GABA Neurotransmitter Systems Research Articles

Divergent suicidal symptomatic activations converge on somato-cognitive action network in depression.

Individuals with depression have the highest lifetime prevalence of suicide attempts (SA) among mental illnesses. Numerous neuroimaging studies have developed biomarkers from task-related neural activation in depressive patients with SA, but the findings are inconsistent. Empowered by the contemporary interconnected view of depression as a neural system disorder, we sought to identify a specific brain circuit utilizing published heterogeneous neural activations. We systematically reviewed all published cognitive and emotional task-related functional MRI studies that investigated differences in the location of neural activations between depressive patients with and without SA. We subsequently mapped anunderlying brain circuit functionally connecting to each experimental activation using a large normative connectome database (n = 1000). The identified SA-related functional network was compared to the network derived from the disease control group. Finally, we decoded this convergent functional connectivity network using microscale transcriptomic and chemo-architectures, and macroscale psychological processes. We enrolled 11 experimental tasks from eight studies, including depressive patients with SA (n = 147) and without SA (n = 196). The heterogeneous SA-related neural activations localized to the somato-cognitive action network (SCAN), exhibiting robustness to little perturbations and specificity for depression. Furthermore, the SA-related functional network was colocalized with brain-wide gene expression involved in inflammatory and immunity-related biological processes and aligned with the distribution of the GABA and noradrenaline neurotransmitter systems. The findings demonstrate that the SA-related functional network of depression is predominantly located at the SCAN, which is an essential implication for understanding depressive patients with SA.

Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems.

Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels. Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms. Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD. Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD. This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).

Parkinson's Disease: A Narrative Review on Potential Molecular Mechanisms of Sleep Disturbances, REM Behavior Disorder, and Melatonin.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. There is a wide range of sleep disturbances in patients with PD, such as insomnia and rapid eye movement (REM) sleep behavior disorder (or REM behavior disorder (RBD)). RBD is a sleep disorder in which a patient acts out his/her dreams and includes abnormal behaviors during the REM phase of sleep. On the other hand, melatonin is the principal hormone that is secreted by the pineal gland and significantly modulates the circadian clock and mood state. Furthermore, melatonin has a wide range of regulatory effects and is a safe treatment for sleep disturbances such as RBD in PD. However, the molecular mechanisms of melatonin involved in the treatment or control of RBD are unknown. In this study, we reviewed the pathophysiology of PD and sleep disturbances, including RBD. We also discussed the potential molecular mechanisms of melatonin involved in its therapeutic effect. It was concluded that disruption of crucial neurotransmitter systems that mediate sleep, including norepinephrine, serotonin, dopamine, and GABA, and important neurotransmitter systems that mediate the REM phase, including acetylcholine, serotonin, and norepinephrine, are significantly involved in the induction of sleep disturbances, including RBD in PD. It was also concluded that accumulation of α-synuclein in sleep-related brain regions can disrupt sleep processes and the circadian rhythm. We suggested that new treatment strategies for sleep disturbances in PD may focus on the modulation of α-synuclein aggregation or expression.

Resting-State Alterations in Behavioral Variant Frontotemporal Dementia are Related to the Distribution of Monoamine and GABA Neurotransmitter Systems

Resting-State Alterations in Behavioral Variant Frontotemporal Dementia are Related to the Distribution of Monoamine and GABA Neurotransmitter Systems

L-theanine and Neumentix mixture improves sleep quality and modulates brain neurotransmitter levels in mice.

