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Agitated depression, also known as melancholia agitata, is a variant of depression characterized by severe symptoms of psychomotor agitation, inner unrest, anxiety, restlessness, prominent vegetative symptoms, and a high risk of suicide. This form of depression is reported to worsen with antidepressants and potentially improve with the use of ECT, lithium, antiepileptics, antipsychotics, and benzodiazepines. We describe a case of a 73-year-old female with a prior history of depression and generalized anxiety disorder who was maintained on flurazepam for 44 years and was admitted for severe depression with psychomotor agitation, prominent vegetative symptoms, thought perseveration, indecisiveness, and psychotic features that emerged following the discontinuation of flurazepam. Symptoms did not resolve with the use of alternative benzodiazepines such as nitrazepam and temazepam and further worsened with the use of several antidepressants. She finally had a complete resolution of these symptoms with a combination of alprazolam, zopiclone, and olanzapine. This case provides insight into this unique variant of depression and the role of GABA agonists in its pathology and management., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Mohamed Salih et al.)

Background: Tuberous Sclerosis Complex (TSC) manifests behaviorally with features of autism, epilepsy, and intellectual disability. Resting state electroencephalography (EEG) offers a window into neural oscillatory activity and may serve as an intermediate biomarker between gene expression and behavioral manifestations. Such a biomarker could be useful in clinical trials as an endpoint or predictor of treatment response. However, seizures and antiepileptic medications also affect resting neural oscillatory activity and could undermine the utility of resting state EEG features as biomarkers in neurodevelopmental disorders such as TSC., Methods: This paper compares resting state EEG features in a cross-sectional cohort of young children with TSC (n=49, ages 12-37 months) to 49 age- and sex-matched typically developing controls. Within children with TSC, associations were examined between resting state EEG features, seizure severity composite score, and use of GABA agonists., Results: Compared to matched typically developing controls, children with TSC showed significantly greater alpha and beta power in permutation cluster analyses iterated across a broad frequency range (2-50Hz). Children with TSC also showed significantly greater aperiodic offset after power spectra were parameterized using SpecParam into aperiodic and periodic components. Within children with TSC, greater seizure severity was significantly related to increased periodic peak beta power. Use of GABA agonists was also independently and significantly associated with increased periodic peak beta power; the interaction between seizure severity and GABA agonist use had no significant effect on peak beta power., Conclusions: The elevated peak beta power observed in children with TSC compared to matched typically developing controls may be driven by both seizures and GABA agonist use. It is recommended to collect seizure and mediation data alongside EEG data for clinical trials. These results highlight the challenge of using resting state EEG features as biomarkers in trials with neurodevelopmental disabilities when epilepsy and anti-epileptic medication are common., Competing Interests: Declarations of interest: CCC, AME, CLW, CH, MH, AS, HTF, and CAN declare no conflict of interest. SJ reports a relationship with TSC Alliance that includes board membership and travel reimbursement

Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

While the trigeminal ganglion is often considered a passive conduit of sensory transmission, neurons and satellite glial cells (SGCs) within it can release neurotransmitters and express neuroreceptors. Some trigeminal ganglion neurons contain the neurotransmitter γ-aminobutyric acid (GABA) and express GABA receptors. There is behavioral evidence that increased GABA levels in the trigeminal ganglion decreases nociception, while a loss of GABA receptors results in hyperalgesia, although the neural mechanisms for this remain to be investigated. In this study, the expression of GABA receptors by trigeminal ganglion neurons that innervate rat labial skin and masseter muscle was compared using immunohistochemistry. The effect of intraganglionic administration of GABA receptor agonists was investigated by single unit recording of trigeminal brainstem and ganglion neuron responses to stimulation of the labial skin and/or masseter muscle in anesthetized rats. The mean frequency of expression of GABA A and GABA B receptors by masseter and labial skin ganglion neurons was 62.5% and 92.7%, and 55.4% and 20.3%, respectively. The expression of both GABA receptors was significantly greater in skin ganglion neurons. Masticatory muscle evoked brainstem trigeminal neuron responses were significantly attenuated by intraganglionic injection of muscimol (GABA A ) but not baclofen (GABA B ). The mechanical sensitivity of slow and fast conducting masticatory muscle afferent fibers was decreased and increased, respectively, by intraganglionic injection of both muscimol and baclofen. Activation of GABA A receptors may exert a gating effect on sensory transmission through the trigeminal ganglion by decreasing putative nociceptive input and enhancing innocuous sensory input., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

About 50% of persons with an alcohol use disorder may have symptoms of alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption. Protracted alcohol withdrawal (PAW), an underestimated and not yet clearly defined clinical condition that follows the acute stage of AWS, is characterized by the presence of substance-specific signs and symptoms (i.e. anxiety, irritability, mood instability, insomnia, craving) common to acute AWS, but persisting beyond the generally expected acute AWS time frames. Considering that PAW symptoms are mainly related to the neuro-adaptive changes of gamma-aminobutyric acid (GABA) and N -methyl-d-aspartate (NMDA) systems, naltrexone, nalmefene, and disulfiram may not be able to suppress the symptoms of PAW. After treatment of the acute phase of AWS, a more specifically pharmacological therapy able to suppress PAW symptoms could perhaps be used earlier and may be more helpful in preventing the risk of alcohol relapse, which remains higher during the first months of treatment. In light of this, medications acting on GABA and NMDA neurotransmitter systems to counterbalance the up-regulation of NMDA and the down-regulation of GABA could be employed in combination and started as soon as possible.

Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABA A receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α 1 β 2 γ 2 ) and extrasynaptic (α 4 β 2 γ) GABA A receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α 4 β 2 γ) receptor., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction and Aims: There has been a global increase in the availability and use of novel psychoactive substances (NPS) over the last decade. Phenibut (β-phenyl-γ-aminobutyric acid) is a GABAB agonist that is used as an NPS. Here, we bring together published scientific and grey information sources to further understand the prevalence of use, desired effects and acute toxicity of phenibut., Design and Methods: Using European Monitoring Centre for Drugs and Drug Addiction Internet snapshot methodology, we undertook an English language Internet snapshot survey in May 2015 to gather information on the availability and price of phenibut from Internet NPS retailers. To gather information on prevalence of use, desired effects and/or adverse effects, we searched grey literature (online drug discussion forums) and medical literature (PubMed and abstracts from selected International Toxicology conferences)., Results: We found 48 unrelated Internet suppliers selling phenibut in amounts ranging from 5 g (US$1.60, £1.01/g) to 1000 kg (US$0.23, £0.14/g). Capsules containing 200-500 mg of phenibut were available in packs of between 6 (US$4.45, £2.80/g) and 360 (US$0.43, £0.27/g). According to the grey literature, phenibut is taken for its anxiolytic and euphoric properties, with tolerance and withdrawal syndromes commonly reported adverse effects. Phenibut is taken orally at an average dose of 2.4 g. Case reports in the medical literature feature users who present to emergency departments heavily sedated or experiencing withdrawal. There have been no reported deaths relating to phenibut use., Discussion and Conclusions: Phenibut is readily available in the UK from Internet sites selling NPS. Its desired and adverse effects appear similar to other gamma-aminobutyric acid receptor agonists. [Owen DR, Wood DM, Archer JRH, Dargan PI. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev 2016;35:591-596]., (© 2015 Australasian Professional Society on Alcohol and other Drugs.)

Negative emotional responses to the daily life stresses have cumulative effects which, in turn, impose wide-ranging negative constraints on emotional well being and neurocognitive performance (Kalueff and Nutt, 2007; Nadler et al., 2010; Charles et al., 2013). Crucial cognitive functions such as memory and problem solving, as well more short term emotional responses (e.g., anticipation of- and response to- monetary rewards or losses) are influenced by mood. The negative impact of these behavioral responses is felt at the individual level, but it also imposes major economic burden on modern healthcare systems. Although much research has been undertaken to understand the underlying mechanisms of depressed mood and design efficient treatment pathways, comparatively little was done to characterize mood modulations that remain within the boundaries of a healthy mental functioning. In one placebo-controlled experiment, we applied daily prefrontal transcranial Direct Current Stimulation (tDCS) at five points in time, and found reliable improvements on self-reported mood evaluation. Using a new team of experimenters, we replicated this finding in an independent double-blinded placebo-controlled experiment and showed that stimulation over a shorter period of time (3 days) is sufficient to create detectable mood improvements. Taken together, our data show that repeated bilateral prefrontal tDCS can reduce psychological distress in non-depressed individuals.

High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p<0.001), from 0.9% for AWAC=0 to 9.4% for AWAC >35. There was also a significant gradual risk for EMS associated with DDB (<0.001). Multivariate analysis demonstrated a significant interaction between DDB and AWAC on EMS risk (p=0.047). Each 20mg/d increase in DDB was associated with an OR of EMS in AWAC >35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Propofol facilitates γ-aminobutyric acid-mediated inhibitory synaptic transmission. In the cerebral cortex, γ-aminobutyric acidergic interneurons target both excitatory pyramidal cells (Pyr) and fast-spiking (FS) and non-FS interneurons. Therefore, the propofol-induced facilitation of inhibitory transmission results in a change in the balance of excitatory and inhibitory inputs to Pyr. However, it is still unknown how propofol modulates γ-aminobutyric acidergic synaptic transmission in each combination of Pyr and interneurons., Methods: The authors examined whether propofol differentially regulates inhibitory postsynaptic currents (IPSCs) depending on the presynaptic and postsynaptic cell subtypes using multiple whole cell patch clamp recording from γ-aminobutyric acidergic interneurons and Pyr in rat insular cortex., Results: Propofol (10 μM) consistently prolonged decay kinetics of unitary IPSCs (uIPSCs) in all types of inhibitory connections without changing paired-pulse ratio of the second to first uIPSC amplitude or failure rate. The FS→Pyr connections exhibited greater enhancement of uIPSC charge transfer (2.2 ± 0.5 pC, n = 36) compared with that of FS→FS/non-FS connections (0.9 ± 0.2 pC, n = 37), whereas the enhancement of charge transfer in non-FS→Pyr (0.3 ± 0.1 pC, n = 15) and non-FS→FS/non-FS connections (0.2 ± 0.1 pC, n = 36) was smaller to those in FS→Pyr/FS/non-FS. Electrical synapses between FS pairs were not affected by propofol., Conclusions: The principal inhibitory connections (FS→Pyr) are the most sensitive to propofol-induced facilitation of uIPSCs, which is likely mediated by postsynaptic mechanisms. This preferential uIPSC enhancement in FS→Pyr connections may result in suppressed neural activities of projection neurons, which in turn reduces excitatory outputs from cortical local circuits.

Background: Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders. Recent major advances have been made in the understanding of the neurobiology and functions of fragile X mental retardation protein, the FMR1 gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to pathways dysregulated in the absence of fragile X mental retardation protein., Conclusion: These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model, and clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess disease-modifying changes that might be associated with treatment. Genes known to be causes of autistic spectrum disorders interact with the translational pathway defective in FXS and it is likely that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction. Thus targeted treatment and clinical trial strategies in FXS may serve as a model for ASD and other cognitive disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This paper presents commentaries on how endoluminal antireflux procedures compare to laparoscopic fundoplication; new endoscopic procedures being studied to treat refractory gastroesophageal reflux disease (GERD); the new Stretta; the relationship between obesity and proton pump inhibitor (PPI) resistance; data concerning acid hypersensitivity and sensory receptors (vallinoid, TRPV1) causing refractory GERD; whether microscopic esophagitis is relevant in determining symptoms of non-erosive reflux disease (NERD); how concomitant functional gastrointestinal disorders affect the PPI response in NERD; the evidence that a functional esophagus is associated with inflammatory bowel syndrome (IBS); the role of GABA agonists in the treatment of refractory GERD; the role of biofeedback and antidepressants in refractory GERD; and endoluminal fundoplication using the EsophyX device., (© 2013 New York Academy of Sciences.)

