GABAergic System Research Articles

The influence of season on glutamate and GABA levels in the healthy human brain investigated by magnetic resonance spectroscopy imaging.

Seasonal changes in neurotransmitter systems have been demonstrated in imaging studies and are especially noticeable in diseased states such as seasonal affective disorder (SAD). These modulatory neurotransmitters, such as serotonin, are influencing glutamatergic and GABAergic neurotransmission. Furthermore, central components of the circadian pacemaker are regulated by GABA (the suprachiasmatic nucleus) or glutamate (e.g., the retinohypothalamic tract). Therefore, we explored seasonal differences in the GABAergic and glutamatergic system in 159 healthy individuals using magnetic resonance spectroscopy imaging with a GABA-edited 3D-MEGA-LASER sequence at 3T. We quantified GABA+/tCr, GABA+/Glx, and Glx/tCr ratios (GABA+, GABA+ macromolecules; Glx, glutamate + glutamine; tCr, total creatine) in five different subcortical brain regions. Differences between time periods throughout the year, seasonal patterns, and stationarity were tested using ANCOVA models, curve fitting approaches, and unit root and stationarity tests, respectively. Finally, Spearman correlation analyses between neurotransmitter ratios within each brain region and cumulated daylight and global radiation were performed. No seasonal or monthly differences, seasonal patterns, nor significant correlations could be shown in any region or ratio. Unit root and stationarity tests showed stable patterns of GABA+/tCr, GABA+/Glx, and Glx/tCr levels throughout the year, except for hippocampal Glx/tCr. Our results indicate that neurotransmitter levels of glutamate and GABA in healthy individuals are stable throughout the year. Hence, despite the important correction for age and gender in the analyses of MRS derived GABA and glutamate, a correction for seasonality in future studies does not seem necessary. Future investigations in SAD and other psychiatric patients will be of high interest.

Exposure to Juvenile Stress Induces Epigenetic Alterations in the GABAergic System in Rats.

Epigenetics is a gene-environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (GAD65, GAD67). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of GAD65 in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend was captured, and higher GAD65 methylation was found in JS. In addition, RNA levels were found to be decreased in JS compared to JSe and JS + AS. These findings can point to a possible mechanism: while juvenile stress may enhance a better coping strategy with life challenges, additional stress in adulthood may trigger a contradictory response, either beneficial or harmful.

Exposure to chlorpyrifos during pregnancy differentially affects social behavior and GABA signaling elements in an APOE- and sex-dependent manner in a transgenic mouse model

The massive use of chlorpyrifos (CPF) has been associated with an increased prevalence of neurodevelopmental disorders. Some previous studies have shown that prenatal, but not postnatal, CPF exposure causes social behavior deficits in mice depending on sex while others have found that in transgenic mice models carrying the human apolipoprotein E (APOE) ε3 and ε4 allele confer different vulnerabilities to either behavioral or metabolic disorders after CPF exposure. This study aims to evaluate, in both sexes, how prenatal CPF exposure and APOE genotype impact on social behavior and its relation to changes in GABAergic and glutamatergic systems. For this purpose, apoE3 and apoE4 transgenic mice were exposed through the diet to 0 or 1 mg/kg/day of CPF, between gestational day 12 and 18. A three-chamber test was used to assess social behavior on postnatal day (PND) 45. Then, mice were sacrificed, and hippocampal samples were analyzed to study the gene expression of GABAergic and glutamatergic elements. Results showed that prenatal exposure to CPF impaired social novelty preference and increased the expression of GABA-A α1 subunit in females of both genotypes. In addition, the expression of GAD1, the ionic cotransporter KCC2 and the GABA-A α2 and α5 subunits were increased in apoE3 mice, whereas CPF treatment only accentuated the expression of GAD1 and KCC2. Nevertheless, future research is needed to evaluate whether the influences detected in the GABAergic system are present and functionally relevant in adults and old mice.

