[123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain.
ABSTRACT SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 +/- 0.01 mg/kg (mean +/- SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with < 3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. < 3%) of BZ receptors and that BZ binding sites have a significant (i.e. > 97%) receptor reserve.
- SourceAvailable from: Paul Robert Alexander Stokes
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- "The aim of this present study was to determine whether a reduction in synaptic α1- subtype GABA-BZR affinity produced by increases in synaptic GABA levels could be detected in the living human brain. We used tiagabine, which increases synaptic GABA levels by selectively inhibiting the GABA transporter 1 (GAT1) in experimental animal studies (Fink-Jensen et al., 1992; Richards and Bowery, 1996; Sybirska et al., 1993) and in a human case report (During et al., 1992). Tiagabine also produces physiological changes consistent with increased GABA concentrations in recent MEG studies (Muthukumaraswamy et al., 2013; Muthukumaraswamy et al., 2012). "
ABSTRACT: The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [11C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [11C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [11C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [11C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [11C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [11C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.NeuroImage 05/2014; 99. DOI:10.1016/j.neuroimage.2014.05.035 · 6.36 Impact Factor
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- "In each test session, a different drug was administered at a dosage selected to have mild psychogenic and sedating effects (Boroojerdi, Battaglia, Muellbacher, & Cohen, 2001). The following agents were used (within subjects): (i) DM (120 mg, 40 ml of Dampo syrup), a potent noncompetitive NMDA receptor antagonist (Wong, Coulter, Choi, & Prince, 1988); (ii) LZP (1.5 mg, pill), a short-acting benzodiazepine that at this dose produces functional potentiation in specifically the GABA A receptors (Sybirska et al., 1993); and (iii) SCO (1.5-mg dermal patch behind the ear), a muscarinic receptor antagonist (Frey et al., 1992). Because the intake differed for all three drugs, the subjects received a pill, syrup, and a patch behind the ear in each session. "
ABSTRACT: Consciousness can be manipulated in many ways. Here, we seek to understand whether two such ways, visual masking and pharmacological intervention, share a common pathway in manipulating visual consciousness. We recorded EEG from human participants who performed a backward-masking task in which they had to detect a masked figure form its background (masking strength was varied across trials). In a within-subject design, participants received dextromethorphan (a N-methyl-d-aspartate receptor antagonist), lorazepam (LZP; a GABA(A) receptor agonist), scopolamine (a muscarine receptor antagonist), or placebo. The behavioral results show that detection rate decreased with increasing masking strength and that of all the drugs, only LZP induced a further decrease in detection rate. Figure-related ERP signals showed three neural events of interest: (1) an early posterior occipital and temporal generator (94-121 msec) that was not influenced by any pharmacological manipulation nor by masking, (2) a later bilateral perioccipital generator (156-211 msec) that was reduced by masking as well as LZP (but not by any other drugs), and (3) a late bilateral occipital temporal generator (293-387 msec) that was mainly affected by masking. Crucially, only the intermediate neural event correlated with detection performance. In combination with previous findings, these results suggest that LZP and masking both reduce visual awareness by means of modulating late activity in the visual cortex but leave early activation intact. These findings provide the first evidence for a common mechanism for these two distinct ways of manipulating consciousness.Journal of Cognitive Neuroscience 04/2012; 24(4):965-74. DOI:10.1162/jocn_a_00197 · 4.09 Impact Factor
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- "Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors , which may also explain its marked amnesic effect. The main pharmacological effects of lorazepam are the enhancement of GABA at the GABAA receptor . Benzodiazepine drugs including lorazepam increase the inhibitory processes in the cerebral cortex. "
ABSTRACT: Stress is very common and affects as many as one in eight every people in their teen years. Depression, which is common form of stress related disorder affects people of every color, race, economic status, or age. However, it does seem to affect more females than males during adolescence and adulthood. Stress affects mind, body, and behavior in many ways. The signs and symptoms of stress vary from person to person, but all have the potential to harm our health, emotional wellbeing, and relationships with others. The stress response of the body is meant to protect and support us in maintaining stability. Our body is constantly adjusting to its surroundings. When a physical or mental event threatens this equilibrium, we react to it. Anxiety is characterized by a persistent and disproportionate fear unrelated to any genuine risk. It can increase to an extent that may interfere with even normal routine of life and person may feel apprehensive regarding happenings of normal things in life. The present paper discusses anti-anxiety potential of 15 anxiolytics with emphasis on their pre-clinical and clinical reports.majority of drugs have been found to be acting through modulation of serotonin and gamma butyric acid (GABA) neurotransmitters.