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) has been known for the processing and transmission of orofacial nociceptive information. Taurine, one of the most plentiful free amino-acids in humans, has proved to be involved in pain modulation. In this study, using whole-cell patch clamp technique, we investigated the direct membrane effects of taurine and the action mechanism behind taurine-mediated responses on the SG neurons of the Vc. Taurine showed non-desensitizing and repeatable membrane depolarizations and inward currents which remained in the presence of amino-acid receptors blocking cocktail (AARBC) with tetrodotoxin, indicating that taurine acts directly on the postsynaptic SG neurons. Further, application of taurine at different doses (10  μM to 3 mM) showed a concentration dependent depolarizations and inward currents with the EC50 of 84.3  μM and 723  μM, respectively. Taurine-mediated responses were partially blocked by picrotoxin (50  μM) and almost completely blocked by strychnine (2  μM), suggesting that taurine-mediated responses are via glycine receptor (GlyR) activation. In addition, taurine (1 mM) activated extrasynaptic GABA(A) receptor (GABA(A)R)-mediated currents. Taken together, our results indicate that taurine can be a target molecule for orofacial pain modulation through the activation of GlyRs and/or extrasynaptic GABA(A)Rs on the SG neurons.

Treatment of tics and Gilles de la Tourette syndrome (GTS) by nondopaminergic drugs was initiated more than three decades ago. These approaches were driven by the wish to circumvent antipsychotic-related side effects (metabolic disturbances, parkinsonian syndromes, tardive dyskinesia) or to use these treatments as a valuable add-on therapy in patients at least partially refractory to antipsychotics. In this review, we will therefore discuss the potential value of treating tics with alpha2 receptor agonists, nicotine, tetrabenazine, GABA agonists, botulinum toxin, cannabinoids, and immune modulators (plasmapheresis, intravenous immunoglobulins, antibiotic prophylaxis). Future directions for clinical trials based on our expanding understanding of the pathophysiology of GTS with regard to cholinergic, glutamatergic, and histaminergic neurotransmission will also be briefly outlined., (© 2013 Elsevier Inc. All rights reserved.)

We examined GABAergic modulation on "slow" oscillation (<1.0 Hz) of the procerebrum in the terrestrial mollusk, Limax valentianus. Short application of GABA-receptor agonists slightly increased the frequency of a periodic oscillation in the procerebrum, whereas persistent application decreased it. GABA-receptor antagonists decreased the oscillatory frequency. The GABA-like immunoreactivities were found in the neuropil and the cell body layers of the procerebrum. Because GABAergic inhibition is known to be essential for the generation of "fast" synchronous neuronal oscillation in the CNSs in othre many animals, our present findings are first evidence suggesting that GABA modulates 'slow' oscillation in the CNS.

Background: Propofol produces its major actions via γ-aminobutyric acid type A (GABA(A)) receptors. At low concentrations, propofol enhances agonist-stimulated GABA(A) receptor activity, and high propofol concentrations directly activate receptors. Etomidate produces similar effects, and there is convincing evidence that a single class of etomidate sites mediate both agonist modulation and direct GABA(A) receptor activation. It is unknown if the propofol binding site(s) on GABA(A) receptors that modulate agonist-induced activity also mediate direct activation., Methods: GABA(A) α1β2γ2L receptors were heterologously expressed in Xenopus oocytes and activity was quantified using voltage clamp electrophysiology. We tested whether propofol and etomidate display the same linkage between agonist modulation and direct activation of GABA(A) receptors by identifying equiefficacious drug solutions for direct activation. We then determined whether these drug solutions produce equal modulation of GABA-induced receptor activity. We also measured propofol-dependent direct activation and modulation of low GABA responses. Allosteric coagonist models similar to that established for etomidate, but with variable numbers of propofol sites, were fitted to combined data., Results: Solutions of 19 μM propofol and 10 μM etomidate were found to equally activate GABA(A) receptors. These two drug solutions also produced indistinguishable modulation of GABA-induced receptor activity. Combined electrophysiological data behaved in a manner consistent with allosteric coagonist models with more than one propofol site. The best fit was observed when the model assumed three equivalent propofol sites., Conclusions: Our results support the hypothesis that propofol, like etomidate, acts at GABA(A) receptor sites mediating both GABA modulation and direct activation.

Introduction: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage., Methods and Outcomes: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA)., Results: We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions., Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.

Goal-directed behavior is governed by internal physiological states and external incentives present in the environment (e.g. hunger and food). While the role of the mesocorticolimbic dopamine (DA) system in behavior guided by environmental incentives has been well studied, the effect of relevant physiological states on the function of this system is less understood. The current study examined the role of the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAcc) in the kind of food-reinforced behaviors known to be sensitive to the internal state produced by food deprivation conditions. Operant lever-press reinforced on fixed ratio 1 (FR1) and progressive ratio (PR) schedules was tested after temporary inactivation of, or DA receptor blockade in, the prelimbic mPFC or NAcc core of rats with differing levels of food deprivation (0, 12 and 36-h). Food deprivation increased PR breakpoints, as well as the number of lever-presses emitted on the FR1 schedule. Both temporary inactivation and DA blockade of NAcc reduced breakpoints across deprivation conditions, while temporary inactivation and DA blockade of mPFC reduced breakpoints only in food-deprived rats. Neither manipulation of mPFC and NAcc had any effect on behavior reinforced on the FR1 schedule. Thus, mPFC and NAcc were differentially relevant to the behaviors tested-NAcc was recruited when the behavioral cost per reinforcer was rising or high regardless of food deprivation conditions, while mPFC was recruited when food-deprived animals behaved through periods of sparse reinforcement density in order to maximize available gain., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

