GABAergic Neurotransmitter Systems Research Articles

Evaluation of antiepileptic activity of ethanolic extract of garlic containing 3.25% allicin in experimental animals

IntroductionEpilepsy is a condition of the brain that causes seizures and affects a significant portion of the global population, and current treatments often have limited efficacy and undesirable side effects. Throughout history, people have utilized garlic for its medicinal properties to address diverse health concerns. Allicin is a major component of garlic. We conducted an experiment to evaluate the antiepileptic properties of an ethanolic extract of garlic (EEG) with 3.25% allicin content using acute epilepsy models. MethodsFor our experiment, we employed 72 Swiss albino mice, which were divided into six separate groups. Chemo-convulsant PTZ and strychnine HCL were used to induce epileptic activity in the mice, and the standard used was diazepam (5 mg/kg p.o.). Our study evaluated the effectiveness of an ethanolic garlic extract (EEG) with the same potency as allicin at doses of 25, 50, and 100 mg/kg (p.o.). on epileptic activity was assessed using a variety of parameters. The GABA level of mice brains was also estimated. ResultsThe allicin treatment led to a notable decrease in the duration and increase in the latency of seizures that were induced by PTZ and strychnine. The extract also showed a significant decrease in the mortality rate. Test allicin intervention restored brain GABA levels in a dose-dependent manner. ConclusionOur study indicates that the EEG containing 3.25% allicin has the potential as an antiepileptic agent, possibly due to its modulation of the GABAergic neurotransmitter systems.

0032 ADA Functional Polymorphism Modulates REM Sleep Following Total Sleep Deprivation

Abstract Introduction Adenosine Deaminase (ADA) regulates extracellular levels of adenosine, a brain correlate of sleep homeostasis. A single nucleotide polymorphism (SNP) of the ADA gene (rs73598374) is known to be associated with increased homeostatic pressure for NREM sleep after total sleep deprivation (TSD). Whether this genotype effect also impacts REM sleep after TSD has not been systematically investigated. The limit cycle reciprocal interaction model posits that NREM/REM cycles are regulated by cholinergic and GABAergic neurotransmitter systems. While NREM/REM regulation is also thought to be mediated by sleep homeostatic state, evidence of an association with adenosine levels has not been reported. Here we investigate the influence of ADA on REM sleep at baseline and following TSD. Methods N=48 healthy, normal sleepers (ages 27.7 + 5.3, 23 females) participated in one of three in-laboratory TSD studies. Following 10h baseline sleep (22:00–08:00), participants underwent 38h TSD, with subsequent 10h recovery sleep (22:00–08:00). Sleep periods were recorded polysomnographically and scored visually according to AASM criteria. Genomic DNA was extracted from whole blood, and the ADA SNP was assayed using real-time PCR. Sleep stages were analyzed using mixed-effect ANOVA with fixed effects of ADA genotype, night (baseline vs. recovery), and their interaction, controlling for study, with a random effect over subject on the intercept. Results The frequency of genotypes (G/G: 42, A/G: 6) did not vary from Hardy-Weinberg equilibrium. There was no genotype effect on total sleep time and no genotype by night interaction (p>0.7). However, A allele carriers spent more time in REM during baseline and less during recovery compared to G/G homozygotes (genotype by night interaction: F[1,46]=8.13, p=0.007). Conversely, while not statistically significant (p>0.1), A allele carriers spent less time in NREM during baseline and more during recovery compared to G/G homozygotes. Conclusion ADA genotype was associated with a shift in balance between REM and NREM at baseline, as well as changes therein after TSD, without concomitant effect on total sleep time. This suggests a role for adenosine in mediating REM sleep regulation, possibly through a sleep homeostatic effect on the reciprocal interaction between NREM and REM. Support (if any) CDMRP W81XWH-05-1-0099; ONR N00014-13-C-0063; NIH R21CA16769; ARO W911NF2210223.

