Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus.
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An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA(A) receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA(A) receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3alpha,5alpha-THP as well as the amplitude of GABA(A) receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and gamma-hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABA(A) receptor-mediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABA(A) receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABA(A) receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABA(A) receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in mediating specific central effects of ethanol. (+info)
Propofol combined with lorazepam for severe poly substance misuse and withdrawal states in intensive care unit: a case series and review.
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A safe, rapid, and effective way to detoxify patients from substance misuse is important in facilitating further treatment of their psychiatric or substance use disorder. This paper discusses the treatment of acute withdrawal from polysubstance misuse in three patients in the intensive care unit setting using combined sedation with a benzodiazepine, lorazepam, and a general anaesthetic, propofol. Lorazepam alone was not effective in massive doses in these cases. The advantages and mechanism of action of using multiple agents to control refractory symptoms is discussed. (+info)
Detection of benzodiazepine intake in therapeutic doses by immunoanalysis of urine: two techniques evaluated and modified for improved performance.
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We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake. (+info)
Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning.
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We investigated the effects of lorazepam, a benzodiazepine, on the allocation of study time, memory, and judgment of learning, in a cognitive task where the repetition of word presentation was manipulated. The aim was to assess whether lorazepam would affect the learning processes and/or whether the participants would be aware of the amnesic difficulty. A total of 30 healthy volunteers participated in the study, 15 of whom received a capsule containing the lorazepam drug (0.038 mg/kg) and 15 a placebo capsule. First, the accuracy of delayed judgments of learning (JOL) was measured in both groups. For the JOL ratings, results showed that all the participants benefited from word repetition. Although the overall performance was lower in the lorazepam than in the placebo group, the accuracy of the JOL ratings was preserved by the drug. Second, all the participants benefited from the repetition of learning, although the performances of the lorazepam-treated subjects remained lower than those of the placebo participants. The repetition of learning had an effect on JOL in both groups. Finally, the time spent learning each (allocation study time) pair of words was measured. For the placebo group, results revealed that study time decreased significantly with the frequency of presentation. For the lorazepam group, no effect of presentation frequency was found. Overall, our findings suggest that the lorazepam drug has a differential effect on the monitoring and the control processes involved in a learning task. The implications of these findings are discussed within the theoretical framework of metacognition. (+info)
Lorazepam and driving impairment.
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Lorazepam (Ativan), is a benzodiazepine frequently used to manage anxiety, presurgically, and as a sedative. Common side effects include sedation, dizziness, weakness, unsteadiness, and disorientation. Consequently, lorazepam can have a significant effect on driving ability. We reviewed all positive lorazepam drug-impaired driving cases submitted to the Washington State Toxicology Laboratory between January 1998 and December 2003. The mean concentration found in the blood of these drivers (n = 170) was 0.048 mg/L (std. dev. = 0.06, median = 0.03). Concentrations ranged from < 0.005 to 0.39 mg/L. Eighty-six percent of these drivers tested positive for other drugs in addition to lorazepam that may have contributed to their impairment. There were 23 cases in which lorazepam was the only drug detected. The mean concentration found in the blood of these drivers was 0.051 mg/L (median = 0.03, range < 0.01-0.38). This population was 56% male, with a mean age of 39.5 years, (range 16-72). We obtained Drug Recognition Expert reports containing details of events surrounding arrest and performance on field sobriety tests for 10 of the remaining cases in which no drugs other than lorazepam were present. Lorazepam concentrations in these cases averaged 0.050 mg/L (median = 0.04, range 0.01-0.13 mg/L). This review of these subjects indicates that lorazepam is capable of causing significant impairment to driving and psychomotor abilities, independent of the concentration detected. (+info)
Dynamic competition between contour integration and contour segmentation probed with moving stimuli.
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Line-ends, corners and junctions are important singularities for form analysis, object recognition, depth ordering or motion processing. In this study, we investigate the extent to which processing the motion of line ends depends on the spatial configuration of their immediate surround. To that aim, we used two vertical collinear line segments, translating clockwise or anti-clockwise along a circular path, together with a direction discrimination task. Direction discrimination was measured independently for outer line-ends--at both segments extremities--and inner line-ends--in between collinear segments--using line segments partially occluded by invisible masks such that the direction of either inner or outer line-ends' motion was restricted to a sinusoidal translation along a horizontal axis, and thus irrelevant for the motion task. Under these conditions, access to the direction of inner line-ends is longer and more difficult than it is for outer line-ends. Subsequent experiments show that these effects depend on the degree of collinearity between line segments. Similar experiments were performed after volunteers took a dose of Lorazepam, a benzodiazepine that facilitates the fixation of GABA on GABAA receptors. The results show that the differences between the processing of inner and outer line-ends is reduced, suggesting that the effect of the surround is modulated by inhibitory mechanisms. Using a simple model, we propose that this effect can be explained by a competition between a segmentation process based on surround suppression and contour integration through long-range horizontal connections, at or prior to motion processing stages. (+info)
Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans.
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Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI. (+info)
Short-term steroid treatment increases delta GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects.
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In this study, 48 h administration of 3alpha-OH-5beta-pregnan-20-one (3alpha,5beta-THP) or 17beta-estradiol (E2)+progesterone (P) to female rats increased expression of the delta subunit of the GABA(A) receptor (GABAR) in CA1 hippocampus. Coexpression of alpha4 and delta subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7- tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), following 48 h steroid treatment, and nearly complete blockade by 300 microM lanthanum (La3+). Because alpha4betadelta GABAR are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La3+-sensitive THIP current, representative of current gated by alpha4betadelta GABAR, was measurable only following 48 h steroid treatment. In contrast, the bicuculline-sensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48 h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 microM) and zolpidem (100 nM). These results suggest that 48 h steroid treatment increases expression of alpha4betadelta GABAR which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48 h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle. (+info)