The hippocampus and the perirhinal cortex (PR) are reciprocally connected both directly and indirectly via the entorhinal cortex. Although it has been hypothesized that the two regions should have intimate functional interactions with each other on the basis of the anatomical connectivity, many lesion studies have demonstrated functional dissociations instead between the hippocampus and PR. To show a tight functional relationship between the two regions, we used reversible inactivation techniques targeting both the hippocampus and PR within subjects, combined with a biconditional memory task in which the rat must consider information about objects and their locations. Specifically, rats were implanted with two sets of bilateral cannulas into the hippocampus and PR, and were tested in an object-place paired-associate task in a radial maze. While alternating between two arms, the rats were required to choose one of the objects exclusively associated with a given arm for food. Bilateral muscimol (MUS) injections into either the hippocampus or PR equally produced chance level performance. When a functional disconnection procedure was used to disrupt the interaction between the hippocampus and PR, contralateral MUS injections into the hippocampus and PR resulted in severe impairment in performance. However, inactivating the hippocampus and PR ipsilaterally did not affect the performance. In a simple object discrimination task, the same functional disconnection protocol with MUS did not affect the performance. The results powerfully demonstrate that the hippocampus, the PR, and their functional interactions are all indispensable when objects and their spatial locations must be processed at the same time.

In neurons the rate of K(+)-uptake increases with increasing activity. K(+)-analogues like the heavy metal ion thallium (Tl(+)) can be used, therefore, as tracers for imaging neuronal activity. However, when water-soluble Tl(+)-salts are injected systemically only minute amounts of the tracer enter the brain and the Tl(+)-uptake patterns are influenced by regional differences in blood-brain barrier (BBB) K(+)-permeability. We here show that the BBB-related limitations in using Tl(+) for imaging neuronal activity are no longer present when the lipophilic Tl(+) chelate complex thallium diethyldithiocarbamate (TlDDC) is applied. We systemically injected rodents with TlDDC and mapped the Tl(+)-distribution in the brain using an autometallographic (AMG) technique, a histochemical method for detecting heavy metals. We find that Tl(+)-doses for optimum AMG staining could be substantially reduced, and regional differences attributable to differences in BBB K(+)-permeability were no longer detectable, indicating that TlDDC crosses the BBB. At the cellular level, however, the Tl(+)-distribution was essentially the same as after injection of water-soluble Tl(+)-salts, indicating Tl(+)-release from TlDDC prior to neuronal or glial uptake. Upon sensory stimulation or intracortical microstimulation neuronal Tl(+)-uptake increased after TlDDC injection, upon muscimol treatment neuronal Tl(+)-uptake decreased. We present a protocol for mapping neuronal activity with cellular resolution, which is based on intravenous TlDDC injections during ongoing activity in unrestrained behaving animals and short stimulation times of 5 min.

The synthesis of (R,S)-[4-11C]baclofen, the first 11C-labeled GABAB agonist, was demonstrated via Michael addition of nitro[11C]methane as a key step. A tetrabutylammonium fluoride promoted Michael addition of nitro[11C]methane to methyl p-chlorocinnamate, followed by the nitro-group reduction in the presence of NiCl2 and NaBH4 in aqueous MeOH and alkaline hydrolysis yielded (R,S)-[4-11C]baclofen in 36.4+/-1.8% radiochemical conversion in three steps within 20 min.

The neurological sequelae of chronic Mn exposure include psychiatric, cognitive, and motor deficits, suggesting the potential involvement of multiple neurotransmitter systems and brain regions. Available evidence in rodents suggests that Mn causes dysregulation of glutamatergic and gamma-aminobutyric acidergic (GABAergic) neurotransmitter systems. However, this has never been studied comprehensively in the nonhuman primate brain. Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg, 5.0-6.7 mg Mn/kg, or 8.3-10.0 mg Mn/kg for 7-59 weeks. Total glutamate, glycine, and GABA concentrations were measured by high performance liquid chromatography (HPLC) with fluorescence detection in 13 brain areas in Mn-treated and control monkeys. Neurotransmitter concentrations did not change with chronic Mn exposure. Quantitative autoradiography of the N-methyl-D-aspartate receptor, the GABAa receptor, and glutamate transporters was used to assess their regional distribution. Each of these neurotransmitter receptors remained almost universally unchanged with Mn treatment. Immunohistochemical analysis of glutamine synthetase (GS) demonstrated a selective Mn-induced decrease in the globus pallidus, which could potentially alter synaptic and/or astrocytic levels of glutamate. This study shows that in nonhuman primates with previous documentation of Mn-induced brain pathology, the glutamatergic and GABAergic systems appear to be mostly unaffected by chronic Mn exposure with the exception of reduced GS expression in the globus pallidus.

Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and gamma-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABABR-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABABR protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABABR agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABABR-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.

Objectives: It has been proposed that major depression is associated with a dysfunction of the gamma-aminobutyric acid (GABA) system. This study was planned to investigate whether there are any alterations in GABAergic activities in major depressive patients and, if there are, whether electroconvulsive therapy (ECT) has any effect on these changes., Methods: Twenty-five depressed inpatients who responded to a course of ECT and 23 healthy subjects were included in the study. Serum GABA levels were measured 2 days before and 10 minutes after the first ECT and 3 days after the last ECT, and a baclofen challenge test was performed 2 days before the first ECT and 3 days after the last ECT in the patients. The same tests were carried out only once in the control group., Results: Depressive patients had lower serum GABA levels compared with healthy individuals, and ECT caused a significant increase in these levels. The acute effect of the one-ECT procedure was a huge increase in the baseline GABA levels. Although there was no difference in the maximum alteration in growth hormone with baclofen between the patients and controls before the therapeutic ECT course, it became significantly higher in the depressive patients than in the controls after the treatment., Conclusions: The findings of this study support the GABA deficit hypothesis of major depression because major depressive patients have lower levels of serum GABA that are increased by a completed ECT course. ECT seems to increase brain GABA levels as well as GABAB activity, and these effects may contribute to its mechanism of therapeutic effect.