Neurotoxicity of polystyrene nanoplastics with different particle sizes at environment-related concentrations on early zebrafish embryos

Nanoplastics (NPs) have received global attention due to their wide application and detection in various environmental or biological media. NPs can penetrate physical barriers and accumulate in organisms after being ingested, producing a variety of toxic effects and possessing particle size-dependent effects, distinguishing them from traditional contaminants. This paper explored the neurotoxicity of polystyrene (PS)-NPs of different particle sizes on zebrafish (Danio rerio) embryos at environmental concentrations at the tissue and molecular levels using visualized transgenic zebrafish. Results showed that all particle sizes of PS-NPs produced developmental toxicity in zebrafish embryos and induced neuronal loss, axonal deletion/shortening/hybridization, and developmental and apoptotic-related genetic alterations, ultimately leading to behavioral abnormalities. PS-NPs with smaller sizes may have more severe neurotoxicity due to their entry into the embryo and brain through the chorionic pore before hatching. In addition, PS-NPs at 100 nm and 1000 nm can specifically interfere with GABAergic, cholinergic or serotonergic system and affect neuronal signaling. Our results reveal the neurotoxic risk of NPs, and smaller particle-size NPs may have a greater ecological risk. We anticipate that our study can provide a basis for exploring the toxicity mechanisms of NPs and the environmental risk assessment of NPs.

Effect of developmental stress on the in vivo neuronal circuits related to excitation-inhibition balance and mood in adulthood.

Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.

Impairment of GABA inhibition in insomnia disorders: Evidence from the peripheral blood system.

To explore the change characteristics and related factors of various indexes of GABAergic system in peripheral blood of patients with insomnia disorder. In this study, a total of 30 patients who met the DSM-5 diagnostic criteria for insomnia disorder and 30 normal controls were included. All subjects had a structured clinical interview with the Brief International Neuropsychiatric Disorder Interview, and PSQI was used to evaluate the sleep status of the subjects. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum γ-aminobutyric acid (GABA), and RT-PCR was used to detect GABAA receptor α1 and α2 subunit mRNA. All data were statistically analyzed using SPSS 23.0. Compared with the normal control group, the mRNA levels of GABAA receptor α1 and α2 subunits in the insomnia disorder group were significantly lower, but there was no significant difference in the serum GABA levels between the two groups. And in the insomnia disorder group, there was no significant correlation between the GABA levels and the mRNA expression levels of α1 and α2 subunits of GABAA receptors. Although no significant correlation was found between PSQI and serum levels of these two subunit mRNAs, its component factors sleep quality and sleep time were negatively correlated with GABAA receptor α1 subunit mRNA levels, and daytime function was inversely correlated with GABAA receptor α2 subunit mRNA levels. The inhibitory function of serum GABA in patients with insomnia may be impaired, and the decreased expression levels of GABAA receptor α1 and α2 subunit mRNA may become a reliable indicator of insomnia disorder.

Understanding the function of the GABAergic system and its potential role in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly disabling chronic autoimmune disease. Multiple factors contribute to the complex pathological process of RA, in which an abnormal autoimmune response, high survival of inflammatory cells, and excessive release of inflammatory factors lead to a severe chronic inflammatory response. Clinical management of RA remains limited; therefore, exploring and discovering new mechanisms of action could enhance clinical benefits for patients with RA. Important bidirectional communication occurs between the brain and immune system in inflammatory diseases such as RA, and circulating immune complexes can cause neuroinflammatory responses in the brain. The gamma-aminobutyric acid (GABA)ergic system is a part of the nervous system that primarily comprises GABA, GABA-related receptors, and GABA transporter (GAT) systems. GABA is an inhibitory neurotransmitter that binds to GABA receptors in the presence of GATs to exert a variety of pathophysiological regulatory effects, with its predominant role being neural signaling. Nonetheless, the GABAergic system may also have immunomodulatory effects. GABA/GABA-A receptors may inhibit the progression of inflammation in RA and GATs may promote inflammation. GABA-B receptors may also act as susceptibility genes for RA, regulating the inflammatory response of RA via immune cells. Furthermore, the GABAergic system may modulate the abnormal pain response in RA patients. We also summarized the latest clinical applications of the GABAergic system and provided an outlook on its clinical application in RA. However, direct studies on the GABAergic system and RA are still lacking; therefore, we hope to provide potential therapeutic options and a theoretical basis for RA treatment by summarizing any potential associations.

