed to ethanol (EtOH; 100 mM) in culture for various time periods. It was found that chronic EtOH exposure increased the arachidonyl-specific phospholipase A2 (PLA2) activity significantly in both cytosol (1.6-fold) and membrane (2.2-fold) fractions when 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine was used as a substrate. This arachidonyl-specific PLA2 activity progressively increased with increasing duration of EtOH exposure and reached peak level at 72-hr EtOH exposure (chronic). A significant amount of the PLA2 activity was associated with the membrane fraction. No significant difference in PLA2 activity was observed when 1-palmitoyl-2 oleoyl or linoleoyl-sn-glycero-3-phosphocholine was used as a substrate. It was also found that co-treatment of neuroblastoma cells with ganglioside GM1 reduced the EtOH-induced activation of arachidonyl-specific PLA2 activity. The present results indicate that arachidonic acid-specific PLA2 may play a role in adaptation mechanisms to chronic EtOH in cultured neuroblastoma cells. Ganglioside GM1, in part, may exert its neuroprotective effects by modulating arachidonyl-specific PLA2 activity in chronic EtOH-exposed neuroblastoma cells.
Alcoholism Clinical and Experimental Research 11/1997; 21(7):1199-203. · 3.34 Impact Factor