Taurine has been suggested to modulate nociceptive information at the spinal cord level. In this study, the pharmacological properties of taurine were investigated in adult rat substantia gelatinosa (SG) neurons using whole-cell patch-clamp method. We found that taurine seemed to have higher efficacy than glycine on glycine receptors in SG neurons. An increase in chloride conductance was responsible for taurine-induced currents. Taurine at 0.3 mM activated glycine receptors, whereas at 3 mM activated both glycine and gamma-aminobutyric acid A receptors. The currents activated by coapplication of taurine and glycine are cross inhibitive. Altogether these results show that taurine might represent another important neurotransmitter or modulator in SG neurons, which may be involved in antinociception.

On- and off-center geniculate afferents form two major channels of visual processing that are thought to converge in the primary visual cortex. However, humans with severely reduced on responses can have normal visual acuity when tested in a white background, which indicates that off channels can function relatively independently from on channels under certain conditions. Consistent with this functional independence of channels, we demonstrate here that on- and off-center geniculate afferents segregate in different domains of the cat primary visual cortex and that off responses dominate the cortical representation of the area centralis. On average, 70% of the geniculate afferents converging at the same cortical domain had receptive fields of the same contrast polarity. Moreover, off-center afferents dominated the representation of the area centralis in the cortex, but not in the thalamus, indicating that on- and off-center afferents are balanced in number, but not in the amount of cortical territory that they cover.

The medial prefrontal cortex has been suggested to play a role in drug addiction due to its involvement in the reinstatement of drug seeking. In the present study, the role of the prelimbic cortex in persistent responding maintained by the earned presentations of a drug-paired conditioned reinforcer was studied. Temporary inactivation of the prelimbic, prefrontal cortex of rats had no effect on this persistent response, but did impair its initial acquisition, maintained by the drug-paired conditioned reinforcer. The lesion also impaired re-acquisition of this response after extinction by omission of the contingent conditioned reinforcer. These results suggest that the prelimbic cortex has a selective role in the acquisition, or re-acquisition, of instrumental responses for drug-paired conditioned reinforcers, that may be important in relapse to drug seeking. Anatomical controls with placements in the infralimbic cortex showed longer-lasting impairments in the acquisition of this response, consistent with the suggestion that the prelimbic and infralimbic cortices mediate different aspects of behavior, with the infralimbic being more specialized for habits. The implications of the present findings toward the understanding of drug seeking and relapse behaviors and the separate brain systems that may underlie them are discussed.

Transection of the direct cortico-motoneuronal pathway at the mid-cervical segment of the spinal cord in the macaque monkey results in a transient impairment of finger movements. Finger dexterity recovers within a few months. Combined brain imaging and reversible pharmacological inactivation of motor cortical regions suggest that the recovery involves the bilateral primary motor cortex during the early recovery stage and more extensive regions of the contralesional primary motor cortex and bilateral premotor cortex during the late recovery stage. These changes in the activation pattern of frontal motor-related areas represent an adaptive strategy for functional compensation after spinal cord injury.

We describe the perioperative treatment of a patient diagnosed with Angelman syndrome, which is usually caused by a deletion in chromosome 15. The patient showed the characteristic signs of psychomotor retardation, epilepsy, lack of speech, frequent laughter and happy demeanor, light skin, blue eyes, and blond hair, hyperactivity, and sleep disturbance. He was scheduled for multiple tooth extractions under general anesthesia. Intravenous anesthesia was induced using ketamine, propofol, and rocuronium, and was maintained with low concentrations of sevoflurane. There were no incidents during or after surgery. The chromosomal abnormality that causes Angelman syndrome is located on the same genes that control the production of gamma-aminobutyric acid-A receptors, which are activated by most intravenous and inhaled anesthetic agents. The effect of the condition on the response of these agents is unknown. The combined use of propofol, ketamine, and sevoflurane at low doses provided adequate anesthesia for this patient. Other characteristics of the syndrome that may affect the use of anesthesia in these patients are discussed.

Since the first use of intrathecal (IT) drug infusion systems in the early 1980s, these delivery systems have undergone numerous revisions making them more tolerable, easier to program, and longer lasting. Concurrent with technological advances, the indications for IT pump placement have also been continuously evolving, to the point where the most common indication is now noncancer pain. This article provides an evidence-based review of the indications, efficacy, and complications of IT drug therapy for the most commonly administered spinal analgesics.

Ten newer antiepileptic drugs have been developed since 1990s. These drugs have wider therapeutic spectra, fewer side-effects, and lesser drug-to-drug interactions compared with the older typical antiepileptic drugs. Among them, zonisamide was developed in Japan and has been used from 1989. Gabapentin was at length approved in 2006. The other newer antiepileptic drugs are not approved yet in Japan. Felbamate can not be used in Europe because it may induce lethal hepatic toxicity and aplastic anemia. Vigabatrin is not approved in USA because it may induce permanent visual field deficit. The USA guideline for epilepsy treatment recommends that patients with newly diagnosed epilepsy can be treated with gabapentin, lamotrigine, topiramate, and oxcarbazepine. In contrast, based on epilepsy treatment guideline in England, newer antiepileptic drugs are considered only when patients with newly diagnosed epilepsy are unable to use the older antiepileptic drugs for some reasons. All newer antiepileptic drugs are used for intractable partial epilepsies, and lamotrigine and topiramate can also be used for idiopathic generalized epilepsies. The response rate (seizure reduction rate with 50% or more) and drop-out rate are overlapping among all newer antiepileptic drugs. Gabapentin, levetiracetam, and pregabalin are eliminated from kidney, and they had no drug-to-drug interactions and can be titrated rapidly. The serum concentration of lamotrigine is decreased with co-administration of hepatic enzyme inducing drugs and is increased with co-administration of valproic acid. Hypersensitivity reactions are rare with gavapentin, levetiracetam, topiramate, and tiagabin. Psychoses are reported to be induced with zonisamide, however, they can be induced with the other newer drugs (topiramate, levetiracetam, etc.). Drug-induced psychiatric symptoms, especially depression, may be often underdiagnosed. Many of these newer drugs (gabapentine, lamotrigine, levetiracetam, oxycarbazepine, etc.) have effects on chronic neuropathic pain. Some newer drugs show mood stabilizing effects (lamotrigine, oxycarbazepine, etc.), or antianxiety effect (gabapentin, topiramate, levetiracetam, pregavalin, etc.). Wide range of action to central nervous system of these newer antiepileptic drugs may serve not only for clinical seizure suppression, but also for neuroprotection.