J-difference GABA-edited MRS reveals altered cerebello-thalamo-cortical metabolism in patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common neurological manifestation of liver cirrhosis and is characterized by an increase of ammonia in the brain accompanied by a disrupted neurotransmitter balance, including the GABAergic and glutamatergic systems. The aim of this study is to investigate metabolic abnormalities in the cerebello-thalamo-cortical system of HE patients using GABA-edited MRS and links between metabolite levels, disease severity, critical flicker frequency (CFF), motor performance scores, and blood ammonia levels. GABA-edited MRS was performed in 35 participants (16 controls, 19 HE patients) on a clinical 3T MRI system. MRS voxels were placed in the right cerebellum, left thalamus, and left motor cortex. Levels of GABA+ and of other metabolites of interest (glutamine, glutamate, myo-inositol, glutathione, total choline, total NAA, and total creatine) were assessed. Group differences in metabolite levels and associations with clinical metrics were tested. GABA+ levels were significantly increased in the cerebellum of patients with HE. GABA+ levels in the motor cortex were significantly decreased in HE patients, and correlated with the CFF (r = 0.73; p < .05) and motor performance scores (r = -0.65; p < .05). Well-established HE-typical metabolite patterns (increased glutamine, decreased myo-inositol and total choline) were confirmed in all three regions and were closely linked to clinical metrics. In summary, our findings provide further evidence for alterations in the GABAergic system in the cerebellum and motor cortex in HE. These changes were accompanied by characteristic patterns of osmolytes and oxidative stress markers in the cerebello-thalamo-cortical system. These metabolic disturbances are a likely contributor to HE motor symptoms in HE. In patients with hepatic encephalopathy, GABA+ levels in the cerebello-thalamo-cortical loop are significantly increased in the cerebellum and significantly decreased in the motor cortex. GABA+ levels in the motor cortex strongly correlate with critical flicker frequency (CFF) and motor performance score (pegboard test tPEG), but not blood ammonia levels (NH3).

Involvement of the GABAergic system in PTSD and its therapeutic significance.

The neurobiological mechanism of post-traumatic stress disorder (PTSD) is poorly understood. The inhibition of GABA neurons, especially in the amygdala, is crucial for the precise regulation of the consolidation, expression, and extinction of fear conditioning. The GABAergic system is involved in the pathophysiological process of PTSD, with several studies demonstrating that the function of the GABAergic system decreases in PTSD patients. This paper reviews the preclinical and clinical studies, neuroimaging techniques, and pharmacological studies of the GABAergic system in PTSD and summarizes the role of the GABAergic system in PTSD. Understanding the role of the GABAergic system in PTSD and searching for new drug targets will be helpful in the treatment of PTSD.

Exploring the Role of Neurotransmitters in Multiple Sclerosis: An Expanded Review

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Although emerging evidence has shown that changes in neurotransmitter levels in the synaptic gap may contribute to the pathophysiology of MS, their specific role has not been elucidated yet. In this review, we aim to analyze preclinical and clinical evidence on the structural and functional changes in neurotransmitters in MS and critically discuss their potential role in MS pathophysiology. Preclinical studies have demonstrated that alterations in glutamate metabolism may contribute to MS pathophysiology, by causing excitotoxic neuronal damage. Dysregulated interaction between glutamate and GABA results in synaptic loss. The GABAergic system also plays an important role, by regulating the activity and plasticity of neural networks. Targeting GABAergic/glutamatergic transmission may be effective in fatigue and cognitive impairment in MS. Acetylcholine (ACh) and dopamine can also affect the T-mediated inflammatory responses, thereby being implicated in MS-related neuroinflammation. Also, melatonin might affect the frequency of relapses in MS, by regulating the sleep-wake cycle. Increased levels of nitric oxide in inflammatory lesions of MS patients may be also associated with axonal neuronal degeneration. Therefore, neurotransmitter imbalance may be critically implicated in MS pathophysiology, and future studies are needed for our deeper understanding of their role in MS.

Pharmacological Potential of cis-jasmone in Adult Zebrafish (Danio rerio).