L-theanine (L-THE), a natural amino acid found in green tea, has been shown to improve anxiety and sleep. Neumentix proprietary spearmint extract (PSE), which is commonly found in beverage flavoring a pharmaceutical, also has a wide range of health benefits, including cognitive performance improvement. Four experiments tested the effects of L-THE and PSE on sleep: a direct sleeping test, pentobarbital-induced sleeping test, sub-hypnotic pentobarbital-induced sleeping test, and sodium barbital-induced sleeping test. Presence of neurotransmitters in brain tissue was detected by liquid chromatography mass spectroscopy (HP LC-MS) during these studies. Pentobarbital-induced sleeping and sodium barbital-induced sleeping tests examined the potential effect of L-THE/PSE mixture on synergistic sleep, while neurotransmitter levels in the brain were determined by the high performance liquid chromatography/mass spectroscopy (HPLC/MS) method. L-THE and L-THE/PSE mixture showed increased sleep duration and shortened sleep latency when co-administrated with pentobarbital or sodium barbital. The mixture also increased sleeping rate when co-administrated with the pentobarbital at sub-hypnotic dose. Additionally, the L-THE, PSE and L-THE/PSE mixture significantly increased the concentrations of acetylcholine (Ach), γ-aminobutyric acid (GABA), and decreased the concentration of serotonin (5-HT) in the brain. These data demonstrated that L-THE/PSE mixture regulates sleep disorders via the GABA receptor and neurotransmitter systems.

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression.

In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.

Current and Novel Psychopharmacological Drugs for Anxiety Disorders.

Anxiety disorders, including panic disorder/agoraphobia (PDA), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and others, are the most prevalent mental disorders. In this paper, recommendations are given for the psychopharmacological treatment of these disorders which are based on comprehensive treatment guidelines, meta-analyses, and systematic reviews of available randomized controlled studies. Anxiety disorders can effectively be treated with psychotherapy, pharmacotherapy, or a combination of both. First-line drugs are the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Benzodiazepines are not recommended for routine use due to their possible addiction potential. Other treatment options include the calcium modulator pregabalin, tricyclic antidepressants, buspirone, moclobemide, and others. Drug treatment can be combined with psychological treatments. Novel treatment strategies include medications that act on GABA, glutamate, and other neurotransmitter systems. After remission, medications should be continued for 6 to 12months.

Clethodim exposure induced development toxicity and behaviour alteration in early stages of zebrafish life

Clethodim is one of the most widely used herbicides in agriculture, however, its potential toxic effects on organisms and the underlying toxicity mechanism are still poorly understood. In this study, zebrafish embryos at 6 h post-fertilization (hpf) were exposed to 10 mg/L, 20 mg/L, and 30 mg/L clethodim for up to 24 hpf, and zebrafish larvae at 6 days post-fertilization (dpf) were exposed to the same density gradient for 24 h. Our results showed that clethodim could cause head and cardiovascular malformations in embryos: blurred brain ventricles, unapparent brain regions, condensation of nucleus and cytoplasm in brain cells, increased intercellular space, developmental malformations of eyes and ears, reduced neonatal neurons, disorder migration of neural ridge cells; morphological aberrations of the vascular ICM, slowing of heart beat and blood flow, reduction of circulating red blood cells, and delayed development of head and tail blood vessels. These defects could be a result of clethodim-induced oxidative stress and decreased acetylcholinesterase (AChE) activity, which in turn affected the expression of neurodevelopmental genes, decreased ATPase activity, and ultimately led to developmental malformations. The swimming behaviour of zebrafish larvae was observed to decrease with increasing concentration of clethodim exposure, but the angular velocity and mobility increased. These could be due to reduced AChE activity and disturbed gene expression of GABA, dopamine and glutamatergic neurotransmitter systems, which thus altered the locomotor behaviour. In summary, we found that clethodim induces developmental toxicity and neurotoxicity in zebrafish embryos and larvae.

Behavioral and neurobiological mechanisms of punishment: implications for psychiatric disorders

Punishment involves learning about the relationship between behavior and its adverse consequences. Punishment is fundamental to reinforcement learning, decision-making and choice, and is disrupted in psychiatric disorders such as addiction, depression, and psychopathy. However, little is known about the brain mechanisms of punishment and much of what is known is derived from study of superficially similar, but fundamentally distinct, forms of aversive learning such as fear conditioning and avoidance learning. Here we outline the unique conditions that support punishment, the contents of its learning, and its behavioral consequences. We consider evidence implicating GABA and monoamine neurotransmitter systems, as well as corticostriatal, amygdala, and dopamine circuits in punishment. We show how maladaptive punishment processes are implicated in addictions, impulse control disorders, psychopathy, anxiety, and depression and argue that a better understanding of the cellular, circuit, and cognitive mechanisms of punishment will make important contributions to next generation therapeutic approaches.