Refinement of the neural circuit during brain maturation is regulated by experience-driven neural activity. In the mammalian visual cortex, monocular visual deprivation (MD) in the early postnatal life causes a significant loss of cortical responses to a deprived eye and the retraction of input axons serving the deprived eye. A competitive interaction between inputs serving both eyes has been supposed to underlie the effects of MD because the loss of cortical response is much weaker when both eyes are deprived of vision. Also, the input axons do not retract after binocular deprivation. Here, we report that uncorrelated activity between presynaptic and postsynaptic neurons can solely lead to the retraction of geniculocortical axons in the absence of activity imbalance between two inputs. We analyzed the morphology of geniculocortical axons in a pharmacologically inhibited visual cortex of animals with normal vision and of binocularly deprived animals. In the normal vision animals, the axonal arbors in the inhibited cortex showed robust retraction. On the other hand, the arbors in binocularly deprived animals remained mostly intact. These results suggest that a homosynaptic associative mechanism, rather than a heterosynaptic competition between inputs, may play an important role in experience-driven axon retraction.

With the introduction of several new antiepileptic drugs into clinical practice, renewed attention has been focussed on treatment-emergent adverse effects, including mood disorders. There are several possible causes of psychiatric disorders in patients with epilepsy, including antiepileptic drugs, and it is often difficult to determine whether psychopathological manifestations, especially depressive symptoms, are due to drug therapy or to multiple other factors. Assessment of the negative effects of antiepileptic drugs on mood should always consider all potential factors. Case series, audits and open observational studies can identify psychopathological features, case-control studies are useful for identifying the endophenotypes of patients at risk of adverse effects on mood, and controlled clinical trials give good estimates of incidence of such effects, adjusted for the spontaneous occurrence of symptoms. The barbiturates, vigabatrin and topiramate show greater associations with the occurrence of depressive symptoms than other antiepileptic drugs, presenting in up to 10% of all patients, but even more so in susceptible patients. Data on zonisamide are scarce but it seems that mood disorders may occur in approximately 7% of patients who are receiving high dosages of this drug. In most cases, the use of monotherapy, with slow titration schedules, can significantly reduce the incidence of mood disorders. Tiagabine, levetiracetam and felbamate present an intermediate risk, with prevalence of depression of about 4% or lower. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin and lamotrigine are all associated with low risks for depression (<1%), and several of these antiepileptic drugs seem to have a positive effect on mood. Antiepileptic drugs can negatively affect mood and behaviour by different mechanisms: potentiation of GABA neurotransmission, folate deficiency, pharmacodynamic interactions with other antiepileptic drugs in polytherapy regimens, forced normalisation. Individuals with a personal or family history of depression should be carefully followed after initiation of therapy with a new antiepileptic drug, especially if structural brain abnormalities such as hippocampal sclerosis are present.

Thalamocortical neurons in mammals fire action potentials in two different modes, burst or tonic, depending on the cellular state. The burst firing is driven by the low threshold Ca2+ spike that is generated by Ca2+ influx through T-type Ca2+ channels, and has long been implicated in the pathogenesis of absence epilepsy and the regulation of sleep rhythms. The recent availability of the knock-out mice for the alpha1G locus, encoding the predominant form of T-type channels in thalamocortical neurons, has provided an opportunity to examine those ideas at the level of organism. In this review we will describe recent results demonstrating the essential role of thalamic bursts in certain forms of absence seizures and in some of the sleep rhythms. Available information so far reveals the sensory gating role of thalamic bursts, and thus of alpha1G T-type channels. Understanding of the molecular targets involved in pathophysiological mechanisms will help develop drugs to control those pathological states.

General anesthetics, including etomidate, act by binding to and enhancing the function of GABA type A receptors (GABA(A)Rs), which mediate inhibitory neurotransmission in the brain. Here, we used a radiolabeled, photoreactive etomidate analog ([(3)H]azietomidate), which retains anesthetic potency in vivo and enhances GABA(A)R function in vitro, to identify directly, for the first time, amino acids that contribute to a GABA(A)R anesthetic binding site. For GABA(A)Rs purified by affinity chromatography from detergent extracts of bovine cortex, [(3)H]azietomidate photoincorporation was increased by GABA and inhibited by etomidate in a concentration-dependent manner (IC(50) = 30 microm). Protein microsequencing of fragments isolated from proteolytic digests established photolabeling of two residues: one within the alphaM1 transmembrane helix at alpha1Met-236 (and/or the homologous methionines in alpha2,3,5), not previously implicated in etomidate function, and one within the betaM3 transmembrane helix at beta3Met-286 (and/or the homologous methionines in beta1,2), an etomidate sensitivity determinant. The pharmacological specificity of labeling indicates that these methionines contribute to a single binding pocket for etomidate located in the transmembrane domain at the interface between beta and alpha subunits, in what is predicted by structural models based on homology with the nicotinic acetylcholine receptor to be a water-filled pocket approximately 50 A below the GABA binding site. The localization of the etomidate binding site to an intersubunit, not an intrasubunit, binding pocket is a novel conclusion that suggests more generally that the localization of drug binding sites to subunit interfaces may be a feature not only for GABA and benzodiazepines but also for etomidate and other intravenous and volatile anesthetics.

