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Annals of the New York Academy of Sciences 12/2006; 739(1):292 - 298. · 3.15 Impact Factor
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ABSTRACT: This research explored the effect of cytokines and neurosteroids on the GABAergic and I glutamatergic neurotransmitter systems in the CNS. lnterleukin-1 (IL-1) augmented GABAA receptor function in behavioral, neurochemical and electrophysiological paradigms both in vivo and in vitro. These effects of IL-1 were inhibited by the IL-1 receptor antagonist suggesting an indirect effect of IL-1 at its own receptor in the modulation of the GABAA receptor. Subsequent experiments demonstrated a negative modulatory role of IL-1 on NMDA receptor-mediated intracellular calcium increases which was unique to both IL-1 and to the NMDA receptor. These results provided the first direct evidence of a functional interaction of IL-1 with the NMDA receptor and implies a beneficial role of this cytokine in neurodegenerative processes. Additional work in our laboratory confirmed that pregnenolone sulfate (PS) potentiated the NMDA receptor-mediated increases in calcium flux, most likely acting at a unique steroid recognition site on the NMDA receptor. Further studies demonstrated a neurotoxic effect of PS on these cortical neurons in vitro. This study also demonstrated a synergistic toxic effect of PS and NMDA/glycine, providing additional evidence of the possible involvement of PS in the excitotoxic damage.
08/1997;
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ABSTRACT: The GABAA receptor, as assessed by ligand binding and chloride flux measurement in vivo and in vitro, is down-regulated in response to chronic benzodiazepine exposure. The mRNA levels of the 1 and 2 subunits of the receptor are also reduced. We have isolated the promoter of the gene encoding the 1 subunit of the GABAA receptor to elucidate the regulatory mechanism of its expression. A DNA segment 650 bp long has been Isolated that includes 151 bp of untranslated 5’end of the cDNA sequence and 500 bp of potential promoter-enhancer region. The transcriptional activity of this DNA segment linked to the firefly luciferase gene showed a strong orientation specificity. The promoter activity was localized to a 60-bp segment by deletion mapping. Mobility shift binding assay results suggest that this segment may interact with one or more factors in HeLa cell nuclear extracts to form a transcriptional complex. Primary cultures of embryonic chick cortical cells transfected with the promoter-luciferase construct were treated chronically with lorazepam. Transcriptional activity of this promoter construct was strongly repressed by chronic administration of lorazepam.
Journal of Neurochemistry 03/1994; 62(4):1643 - 1646. · 4.06 Impact Factor
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ABSTRACT: Tolerance to the sedative and anticonvulsant effects of benzodiazepines has been reported, but cross-tolerance among benzodiazepines is poorly characterized. To evaluate cross-tolerance between lorazepam and alprazolam in a reliable anticonvulsant pharmacodynamic model, we treated mice with either drug for 14 days, and with the two drugs sequentially for 7 days each. Pentylenetetrazole-induced seizure thresholds were similar in mice treated for 14 days with lorazepam or alprazolam, 2 mg/kg/day. For both compounds, a discontinuation effect characterized by reduced seizure threshold occurred at 4 days after discontinuation. Substitution of alprazolam for lorazepam after 1 week, and vice versa, did not interrupt tolerance. [3H]flumazenil binding in vivo was downregulated in cortex after 14 days of either drug. However, binding was also reduced in hippocampus for lorazepam but not for alprazolam. Substitution of alprazolam for lorazepam resulted in downregulation in cortex only, similar to lorazepam alone. Conversely, substitution of lorazepam for alprazolam led to binding changes similar to lorazepam alone. These data demonstrate cross-tolerance to the convulsant effects of pentylenetetrazole between lorazepam and alprazolam. However, effects of the two compounds on benzodiazepine receptor binding in hippocampus remain distinct.