The impact of antidepressant medications on glutamatergic and GABAergic neurotransmitter systems: a systematic review of pharmacological [1H] MRS studies

The impact of antidepressant medications on glutamatergic and GABAergic neurotransmitter systems: a systematic review of pharmacological [1H] MRS studies

Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice

BackgroundNeuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these disorders. However, it remains unclear whether insufficient DNA repair and resulting DNA damage are causally connected to their aetiopathology, or if increased levels of DNA damage observed in patient tissues merely accumulate as a consequence of cellular dysfunction. To assess a potential causal role for deficient DNA repair in the development of these disorders, we behaviourally characterized a mouse model in which CaMKIIa-Cre-driven postnatal conditional knockout (KO) of the core base-excision repair (BER) protein XRCC1 leads to accumulation of unrepaired DNA damage in the forebrain.ResultsCaMKIIa-Cre expression caused specific deletion of XRCC1 in the dorsal dentate gyrus (DG), CA1 and CA2 and the amygdala and led to increased DNA damage therein. While motor coordination, cognition and social behaviour remained unchanged, XRCC1 KO in the forebrain caused increased anxiety-like behaviour in males, but not females, as assessed by the light–dark box and open field tests. Conversely, in females but not males, XRCC1 KO caused an increase in learned fear-related behaviour in a cued (Pavlovian) fear conditioning test and a contextual fear extinction test. The relative density of the GABA(A) receptor alpha 5 subunit (GABRA5) was reduced in the amygdala and the dorsal CA1 in XRCC1 KO females, whereas male XRCC1 KO animals exhibited a significant reduction of GABRA5 density in the CA3. Finally, assessment of fast-spiking, parvalbumin-positive (PV) GABAergic interneurons revealed a significant increase in the density of PV+ cells in the DG of male XRCC1 KO mice, while females remained unchanged.ConclusionsOur results suggest that accumulation of unrepaired DNA damage in the forebrain alters the GABAergic neurotransmitter system and causes behavioural deficits in relation to innate and learned anxiety in a sex-dependent manner. Moreover, the data uncover a previously unappreciated connection between BER deficiency, unrepaired DNA damage in the hippocampus and a sex-specific anxiety-like phenotype with implications for the aetiology and therapy of neuropsychiatric disorders.

Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain.

Growing evidence indicates a link between changes in the medial prefrontal cortex and the pathophysiology of chronic pain. In particular, chronic pain is associated with altered medial prefrontal anatomy and biochemistry. Due to the comorbid affective disorders seen across all pain conditions, the medial prefrontal cortex is a region of significance as it is involved in emotional processing. We have recently reported that a decrease in medial prefrontal N-acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. Therefore, we compared medial prefrontal neurochemistry in 24 people with chronic pain conditions to 24 age and sex-matched healthy controls with no history of chronic pain. GABA-edited MEGA-PRESS was used to measure GABA+ levels, and short TE PRESS was used to measure glutamate levels in the medial prefrontal cortex. Psychometric measures regarding pain intensity a week before scanning, during the scan and the total duration of chronic pain, were also recorded and compared to measured GABA+ and glutamate levels. This study reveals that the presence of chronic pain is associated with significant decreases in medial prefrontal GABA+ and glutamate. These findings support the hypothesis that chronic pain is associated with altered medial prefrontal biochemistry. The dysregulation of glutamatergic and GABAergic neurotransmitter systems supports a model of disinhibition of chronic pain, which may play a key role in both the experience of persistent pain and its associated affective disturbances. This study reveals a significant reduction in γ-aminobutyric acid (GABA+ ) and glutamate within the medial prefrontal cortex in chronic pain sufferers. While the current findings should be considered with reference to a small sample size, the disruption to normal excitatory and inhibitory medial prefrontal cortex function may be key in the development and maintenance of chronic pain and comorbid mental health disorders.

Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 – 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < − 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.

Characterization of the GABAergic system in Asian clam Corbicula fluminea: Phylogenetic analysis, tissue distribution, and response to the aquatic contaminant carbamazepine