To test the hypothesis that GABA(B) receptor efficacy in the behaving rat decreases after partial hippocampal kindling, we measured GABA(B) receptor efficacy by the number of wet dog shakes (WDSs) induced by baclofen (5mM in 0.2muL of saline) infusion into the dorsal hippocampus; these WDSs were blocked by prior infusion of GABA(B) receptor antagonist CGP55845A. Rats were given 15 afterdischarges (ADs) evoked in CA1 over 3 days or control stimulations. The partially kindled rats (after 15 ADs) showed a significant decrease in baclofen-induced WDSs as compared to control rats, on days 1, 4 and 21 after kindling. In contrast, kindled and control rats did not show a significant difference in WDSs induced by hippocampal infusion of GABA(A) receptor antagonist bicuculline. Also, the number of WDSs induced after subcutaneous injection of serotonin-2A/2C agonist+/-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane was not different between kindled and control rats on 4 and 21 days after kindling. We further tested the hypothesis that the decrease in hippocampal AD-induced WDSs during kindling is caused by a decrease in GABA(B) receptor efficacy. However, we found no convincing evidence to support the latter hypothesis since the AD-induced WDSs were not suppressed by hippocampal infusion of CGP55845A, with the exception that CGP55845A infusion into ventral hippocampus suppressed both hippocampal ADs and WDSs. Together with results derived from previous electrophysiological studies in vitro, it is suggested that a decrease of GABA(B) receptor, possibly GABA(B) autoreceptor, efficacy may explain the decrease of baclofen-induced WDSs after hippocampal kindling.

Although proton pump inhibitors have become the mainstay of treatment in gastro-oesophageal reflux disease (GORD), there are still unmet needs in the management of this very common disorder. For example, all current proton pump inhibitors have a relatively slow onset of action and their activity is limited mainly to the post-prandial period with far less effective inhibition of nocturnal acid secretion. In order to achieve more potent, rapid and sustained acid inhibition several compounds are currently under development, such as new proton pump inhibitors with a prolonged plasma half-life, potassium competitive ATPase blockers (PCABs), histamine H3 agonists, and gastrin antagonists. Acid suppression does not, however, cure the disease and relapses are frequently observed after discontinuation of proton pump inhibitor therapy. Among the different abnormalities involved in the pathophysiology of this multifactorial disease, transient lower oesophageal sphincter relaxations represent the major mechanism responsible for episodes of reflux. Baclofen, the prototype GABA(B) receptor agonist, is one of the most potent inhibitors of transient lower oesophageal sphincter relaxations identified. To date the transfer of these relaxation-controlling pharmacological agents into clinical practice has however been hampered by the occurrence of unacceptable side effects. Beside "anti-relaxation therapy", the potential of novel prokinetics such as motilin agonists has been explored, especially since the motilin receptor has been cloned. Thus far the broad therapeutic value of prokinetics in GORD does, however, seem very limited in terms of efficacy with respect to oesophageal motility and acid exposure. Lastly, further research is necessary to better understand the complex mechanisms involved in oesophageal sensitivity and mucosal defence.

Hippocampal infusions of glucose reverse memory deficits in spontaneous alternation and in a continuous multiple trial inhibitory avoidance task. The current experiments tested whether glucose metabolism may participate in these effects of glucose. Specifically, these experiments determined whether the glycolytic metabolite pyruvate would mimic these effects of glucose. Male Sprague-Dawley rats were given septal infusions of vehicle or the gamma-aminobutyric acid (GABA) receptor agonist muscimol (0.15 nmol for spontaneous alternation or 5 nmol for continuous multiple trial inhibitory avoidance) combined with hippocampal infusions of vehicle or pyruvate (200 nmol) 15 min prior to assessing spontaneous alternation or training in a continuous multiple trial inhibitory avoidance task. The infusions of muscimol decreased percent alternation scores and continuous multiple trial inhibitory avoidance retention latencies tested 48 h after training. More importantly, hippocampal infusions of pyruvate reversed the deficits produced by septal infusions of muscimol on both tasks. These findings show for the first time that hippocampal infusions of pyruvate influence memory and suggest that glucose may affect memory via glycolytic metabolism.

The mechanism by which physiological synaptic NMDA receptor activity promotes neuronal survival is not well understood. Here, we show that that an episode of synaptic activity can promote neuroprotection for a long time after that activity has ceased. This long-lasting or "late phase" of neuroprotection is dependent on nuclear calcium signaling and cAMP response element (CRE)-mediated gene expression. In contrast, neuroprotection evoked acutely by ongoing synaptic activity relies solely on the activation of the phosphatidylinositol 3-kinase/Akt pathway. This "acute phase" does not require nuclear calcium signaling and is independent of activation of the CRE-binding protein (CREB) family of transcription factors. Thus, activity-dependent neuroprotection comprises two mechanistically distinct phases that differ in their spatial requirements for calcium and in their reliance on the CREB family.

