Significant reductions in human visual gamma frequency by the gaba reuptake inhibitor tiagabine revealed by robust peak frequency estimation.

The frequency of visual gamma oscillations is determined by both the neuronal excitation-inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [] (Neuropsychopharmacology 38(6):1105-1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans. Hum Brain Mapp 37:3882-3896, 2016. © 2016 Wiley Periodicals, Inc.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

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, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]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 [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]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 [(11)C]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 [(11)C]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.

Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.

Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate.

It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults. Fifty-four participants, of mean age 23.1 years (sd 4.68), 29 male, were randomised into three parallel groups. Each group received one of the three drugs, dosed incrementally over a 3-week period to reach daily doses of 150 mg/day venlafaxine and 200 mg/day pregabalin. Blood pressure sphygmomanometer measurements, heart rate measurements, and orthostatic challenges recorded continuously beat-to-beat were performed weekly over this period and 5 days after treatment cessation. Results showed resting systolic blood pressure (SBP) and resting and standing diastolic blood pressure (DBP) and heart rate (HR) were significantly raised by venlafaxine compared with the pregabalin and placebo groups. SBP drop on standing was larger, the resulting overshoot was smaller, and recovery was slower on venlafaxine. HR recovery was significantly impaired by venlafaxine. CV changes were observed after only 1 week of dosing at 112.5 mg/day. These effects of venlafaxine are likely to be due to its action of noradrenergic reuptake inhibition.

A translational, caffeine-induced model of onset insomnia in rats and healthy volunteers.

RATIONALE: Insomnia is a common and disabling complaint for which there is a need for improved treatments. Successful drug discovery relies on the use of appropriate animal models to assess likely outcome in the clinic. OBJECTIVES: The purpose of this study was to develop a translational, caffeine-induced model of insomnia in rats and healthy volunteers. We used sleep onset latency (SOL) as a comparable sleep measure between the two species. The model was validated by two effective sleep-promoting agents with different pharmacology, zolpidem and trazodone, which have GABA-ergic and serotonergic mechanisms, respectively. MATERIALS AND METHODS: In rats, radiotelemetry transmitters with electroencephalogram and electromyogram electrodes were implanted for sleep recording. Animals were administered with caffeine alone (10 mg/kg) or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg), or vehicle, in crossover experiments. Home polysomnography was performed in 12 healthy male volunteers in a randomised, placebo-controlled, 4-week crossover study. Subjects received placebo, caffeine (150 mg) or caffeine in combination with zolpidem (10 mg) or trazodone (100 mg). Subjective sleep effects in volunteers were assessed using the Leeds Sleep Evaluation Questionnaire. RESULTS: Caffeine caused a significant prolongation in objective SOL in rats and humans. This effect was sensitive to zolpidem and trazodone, both of which attenuated the caffeine-induced increase in SOL. Furthermore, both hypnotics restored the disruption in subjective measures of sleep onset caused by caffeine in volunteers. CONCLUSIONS: This model therefore provides a promising paradigm in which we can study novel treatments for sleep disorders and an opportunity for direct comparison of results between rodents and humans.

The use of sleep measures to compare a new 5HT1A agonist with buspirone in humans.

The partial agonist buspirone has a REM (rapid eye movement) suppressing effect on human sleep probably via a 5HT(1A) receptor in the pontine area. Eptapirone is a new 5HT(1A) agonist with a greater intrinsic effect than buspirone. The objective of this study was to examine the effects of eptapirone on sleep architecture, particularly REM sleep, in normal volunteers and compare it with buspirone and placebo. This was a randomized, double-blind placebo-controlled four-way crossover study in 12 healthy volunteers. Volunteers were screened to ensure that they had normal overnight sleep EEG (electroencephalogram) and were extensive CYP 2D6 metabolizers. Sleep was recorded on pairs of nights on four occasions, with medication being taken before the second night. Treatments were eptapirone 1.5mg at 10 AM, eptapirone 1.5mg at 11 PM, buspirone 20mg at 11 PM and placebo. Standard measures of sleep were derived and compared among the four treatments using ANOVA. REM sleep was significantly suppressed supporting the proposition that activation of post-synaptic 5HT(1A) receptors reduces REM sleep. Sleep fragmentation increased by both drugs. REM sleep suppression was significantly greater with morning eptapirone than with buspirone. Wakefulness in sleep was significantly greatest after morning eptapirone. REM sleep effects were greatest after evening eptapirone, suggesting a greater effect on central serotonin receptors than that of buspirone.

Elevating endogenous GABA levels with GAT-1 blockade modulates evoked but not induced responses in human visual cortex.

The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ∼80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations.

Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [(11)C]Ro15-4513 PET images.

This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [(11)C]Ro15-4513 time-activity curves was used to describe distribution volume (V(T)) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant V(T) decrease (~10%) in [(11)C]flumazenil, but no decrease in [(11)C]Ro15-4513 binding. Further analysis of [(11)C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

Sleep and its disorders in translational medicine.