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter involved in the neuro-endocrine-immune (NEI) system. In this study, we sequenced the partial length of cDNA fragments of three genes involved in GABA neurotransmitter system of the Asian clam (Corbicula fluminea) (GABAA receptor-associated protein (GABARAP), GABARAPL2 and GABA transporter (GAT-1)). These genes exhibited high amino acid sequence identity compared with other invertebrate orthologs. Expression patterns of the three genes were determined in mantle, gill, gonad, digestive gland and muscle, and the steady state levels of mRNA for each were determined to be highest in gonad and lowest in muscle. To determine their regulation by pharmaceuticals that are present as contaminants in waterways, clams were exposed to carbamazepine (CBZ) for 30 days. CBZ is an agonist for GABA receptors and is an anticonvulsant pharmaceutical that is often detected in aquatic ecosystems. GABARAP and GABARAPL2 mRNA levels were significantly downregulated by 5 and 50 μg/L CBZ in mantle and gill (p < 0.05), while in the gonad and digestive gland, steady state levels (p < 0.05) were decreased with exposure to all three doses. GAT-1 mRNA was upregulated by CBZ (p < 0.05) in the mantle and gill at all three doses tested and in the gonad and digestive system with 5 and 50 μg/L. These data suggest that CBZ disrupt the expression of the GABAergic neurotransmitter system in C. fluminea. Moreover, GABARAP, GABARAPL2 and GAT-1 may be useful biomarkers for the screening of substances that are hazardous to the NEI system of mollusks.

Electro-acupuncture alleviates adolescent cocaine exposure-enhanced anxiety-like behaviors in adult mice by attenuating the activities of PV interneurons in PrL.

We recently found that adolescent cocaine exposure (ACE) resulted in an enhancement of the γ-aminobutyric acid (GABA) neurotransmitter system in the prelimbic cortex (PrL) of adult mice. Here, we aim to further investigate the role of GABAergic transmission, especially parvalbumin (PV) interneurons within PrL in the development of ACE-induced anxiety-like behavior, and to assess whether and how electro-acupuncture (EA) therapeutically manage the ACE-induced abnormal behaviors in adulthood. ACE mice exhibited the enhanced anxiety-like behaviors in their adulthood, accompanied by increased GABAergic transmission and PV interneurons in PrL. Chemogenetic blocking PV interneurons in PrL alleviated ACE-enhanced anxiety-like behaviors in mice. Importantly, 37-day EA treatments (mixture of 2Hz/100Hz, 1mA, 30minutes once a day) at the acupoints of Yintang (GV29) and Baihui (GV20) also alleviated ACE-induced anxiety-like behaviors, and rescued ACE-impaired GABAergic neurotransmitter system and PV interneurons in PrL. In parallel, EA treatments further suppressed the activities of pyramidal neurons in PrL, suggesting that EA treatments seem to perform it beneficial effects on the ACE-induced abnormal emotional behaviors by "calming down" the whole PrL. Collectively, these findings revealed that hyper-function of GABAergic transmission, especially mediating by PV interneurons in PrL may be key etiology underlying ACE-induced anxiety-like behaviors. At least by normalizing the function of GABAergic and PV interneurons, EA may represent a promising therapeutic strategy for managing adolescent substance use-related emotional disorders.

Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice

The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.

Некоторые аспекты исследования центрального механизма антиноцицептивного действия нового анальгетика из класса гексаазаизовюрцитанов

Possible involvement of μ1- and κ-opioid receptors and cannabinoid type 1 receptors (CB1) into the mechanism of analgesic activity of the experimental drug product "Thiowurtzine, (capsule 120 mg)" synthesized on the basis of active pharmaceutical substance 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo [5,5,0,03,11,05,9]dodecane was studied in vivo using the hot plate test and acetic acid writhing test. The involvement of κ-opioid receptors and noninvolvement of μ1-receptors and CB1 receptors in the mechanism of thiowurtzine analgesia were demonstrated. The mechanism of interaction of the test analgesic with opioid receptors differs from that of the reference drug tramadol. The interaction of thiowurtzine with serotonergic, GABAergic, and muscarinic cholinergic neurotransmitter systems was studied in vivo using pharmacological analyzers. The absence of muscarinic cholinolytic effect of thiowurtzine was demonstrated in the model of arecoline-induced tremor. The central serotonin-blocking activity of the analgesic was revealed in the model of 5-hydroxytryptophan hyperkinesis in mice. Anticonvulsant activity was demonstrated in the corazol convulsions test, which attested to the presence of a GABAergic component. The mechanism of central analgesia caused by the drug product "Thiowurtzine, capsule 120 mg" appeared to be polymodal. The antinociceptive activity of the analgesic was comparable to that of tramadol.