Neural and genetic determinants of creativity

Creative thinking plays a vital role in almost all aspects of human life. However, little is known about the neural and genetic mechanisms underlying creative thinking. Based on a cross-validation based predictive framework, we searched from the whole-brain connectome (34,716 functional connectivities) and whole genome data (309,996 SNPs) in two datasets (all collected by Southwest University, Chongqing) consisting of altogether 236 subjects, for a better understanding of the brain and genetic underpinning of creativity. Using the Torrance Tests of Creative Thinking score, we found that high figural creativity is mainly related to high functional connectivity between the executive control, attention, and memory retrieval networks (strong top-down effects); and to low functional connectivity between the default mode network, the ventral attention network, and the subcortical and primary sensory networks (weak bottom-up processing) in the first dataset (consisting of 138 subjects). High creativity also correlates significantly with mutations of genes coding for both excitatory and inhibitory neurotransmitters. Combining the brain connectome and the genomic data we can predict individuals' creativity scores with an accuracy of 78.4%, which is significantly better than prediction using single modality data (gene or functional connectivity), indicating the importance of combining multi-modality data. Our neuroimaging prediction model built upon the first dataset was cross-validated by a completely new dataset of 98 subjects (r = 0.267, p = 0.0078) with an accuracy of 64.6%. In addition, the creativity–related functional connectivity network we identified in the first dataset was still significantly correlated with the creativity score in the new dataset (p<10−3). In summary, our research demonstrates that strong top-down control versus weak bottom-up processes underlie creativity, which is modulated by competition between the glutamate and GABA neurotransmitter systems. Our work provides the first insights into both the neural and the genetic bases of creativity.

Neurosteroids and oxysterols as potential therapeutic agents for glaucoma and Alzheimer's disease.

Glaucoma is one of the most frequent causes of visual impairment worldwide and involves selective damage to retinal ganglion cells (RGCs) resulting in degeneration of neural pathways connecting retina to visual cortex. It is of interest that similarities in pathological changes have been described in Alzheimer's disease (AD), the most common cause of progressive memory loss and dementia in older people. Accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau is thought to contribute to apoptotic neuronal death in Alzheimer's disease, and similar changes have been linked to apoptotic RGC death in glaucoma. Both glaucoma and Alzheimer's disease also suffer from a lack of effective treatments prompting a search for novel therapeutic interventions. Neurosteroids (NSs) (including oxysterols) are endogenous molecules synthesized in the nervous system from cholesterol that can modulate glutamate and GABA receptors, the primary mediators of fast excitatory and inhibitory neurotransmission in the brain, respectively. Because changes in the glutamate and GABA neurotransmitter systems contribute to the pathogenesis of AD and glaucoma, NSs are possible therapeutic targets for these disorders. In this review, we present recent evidence supporting pathological links between Alzheimer's disease and glaucoma, and focus on the possible role of NSs in these diseases and how NSs might be developed for therapeutic purposes.

Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

The study of monozygotic twins discordant for Attention Deficit Hyperactivity Disorder can elucidate mechanisms that contribute to the disorder, which affects around 7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, standard deviation 1.9 years), we find that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole blood DNA from the same twins, we find a significant enrichment of epigenetic differences in genes expressed in these ‘discordant’ brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs – such as copy number and rare, single nucleotide variants- did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated GABA, dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

Age-Related Neurochemical Changes in the Vestibular Nuclei.

There is evidence that the normal aging process is associated with impaired vestibulo-ocular reflexes (VOR) and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa’s ganglion and the vestibular nucleus complex (VNC), it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarizes and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics.

CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles.

Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor–receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4. The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis, and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.