The study of sleep is a useful approach to studying the brain in psychiatric disorders and in investigating the effects of psychotropic drugs. Sleep physiology lends itself well to pharmacological and physiological manipulation, as it has the advantage of a functional output, the electroencephalograph, which is common to all mammals, and can be measured in freely moving (or naturally sleeping) animals under controlled laboratory conditions or in a naturalistic home environment. The complexity of sleep architecture varies between species but all share features which are comparable. In addition, sleep architecture is sensitive to changes in brain neurotransmitters such as serotonin, so cross-species sleep measurement can be combined with pharmacological manipulation to investigate the receptor mechanisms controlling sleep-wake regulation and sleep architecture in response to known and novel agents. Translational approaches such as these have improved our understanding of sleep circuitry and facilitated the development of new treatments for sleep disorders, particularly insomnia. This review provides examples of how research findings within the sleep field have been translated between animal models, healthy volunteers and patient populations with particular focus on the serotonergic system.

NAPSAQ-1: National Patient Sleep Assessment Questionnaire in depression.

Objectives. Sleep disturbance is a common feature of depression. Symptoms often persist after treatment of the depressive episode, representing a risk factor for relapse. There is a lack of data regarding the nature of sleep disturbance in depression in the UK. Methods. We surveyed patients' views about their depressive symptoms and associated sleep difficulties. We received 513 responses via postal questionnaire. Results. A total of 97% reported sleep difficulties during depression: symptoms of insomnia were more frequently reported than hypersomnia. Ninety-nine percent of those with sleep problems also reported daytime symptoms including lack of concentration, exhaustion and lethargy, no energy and feeling sleepy; 40% admitted napping during the day; 59% indicated that poor sleep greatly affected their quality of life (QOL); 34% considered it to be "very distressing"; 69% of respondents were taking antidepressant medication at the time (44% said it improved their sleep, 56% said it had no effect or worsened their sleep); 69% had sought extra treatment for their sleep problems. Conclusions. Sleep disturbance in depression is a common and distressing problem that seems relatively unresolved by treatment. There is a need for more successful management in order to improve QOL in these patients and reduce a factor in depressive relapse.

Equivalent effects of acute tryptophan depletion on REM sleep in ecstasy users and controls.

INTRODUCTION: This study sought to test the association between 3,4-methylenedioxymethamphetamine use, serotonergic function and sleep. MATERIALS AND METHODS: Ambulatory polysomnography was used to measure three nights sleep in 12 ecstasy users and 12 controls after screening (no intervention), a tryptophan-free amino acid mixture (acute tryptophan depletion (ATD)) and a tryptophan-supplemented control mixture. RESULTS: ATD significantly decreased rapid eye movement (REM) sleep onset latency, increased the amount of REM sleep and increased the amount of stage 2 sleep in the first 3 h of sleep. There was no difference between ecstasy users' and controls' sleep on the screening night or after ATD. DISCUSSION: These findings imply that the ecstasy users had not suffered significant serotonergic damage as indexed by sleep.

Brain dopamine response in human opioid addiction.

BACKGROUND: Drugs of dependence cause dopamine release in the rat striatum. Human neuroimaging studies have shown an increase in dopamine in the equivalent region in response to stimulants and other drugs. AIMS: We tested whether opioids provoke dopamine release and its relationship to the subjective experience. METHOD: In two combined studies 14 heroin addicts on methadone maintenance treatment underwent two positron emission tomography brain scans of the dopamine system using [(11)C]-raclopride following an injection of placebo and either 50 mg intravenous diamorphine or 10 mg subcutaneous hydromorphone in a double-blind, random order design. RESULTS: Both opioids produced marked subjective and physiological effects, but no measurable change in [(11)C]-raclopride binding. CONCLUSIONS: The absence of a dopamine response to opioid agonists contrasts with that found with stimulant drugs and suggests dopamine may not play the same role in addiction to opioids. This questions the role of dopamine in the subjective experience of heroin in opioid addicts.

Sleep disturbances in depression and the effects of antidepressants.

Depressed patients often report sleep problems, which usually include difficulties with initiation and maintenance of sleep, as well as poor subjective quality of sleep. Such reports are confirmed by objective analysis of depressed patients' sleep through polysomnography, although there is no exact correspondence between subjective and objective measurements. In the present paper, we discuss some methodological problems related to the subjective estimates of sleep. Further, we review the differential effects of the various classes of antidepressants on subjective sleep parameters, as well as on sleep onset latency, continuity of sleep, sleep efficiency and rapid eye movement (REM) sleep verified with sleep recordings. Finally, we discuss the attempts to use these and other indices, such as delta sleep ratio (DSR), as signposts of the course of the illness, and predictors of response to treatment.