Decreased GABA concentrations in left prefrontal cortex of methamphetamine dependent patients: A proton magnetic resonance spectroscopy study

Increasing evidence suggested the dorsolateral prefrontal cortex (DLPFC) is implicated in the pathogenesis of methamphetamine use disorder. Metabolites changes of DLPFC may mediate the progression of addiction. We used proton magnetic resonance spectroscopy (1H-MRS) to examine the changes of metabolites in the left DLPFC in individuals with methamphetamine dependence compared to healthy controls. Fifty patients and twenty age-matched healthy controls participated in this study. The 1H MRS data were automatically fit with linear combination model for quantification of metabolite levels of γ-aminobutyric acid (GABA), glutamate + glutamine (Glx) and other metabolites across groups. The GABA and Glx levels were calculated with the unsuppressed water signal as reference. Methamphetamine users showed reduced GABA and GABA/Glx in left DLPFC than healthy controls. Furthermore, the concentration of GSH, GPC, Ins, NAA, GPC + PCh, NAA + NAAG, Cr + PCr were lower in individuals with methamphetamine dependence compared with controls. The patients group's relative GABA and Glx metabolite concentrations were significantly correlated with age and duration of withdrawal. Our preliminary findings provide the first report of abnormal levels of GABA in left DLPFC of patients with methamphetamine use disorder, indicating that dysregulation of the GABAergic neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of methamphetamine dependence.

Neurochemical and behavioral analysis by acute exposure to bisphenol A in zebrafish larvae model

Bisphenol A (BPA) is a chemical monomer widely used in the production of hard plastics for food containers and personal items. Through improper industrial control and disposal, BPA has become a pervasive environmental contaminant, and toxicological studies have shown potent xenobiotic endocrine disruptor activity. Prenatal exposure in particular can lead to infertility and nervous system disorders characterized by behavioral aggression, depression, and cognitive impairment, thus necessitating careful hazard assessment.In this study, we evaluated BPA accumulation rate, blood-brain barrier (BBB) permeability, lethality, cardiotoxicity, behavioral effects, and impacts on multiple neurochemical pathways in zebrafish larvae. The bioconcentration factor (BCF) ranged from 1.95 to 10.0, resulting in a high rate of accumulation in the larval body. Also, high BBB permeability allowed BPA to accumulate at similar rates in both zebrafish and adult mouse (blood to brain concentration ratios of 3.2–6.7 and 1.8 to 5.5, respectively). In addition, BPA-exposed zebrafish larvae exhibited developmental deformities, reduced heart rate, and impaired behavioral patterns, including decreased total distance traveled, slower movement velocity, and altered color-preference. These impairments were associated with inhibition of the phenylalanine to dopamine synthesis pathway and an imbalance between excitatory and inhibitory neurotransmitter systems. Our results suggest that behavioral alteration in BPA-exposed zebrafish result from high accumulation and ensuing dysregulation of serotonergic, kynurenergic, dopaminergic, cholinergic, and GABAergic neurotransmitter systems. In conclusion, similarities in toxic responses to mammalian models highlight the utility of the zebrafish larva as a convenient model for screening environmental toxins.

APOE genetic background and sex confer different vulnerabilities to postnatal chlorpyrifos exposure and modulate the response to cholinergic drugs

Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups.

Dietary of n-3 polyunsaturated fatty acids influence neurotransmitter systems of rats exposed to unpredictable chronic mild stress

Emerging evidence suggest that neuromodulators are the critical factor involved in depression. This study aimed to investigate the effects of unpredictable chronic mild stress (CUMS) and n-3 polyunsaturated fatty acids (n-3 PUFAs) on central nervous system. The depressive-like behaviors induced by CUMS were assessed by sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to quantify the levels of neurotransmitters and their metabolites involved in serotonergic, dopaminergic, noradrenergic, GABAergic neurotransmitter systems in hippocampus and prefrontal cortex. Repeated CUMS caused depressive-like behaviors of rats, associated with the alteration of neurotransmitters in brain, including the decreasing DA level, the increasing NE and GABA level, and the increasing 5-HT turnover rate in hippocampus, which could be partly alleviated by sufficient n-3 PUFAs supplementation. The influence of stress and diet on neurotransmitters in the prefrontal cortex was slight. However, it was obvious that supplementary of n-3 PUFAs relieved the decreasing DA/NE between-metabolite ratio 1,2 and DA/5-HT between-metabolite ratio 1,2 in the prefrontal cortex caused by CUMS. Altered neurotransmitter turnover rates and between-metabolite ratios in brain may be better predictors in depression and antidepressant treatment compared with monoamine neurotransmitters.