Seizure Drug Shows Promise As Cocaine-Addiction Treatment

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSeizure Drug Shows Promise As Cocaine-Addiction TreatmentJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:18 Dec 2013https://doi.org/10.1176/appi.pn.2013.12a1AbstractEvery few years, a promising medication to treat cocaine dependence emerges, only to fizzle. Is the latest one—topiramate—the longed-for treatment or will it too disappoint?Despite decades of zealous scientific effort, an effective medication to treat cocaine addiction remains elusive. Hope for such a treatment is growing, however, based on results of a study published online October 16 in JAMA Psychiatry.The medication topiramate—already approved by the Food and Drug Administration (FDA) to treat seizures and prevent migraines and also used off label to treat alcohol dependence—is now looking promising as a treatment for cocaine dependence as well.The study was headed by Bankole Johnson, M.D., D.Sc., chair of psychiatry at the University of Maryland.Animal research has shown that an intact GABA neurotransmitter system in the nucleus accumbens, corpus striatum, and several other brain structures is critical for cocaine to exert its effects. Animal research has also indicated that medications that enhance GABA function can reduce cocaine’s effects. Thus Johnson and his colleagues hypothesized that topiramate, a medication known to enhance GABA function, might be effective in treating cocaine dependence. They then launched a clinical trial to test this hypothesis.A total of 142 cocaine-dependent adults were recruited to take part in their study. Half were randomized to receive topiramate, and half were randomized to receive a placebo over a 12-week period. The primary outcome variable was the weekly difference from baseline in the proportion of cocaine nonuse days during weeks 6 to 12, the period when subjects’ topiramate doses should have been optimal. Cocaine use was monitored by self-report and urine tests three times a week.Bankole Johnson, M.D., D.Sc.: “A large effectiveness study is being planned to generalize the findings to an even wider population of cocaine addicts.”Bankole Johnson, M.D., D.Sc.The second outcome variable was cocaine craving as measured by two craving scales that had been well validated in previous pharmacotherapy trials for cocaine dependence—the Cocaine Selective Severity Assessment Scale and the Brief Substance Craving Scale.Finally, global functioning was evaluated by a clinician or nurse practitioner using the Clinical Global Impression-Observer Scale and by the subjects themselves using the Clinical Global Impression–Self Scale.Topiramate was significantly more efficacious than placebo in increasing cocaine-nonuse days and urinary cocaine-free weeks, in reducing the frequency and intensity of cocaine craving, and in improving both observer-rated and self-rated global functioning.In short, “We have some great news regarding a treatment for cocaine dependence,” Johnson told Psychiatric News. As he and his colleagues asserted in their report, “Taken together, it is reasonable to propose that topiramate treatment was associated with a clinically meaningful improvement in the severity of cocaine dependence.”They did acknowledge that they could not compare topiramate’s impact with that of any other medication, since no medication has been approved by the FDA to treat cocaine dependence. “Finding a safe and effective medication (or vaccine) for the treatment of cocaine use disorder has been the holy grail of our field for decades,” Petros Levounis, M.D., chair of psychiatry at Rutgers New Jersey Medical School and an addiction psychiatrist, said during an interview. “Every few years, an exciting possibility appears on the pharmacotherapy scene, only to fizzle out a little later. For a long time, topiramate has been thought of as one of the more promising medications for the treatment of cocaine addiction, and the present study supports this notion. We hope that our current optimism for the success of topiramate is not short-lived as was the case for some other drugs. Had the study been longer than 12 weeks, our confidence in the reported encouraging results would be considerably higher.”Indeed, the next step, Johnson and his team explained, will be to undertake a trial of six months or longer to try to replicate and extend their current findings. The study was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. ■ An abstract of “Topiramate for the Treatment of Cocaine Addiction: A Randomized Clinical Trial” is posted at http://archpsyc.jamanetwork.com/article.aspx?articleid=1756816. ISSUES NewArchived

ПОДАВЛЕНИЕ СТРАХА: УЧАСТИЕ ГАМКЕРГИЧЕСКОЙ НЕЙРОМЕДИАТОРНОЙ СИСТЕМЫ

In experiences on rats in the conditions of free behavior at development of a conditioned of passive avoidanсe reflex (the first series) and a defensive reflex and a conditional inhibition (the second series) it is revealed, and elaboration of internal inhibition and Phenibut – a nonspecific agonist of GAMKA and GAMKB receptors cause in experimental animals weakening of freezing arising in a dangerous situation, and a disinhibition of research behavior. Results of experiences in the accounting of data of the literature allow to assume that both factors, and elaboration of internal inhibition, and Phenibut weaken freezing – the phenomenon used in experiments as a biological analog of fear, owing to increase of level of activity of the GABA neurotransmitter system of a brain. Key words: training, freezing, fear, inhibition, disinhibition, GABA, Phenibut.