This study evaluates the pharmacological potential of cis-jasmone (CJ) in adult zebrafish (Danio rerio; aZF). Initially, aZF (n = 6/group) were pretreated (20 µL; p. o.) with CJ (0.1 or 0.3 or 1.0 mg/mL) or vehicle (0.5% Tween 80). The animals were submitted to acute toxicity and locomotion tests, pentylenetetrazole-induced seizure, carrageenan-induced abdominal edema, and cinnamaldehyde-, capsaicin-, menthol-, glutamate-, and acid saline-induced orofacial nociception. The possible mechanisms of anticonvulsant, anxiolytic, and antinociceptive action were evaluated. The involvement of central afferent fibers sensitive to cinnamaldehyde and capsaicin and the effect of CJ on the relative gene expression of TRPA1 and TRPV1 in the brain of aZF were also analyzed, in addition to the study of molecular docking between CJ and TRPA1, TRPV1 channels, and GABAA receptors. CJ did not alter the locomotor behavior and showed pharmacological potential in all tested models with no toxicity. The anticonvulsant effect of CJ was prevented by flumazenil (GABAergic antagonist). The anxiolytic-like effect of CJ was prevented by flumazenil and serotonergic antagonists. The antinociceptive effect was prevented by TRPA1 and TRPV1 antagonists. Chemical ablation with capsaicin and cinnamaldehyde prevented the orofacial antinociceptive effect of CJ. Molecular docking studies indicate that CJ interacted with TRPA1, TRPV1, and GABAA receptors. CJ inhibited the relative gene expression of TRPA1 and TRPV1. CJ has pharmacological potential for the treatment of seizures, anxiety, inflammation, and acute orofacial nociception. These effects are obtained by modulating the GABAergic and serotonergic systems, as well as the TRPs and ASIC channels.

The presence and distribution of gamma-aminobutyric acid and dopamine during the developmental stages of the sea cucumber, Holothuria scabra, with emphasis on settlement organs.

In the sea cucumber, Holothuria scabra, the competent larvae require main settlement organs (SOs), including the ciliary bands (CiBs), tentacles (Ts), podia (PDs), and cues from neurotransmitters, including gamma-aminobutyric acid (GABA) and dopamine (DA), for successful settlement. In the present study, we investigated the spatial distribution of GABA and DA in the developmental stages of H. scabra, with special emphasis on SOs by detecting immunoreactivity (-ir) against these two neurotransmitters. Strong GABA-ir and DA-ir cells and fibers were specifically detected in several SO structures, including CiBs, CiB cells (CiBCs), and long cilia (LCi), of H. scabra larvae. Additionally, we found intense GABA-ir and DA-ir cells in the epithelial lining of bud-papillae (BP) and mesothelium (Me) in the stem (S) region of Ts in larvae and juveniles. Intense GABA-ir and DA-ir were observed in the epineural nerve plexus (ENP) and hyponeural nerve plexus (HNP) of Ts in H. scabra pentactula and juvenile stages. Staining for these two neurotransmitters was particularly intense in the PDs and their nerve fibers. We also found significant changes in the numbers of GABA-ir and DA-ir-positive cells and intensities in the CiBs, Ts, and PDs during the developmental stages. Taken together, we are the first to report on the existence and distribution of GABAergic and dopaminergic systems in structures associated with the settlement. Our findings provide new and important insights into the possible functions of these two neurotransmitters in regulating the settlement of this sea cucumber species.

The opposite effect of convulsant drugs on neuronal and endothelial nitric oxide synthase - A possible explanation for the dual proconvulsive/anticonvulsive action of nitric oxide.

Nitric oxide (NO) participates in processes such as endothelium-dependent vasodilation and neurotransmission/neuromodulation. The role of NO in epilepsy is controversial, attributing it to anticonvulsant but also proconvulsant properties. Clarification of this dual effect of NO might lead to the development of new antiepileptic drugs. Previous results in our laboratory indicated that this contradictory role of NO in seizures could depend on the nitric oxide synthase (NOS) isoform involved, which could play opposite roles in epileptogenesis, one of them being proconvulsant but the other anticonvulsant. The effect of convulsant drugs on neuronal NO (nNO) and endothelial NO (eNO) levels was investigated. Considering the distribution of neuronal and endothelial NOS in neurons and astrocytes, resp., primary cultures of neurons and astrocytes were used as a study model. The effects of convulsant drugs pentylenetetrazole, thiosemicarbazide, 4-aminopyridine and bicuculline on NO levels were studied, using a spectrophotometric method. Their effects on NO levels in neurons and astrocytes depend on the concentration and time of treatment. These convulsant drugs caused an increase in nNO, but a decrease in eNO was proportional to the duration of treatment in both cases. Apparently, nNO possesses convulsant properties mediated by its effect on the glutamatergic and GABAergic systems, probably through GABAA receptors. Anticonvulsant properties of eNO may be the consequence of its effect on endothelial vasodilation and its capability to induce angiogenesis. Described effects last as seizures do. Considering the limitations of these kinds of studies and the unexplored influence of inducible NO, further investigations are required.