Infants born to mothers that smoke while pregnant have a relatively high incidence of central respiratory control abnormalities. Recent studies have shown that prenatal nicotine exposure increases GABA release and the frequency of GABAergic currents, leading to an up-regulation of GABA(A) receptors in central neurones. Activation of GABA(A) receptors inhibits ventilatory activity, with intense activation causing apnoea. These observations lead us to hypothesize that prenatal nicotine exposure alters GABAergic control of respiratory motor pattern in the early neonatal period. Osmotic minipumps were implanted in pregnant Sprague-Dawley rats on the fifth day of gestation, and filled with nicotine (6 mg kg(-1) day(-1), 2.5 microl h(-1)) or physiological saline (2.5 microl h(-1)). Brainstem-spinal cord preparations from 1- to 3-day-old neonates were studied under in vitro conditions. Electrical activity was recorded from the fourth cervical ventral root (C4 VR), which contains the axons of phrenic motoneurones. Bath application of GABA(A) receptor agonists muscimol (250 microM) or pentobarbital sodium (60 microM) to the brainstem led to consistent, reversible and significant reductions in C4 VR burst frequency. In saline-exposed animals, frequency (bursts min(-1)) fell from 6.8 +/- 0.4 to a nadir of 2.8 +/- 0.5 with muscimol, and from 6.5 +/- 0.3 to a nadir of 2.9 +/- 0.3 for pentobarbital; in nicotine-exposed animals, frequency fell from 6.3 +/- 0.4 to 1.0 +/- 0.4 with muscimol and from 6.4 +/- 0.2 to 1.7 +/- 0.4 with pentobarbital (P < 0.05 in all cases). The decrease in C4 VR frequency was significantly greater in nicotine-exposed compared to saline-exposed preparations with both muscimol and pentobarbital (P < 0.001 for both). There were no changes in the amplitude of C4 VR bursts under any condition. The GABA(A) receptor antagonist bicuculline methiodide (8 microM) did not change C4 VR frequency or amplitude in either group, although it was effective in reversing the effects of muscimol. These experiments demonstrate that prenatal nicotine exposure alters the GABAergic regulation of respiratory rhythm in a reduced preparation. The results may lead to a better understanding of the perturbed breathing pattern observed in neonates that are exposed to nicotine in utero.

H Lundbeck A/S, in collaboration with Merck & Co Inc, is developing gaboxadol, a GABAA agonist, for the potential treatment of sleep disorders. The compound is currently undergoing phase III clinical trials.

To image the possible alterations in brain regional GABAA receptor subtype properties in a genetic animal model of human anxiety, mice heterozygous for the deletion of GABAA receptor gamma2 subunit (gamma2+/-) were studied using ligand autoradiographic assays on brain cryostat sections. The [35S]TBPS binding assay was designed to reveal impaired GABA and channel site coupling shown to be more prominent in recombinant alpha1/6beta3 than in alpha1/2beta3gamma2 or beta2 subunit-containing GABAA receptors expressed in HEK 293 cells. Increased GABA-insensitive [35 S]TBPS binding in the gamma2+/- mouse brains was evident in the cerebral cortex and in subcortical regions, the alterations being regionally similar to the loss of gamma2 subnunit-dependent benzodiazepine (BZ) sites as revealed by [3H]Ro 15-4513 autoradiography. As the gamma2 subunit protein is needed for synaptic clustering of GABAA receptors, these results indicate that the extrasynaptic alphabeta3 receptors can be visualized in vitro as atypical GABA-insensitive [35S]TBPS binding sites. The results suggest that GABAAergic synaptic inhibition is widely decreased in the brains of anxiety-prone gamma2+/- mice, while extrasynaptic GABAA receptors are increased. These autoradiographic imaging findings further demonstrate the need to develop GABAA receptor subtype-selective in vivo ligands to aid in assessing the contributions of various subcellular receptor populations in anxious and other patient groups.

Zolpidem is a sedative and hypnotic drug belonging to imidazopyridine family. Zolpidem facilitates GABAA function more selectively than benzodiazepines, and produces a selective hypnotic effect. In comparison with benzodiazepines this mechanism could be reduce liability to induce dependence. Recently, some cases of zolpidem abuse and dependence have been published. The Authors report 2 cases of addiction to high dose of zolpidem and compare them with others described in the literature. Both patients had been reknown drug addicts before their first prescription of zolpidem and a borderline personality disorder was diagnosed. The patients rapidly developed over consumption and dependence of the molecule, when taking doses as high as 240 and 400 mg daily. To get zolpidem, one patient falsifies prescriptions. They don't suffer from the sedative effects while searching for anxiolytic and stimulating effects. They were also dysarthric, confused, high energy for mental and physical activity. The cases of zolpidem abuse and dependence in the literature describe these symptoms and others such as losing sense of orientation in time and space, amnesia and visual hallucinations. The most typical withdrawal symptom is high levels of anxiety. Moreover, one patient presents an epileptic seizure whereas the other display a severe psychiatric complication such a psychosis. In the literature, withdrawal was accompanied by confusion, suicidal ideas, nausea, vomiting, sweat, tremors, tachycardia and insomnia rebound. The epileptic seizures are described but acute psychosis complication is rare. Pharmacological hypotheses are described. The effects of zolpidem on GABAA receptor gene expression are consistent with the reduced tolerance liability of this drug as well as with other ability to induce both physical dependence and withdrawal syndrome. Through the review of the literature, the Authors noted that 50% of the cases of dependence on zolpidem are drug addicts, therefore concluding that drug addicts are more likely to become dependent on zolpidem.

Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulating ipsilateral ventrolateral column (VLC) in the thoracic section were recorded in lumbar motoneurons within the isolated spinal cord of the frog Rana ridibunda. Bath application of the selective GABAB receptor agonist (-)-baclofen (0.05 mM) caused a reduction in the peak amplitude of VLC EPSP. Baclofen did not cause any consistent change in the membrane potential or in the EPSP waveform within frog motoneurones. The selective GABA(B) receptor antagonist saclofen (0.1 mM) completely blocked the effect of (-)-baclofen on VLC EPSP. A decrease in VLC EPSP peak amplitude was also observed during GABA (0.5 mM) application. Unlike (-)-baclofen, inhibition of VLC EPSP induced by GABA was accompanied by a shortening of the EPSP time course and a reduction in membrane input resistance within lumbar motoneurons. The decrease in VLC EPSP peak amplitude induced by (-)-baclofen and GABA was accompanied by an increase in the paired-pulse facilitation. These data provide evidence for a dual pre- and postsynaptic GABAergic inhibition of the VLC monosynaptic EPSP in lumbar motoneurons within the frog spinal cord.