Modulation of cardiopulmonary depressor reflex in nucleus ambiguus by electroacupuncture: roles of opioids and γ-aminobutyric acid.

Stimulation of cardiopulmonary receptors with phenylbiguanide (PBG) elicits depressor cardiovascular reflex responses, including decreases in blood pressure and heart rate mediated in part by the brain stem parasympathetic cardiac neurons in the nucleus ambiguus (NAmb). The present study examined NAmb neurotransmitter mechanisms underlying the influence of electroacupuncture (EA) on the PBG-induced hypotension and bradycardia. We hypothesized that somatic stimulation during EA modulates PBG responses through opioid and γ-aminobutyric acid (GABA) modulation in the NAmb. Anesthetized and ventilated cats were studied during repeated stimulation with PBG or cardiac vagal afferents while low-frequency EA (2 Hz) was applied at P5-6 acupoints overlying the median nerve for 30 min and NAmb neuronal activity, heart rate, and blood pressure were recorded. Microinjection of kainic acid into the NAmb attenuated the PBG-induced bradycardia from -60 ± 11 to -36 ± 11 beats/min. Likewise, EA reduced the PBG-induced depressor and bradycardia reflex by 52 and 61%, respectively. Cardiac vagal afferent evoked preganglionic cellular activity in the NAmb was reduced by EA for about 60 min. Blockade of opioid or GABA(A) receptors using naloxone and gabazine reversed the EA-related modulation of the evoked cardiac vagal activity by 73 and 53%, respectively. Similarly, naloxone and gabazine reversed EA modulation of the negative chronotropic responses from -11 ± 5 to -23 ± 6 and -13 ± 4 to -24 ± 3 beats/min, respectively. Thus EA at P5-6 decreases PBG evoked hypotension and bradycardia as well as the NAmb PBG-sensitive preganglionic cardiac vagal outflow through opioid and GABA neurotransmitter systems.

GABAergic modulation of the 40 Hz auditory steady-state response in a rat model of schizophrenia

Auditory steady-state auditory responses (ASSRs), in which the evoked potential entrains to stimulus frequency and phase, are reduced in magnitude in patients with schizophrenia, particularly at 40 Hz. While the neural mechanisms responsible for ASSR generation and its perturbation in schizophrenia are unknown, it has been hypothesized that the GABAA receptor subtype may have an important role. Using an established rat model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model, 40-Hz ASSRs were elicited from NVHL and sham rats to determine if NVHL rats show deficits comparable to schizophrenia, and to examine the role of GABAA receptors in ASSR generation. ASSR parameters were found to be stable across time in both NVHL and sham rats. Manipulation of the GABAA receptor by muscimol, a GABAA agonist, yielded a strong lesion x drug interaction, with ASSR magnitude and synchronization decreased in NVHL and increased in sham rats. The lesion x muscimol interaction was blocked by a GABAA receptor antagonist when given prior to muscimol administration, confirming the observed interaction was GABAA mediated. Together, these data suggest an alteration involving GABAA receptor function, and hence inhibitory transmission, in the neuronal networks responsible for ASSR generation in NVHL rats. These findings are consistent with prior evidence for alterations in GABA neurotransmitter systems in the NVHL model and suggest the utility of this animal modelling approach for exploring neurobiological mechanisms that generate or modulate ASSRs.

Malfunction in GABA and Glutamate as Pathways to Depression: A Review of the Evidence

With nearly one fifth of the population experiencing depression sometime during their lives, plus the recent finding that depression rivals smoking in its association with mortality, the search for effective pharmacological treatments for depression remains urgent. However, despite this heavy disease burden upon society, the various waves of antidepressants developed in the last 40 years have shown significant side effects and little specific efficacy over placebo. One potential treatment may be via re-establishment of glutamate and GABA neurotransmitter systems that have been shown to malfunction in depressed patients. The literature describing possible causal links between GABA and/or glutamate malfunction and depression is reviewed, plus those studies which provide experimental data to confirm this hypothesis. While there is plausible support for the links between malfunction of these neurotransmitters and depression, few data exist yet regarding development of effective antidepressant medications based upon these findings.