TOXICOLOGICAL CHARACTERISTIC OF DESIGNER DRUGS FROM THE GROUP OF SYNTHETIC OPIOIDS

Toxicological characteristic of designer drugs from the group of synthetic opioids is presented. The historical aspects of illicit drug trafficking are considered. In the illicit drug market of EU countries 38 synthetic opioids, 22 of them belonging to fentanyl derivatives, have been revealed for the period 2005-2017. The widespread use of synthetic opioids among drug addicts has been accompanied by an increase in the number of fatal overdoses. In the United States the number of fatal poisonings by synthetic opioids of fentanyl series increased by 40.3 times between 1999 and 2017. The similar situation is emerging in other countries. This is due to the fact that the biological activity and toxicity of synthetic opioids far exceed those of morphine and heroin. The differences between the metabolism of heroin and synthetic opioids are considered. Data on the toxicity of synthetic opioids are presented. The neurotransmitter mechanisms of their respiratory depression, including disorders of opioid, GABAergic, glutamatergic and serotoninergic neurotransmitter systems are discussed. A brief description of the antidote activity of opioid receptor antagonists in acute poisoning by synthetic opioids is given.

Impulsive Action and Impulsive Choice Are Differentially Associated With Gene Expression Variations of the GABAA Receptor Alfa 1 Subunit and the CB1 Receptor in the Lateral and Medial Orbitofrontal Cortices.

The orbitofrontal cortex (OFC) is a key brain region for decision-making, action control and impulsivity. Quite notably, previous research has identified a double dissociation regarding the role of this cortical territory in impulsive choice. While medial orbitofrontal lesions increase preference for a large but delayed reward, lateral orbitofrontal lesions have the opposite effect. However, there are no data regarding this anatomical dissociation in impulsive action. The neurochemical basis of impulsivity is still being elucidated, however, in recent years a role for the endocannabinoids and the related glutamatergic and GABAergic neurotransmitter systems has been suggested. Here, we submitted male Wistar rats to a delay-discounting task (DDT) or a two-choice serial reaction time task (2-CSRTT) and classified them as high impulsive or low impulsive in either task using cluster analysis. We then examined the gene expression of several elements of the endocannabinoid system or different subunits of certain glutamatergic or GABAergic ionotropic receptors (AMPA, NMDA, or GABAA) in the lateral or medial divisions of their orbitofrontal cortices. Our results confirm, at the gene expression level, the dissociation in the participation of the medial, and lateral divisions of the orbitofrontal cortex in impulsivity. While in the 2-CSRTT (inhibitory control) we found that high impulsive animals exhibited lower gene expression levels of the α1 GABAA receptor subunit in the lateral OFC, no such differences were evident in the medial OFC. When we analyzed DDT performance, we found that high impulsive animals displayed lower levels of CB1 gene expression in the medial but not in the lateral OFC. We propose that GABAergic dynamics in the lateral OFC might contribute to the inhibitory control mechanisms that are altered in impulsive behavior while endocannabinoid receptor gene transcription in the medial OFC may subserve the delay-discounting processes that participate in certain types of impulsiveness.

Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology.

Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, ‘Parkinsonism in cirrhosis’. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.