Psychopharmacologia 03/1993; 111(1):91-95. · 4.08 Impact Factor
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ABSTRACT: Clonazepam administration may lead to tolerance and withdrawal syndromes in clinical use. To assess the effects of this drug in a mouse model, we administered clonazepam (1.5 mg/kg/day) for 1–14 days and evaluated open-field activity, cortical clonazepam concentrations, and binding and function at the GABAA receptor. We also evaluated the same parameters at 1, 2, 4 and 7 days after discontinuation of 7 days of clonazepam administration. During chronic treatment, tolerance developed to the effects of clonazepam on motor activity at 7 days and persisted to 14 days. Cortical clonazepam concentrations did not change significantly during this period. Benzodiazepine receptor binding in vivo was decreased in cortex at days 7 and 14 of clonazepam, but was unchanged in other regions. Binding determined in vitro was also decreased at these points. TBPS (t-butylbicyclophosphorothionate) binding in cortex was slightly, but not significantly, decreased. Muscimol-stimulated chloride uptake was also decreased at days 7 and 14. After clonazepam discontinuation, open-field activity returned to control values at 1 day but was increased above baseline at 4 days. Benzodiazepine binding in vivo and in vitro, as well as TBPS binding, were increased at 4 days. Muscimol-stimulated chloride uptake was also increased at this point. These results indicate that chronic clonazepam administration is associated with tolerance to motoric effects, with discontinuation effects, and with receptor alterations in a mouse model. Clonazepam is similar to other benzodiazepines in this regard.
Psychopharmacologia 05/1991; 104(2):225-230. · 4.08 Impact Factor
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ABSTRACT: Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro 15–1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (>0.2 mg/kg), receptor binding by [3H]Ro 15–1788 likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02–0.05 mg/kg), which resulted in cortex concentrations of 2–7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of ≤0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7–7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7–5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number. The brain concentration vs. receptor occupancy relationships for triazolam and estazolam resemble those for other benzodiaze-pines, but alprazolam appears to be anomalous in that low brain concentrations increase benzodiazepine receptor number.
Journal of Neurochemistry 10/1987; 49(5):1595 - 1601. · 4.06 Impact Factor
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ABSTRACT: Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P < 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P < 0.05), thereby increasing elimination half-life (t½) in elderly men (8.2 vs. 4.7 hours; P < 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P < 0.02), causing increased t½ (7.6 vs. 5.9 hours; P < 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P < 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t½ in obese subjects (13.3 vs. 5.9 hours; P < 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.
Clinical Pharmacology & Therapeutics 07/1987; 42(2):193-200. · 6.04 Impact Factor
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ABSTRACT: The triazalobenzodiazepine compound alprazolam may have unique clinical effects compared to other benzodiazepines, and both behavioral and neurochemical studies have indicated unusual results after acute doses of alprazolam. To determine the effects of chronic dosage in mice, alprazolam (2 mg/ kg/day) was administered via osmotic pumps for 1–14 days, and open-field activity, plasma and brain concentrations, benzodiazepine receptor binding in vivo and in vitro, ([35S]TBPS) binding, and muscimol-stimulated chloride uptake were determined. Alprazolam decreased motor activity after 1 and 2 days, but tolerance developed by day 4 and persisted to day 14. Plasma and brain concentrations remained constant during the 2-week period. Benzodiazepine receptor binding in vivo was decreased at day 4 compared to day 1 in cortex (CX) and hypothalamus (HYPO), and remained depressed to day 14 in CX but not HYPO. Benzodiazepine binding in vitro and [35S]TBPS binding were decreased in CX at day 7. Muscimol-stimulated [36Cl−] uptake was decreased at days 4 and 7 compared to day 1, but at day 14 uptake was similar to day 1. These results indicate that behavioral tolerance and receptor downregulation develop rapidly during chronic alprazolam administration. Behavioral and neurochemical changes were similar to those associated with lorazepam administration, but occurred more rapidly and with different regional specificity.
Biochemical Pharmacology.