O7.6. META-ANALYSIS OF EFFICACY OF COGNITIVE ENHANCERS FOR PATIENTS WITH SCHIZOPHRENIA-SPECTRUM DISORDERS

BackgroundCognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and should therefore be one of the main treatment targets. Pharmacological enhancement of cognition has been a main field of research in the last decades, investigating almost all neurotransmitter systems and reporting positive as well as negative findings. The pathophysiology of cognitive dysfunctions in schizophrenia is complex and many different neurotransmitter systems are involved. This quantitative review provides an overview of studies of pharmacological agents targeting neurotransmitter systems relevant for cognitive deficits in schizophrenia.MethodsIn our systematic search we included pharmacological agents targeting glutamatergic, cholinergic, serotonergic, dopaminergic, GABAergic and noradrenergic neurotransmitter systems, and also a miscellaneous group of agents, including modafinil/armodafinil. We evaluated the effects of cognitive enhancers on overall cognitive functioning as well as on seven cognitive domains, including attention/vigilance, processing speed, reasoning, verbal learning and memory, visual learning and memory, working memory, and verbal fluency.ResultsIn total, 93 studies with 5630 patients were suitable for inclusion in the meta-analysis. The mean sample size was 28.73 (SD=27.13, range=4–203), mean age of the participants was 44.15 years (SD=6.36, as reported by 91 study samples), 68.54% of the sample were men (as reported by 87 study samples), and average illness duration was 15.57 years (SD=6.47, as reported by 63 study samples). Combining all cognitive enhancers across different neurotransmitter systems for the effect on overall cognitive functioning resulted in fifty-one study samples, with a total of 3635 patients. Cognitive enhancers showed a small but significant positive effect size of 0.10 over placebo treatment (p=.023; 95%CI=0.01 to 0.18). Overall, cognitive enhancers showed no positive effects as compared to placebo for the separate domains. When analysing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small but significant effect size on overall cognitive functioning (Hedges’ g=0.19, p=.01), as well as on working memory (Hedges’ g=0.13, p=.04). A sub-analysis of acetylcholinesterase inhibitors (AChEI) within cholinergic system showed a small effect on working memory (Hedges’ g=0.26, p=.03). No other positive effects of cognitive enhancers as compared to placebo were revealed.DiscussionThe current meta-analysis showed very few favorable effects of cognitive enhancers for patients with schizophrenia spectrum disorders. The overall analysis showed small difference between cognitive enhancers and placebo. Most studies were on agents acting on the glutamatergic and the cholinergic system. There is some evidence of positive effects on cognitive functioning for agents acting on glutamatergic system and acetylcholinesterase inhibitors within cholinergic system. There is still a major lack of studies involving agents acting on other systems. Important issues such as dose, treatment duration, including a younger population and subtyping heterogeneous samples should be taken into account for future studies.

Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism.

Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system. Specifically, people with autism have a reduction in parvalbumin (PV)-containing interneurons in the PFC, leading to the suggestion that restoring interneuron function in this region may be a novel therapeutic approach for ASD. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of PV-positive interneurons, which were transplanted into the medial prefrontal cortex (mPFC) of the Poly I:C rodent model of autism. PV interneuron transplants were able to decrease pyramidal cell firing in the mPFC and alleviated deficits in social interaction and cognitive flexibility. Our results suggest that restoring PV interneuron function in the mPFC may be a novel and effective treatment strategy to reduce the core symptoms of autism.

Inhibitory motor dysfunction in parkinson's disease subtypes.

Parkinson's disease (PD) is divided into postural instability gait difficulty (PIGD) and tremor-dominant (TD) subtypes. Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of PD. To evaluate the differences of GABA levels between PD motor subtypes using MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS). COHORT.: SUBJECTS: PD patients were classified into PIGD (n = 13) and TD groups (n = 9); 16 age- and sex-matched healthy controls were also recruited. All subjects were right-handed. All subjects underwent an magnetic resonance spectroscopy scan including MEGA-PRESS at 3.0T. The detected GABA signal also contains signal from macromolecules (MM) and homocarnosine, so it is referred to as GABA+. GABA + levels and Creatine (Cr) levels were quantified in the left basal ganglia (BG) using Gannet 2.0 by Tao Gong. Differences in GABA + levels between the three groups were analyzed using analysis of covariance. The relationship between GABA levels and a unified PD rating scale (UPDRS) was also analyzed. GABA + levels were significantly lower in left BG regions of PD patients compared with healthy controls (P < 0.001). In PD patients, the GABA concentration was lower in the TD group than the PIGD group (P = 0.019). Cr levels in PIGD and TD were lower than controls (P = 0.020; P = 0.002). A significant negative correlation was found in PIGD between GABA levels and UPDRS (r = -0.572, P = 0.041), while no correlation was found in TD (r = -0.339, P = 0.372). Low BG GABA levels in PD patients, and differences between PIGD/TD patients, suggest that GABAergic dysfunction may play an important role in the pathogenesis of Parkinson's disease. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1610-1615.