Phytotherapeutic alternatives for neurodegenerative dementias: Scientific review, discussion and therapeutic proposal.

The incidence and prevalence of age-related neurodegenerative dementias have been increasing. There is no curative therapy and conventional drug treatment can cause problems for patients. Medicinal plants traditionally used for problems associated with ageing are emerging as a therapeutic resource. The main aim is to give a proposal for use and future research based on scientific knowledge and tradition. A literature search was conducted in several searchable databases. The keywords used were related to neurodegenerative dementias, ageing and medicinal plants. Boolean operators and filters were used to focus the search. As a result, there is current clinical and preclinical scientific information on 49 species used in traditional medicine for ageing-related problems, including neurodegenerative dementias. There are preclinical and clinical scientific evidences on their properties against protein aggregates in the central nervous system and their effects on neuroinflammation, apoptosis dysregulation, mitochondrial dysfunction, gabaergic, glutamatergic and dopaminergic systems alterations, monoamine oxidase alterations, serotonin depletion and oestrogenic protection. In conclusion, the potential therapeutic effect of the different medicinal plants depends on the type of neurodegenerative dementia and its stage of development, but more clinical and preclinical research is needed to find better, safer and more effective treatments.

Behavioral and Sensory Deficits Associated with Dysfunction of GABAergic System in a Novel shank2-Deficient Zebrafish Model.

Hyper-reactivity to sensory inputs is a common and debilitating symptom of autism spectrum disorder (ASD), but the underlying neural abnormalities remain unclear. Two of three patients in our clinical cohort screen harboring de novo SHANK2 mutations also exhibited high sensitivity to visual, auditory, and tactile stimuli, so we examined whether shank2 deficiencies contribute to sensory abnormalities and other ASD-like phenotypes by generating a stable shank2b-deficient zebrafish model (shank2b-/-). The adult shank2b-/- zebrafish demonstrated reduced social preference and kin preference as well as enhanced behavioral stereotypy, while larvae exhibited hyper-sensitivity to auditory noise and abnormal hyperactivity during dark-to-light transitions. This model thus recapitulated the core developmental and behavioral phenotypes of many previous genetic ASD models. Expression levels of γ-aminobutyric acid (GABA) receptor subunit mRNAs and proteins were also reduced in shank2b-/- zebrafish, and these animals exhibited greater sensitivity to drug-induced seizures. Our results suggest that GABAergic dysfunction is a major contributor to the sensory hyper-reactivity in ASD, and they underscore the need for interventions that target sensory-processing disruptions during early neural development to prevent disease progression.

Hippocampus: Molecular, Cellular, and Circuit Features in Anxiety.

Anxiety disorders are currently a major psychiatric and social problem, the mechanisms of which have been only partially elucidated. The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation. Yet so far, its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation. Recent advances in imaging, virus tracking, and optogenetics/chemogenetics have permitted elucidation of the activity, connectivity, and function of specific cell types within the hippocampus and its connected brain regions, providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety. Studies of hippocampal neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic systems, have contributed to the interpretation of the underlying neural mechanisms of anxiety. Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation. This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation, based on molecular, cellular, and circuit properties, to provide tailored targets for future anxiety treatment.

Electroacupuncture Ameliorates Cognitive Impairment by Regulating γ-Amino Butyric Acidergic Interneurons in the Hippocampus of 5 Familial Alzheimer’s Disease Mice

Objectivesγ-amino butyric acid (GABA)–ergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer’s disease (AD). Inhibitory interneurons play an important role in the regulation of E/I balance, synaptic transmission, and network oscillation through manipulation of GABAergic functions, showing positive outcomes in AD animal models. Mice expressing 5 familial AD mutation (5xFAD) exhibited a series of AD-like pathology and learning and memory deficits with age. Because electroacupuncture (EA) treatment has been used for a complementary alternative medicine therapy in patients with AD, we aimed to examine any usefulness of EA therapy in GABA interneuron function and its associated synaptic proteins, to determine whether EA could effectively improve inhibitory transmission and network oscillation and eventually alleviate cognitive impairments in 5xFAD mice, and to further elucidate the GABAergic system function underlying the antidementia response of EA. Materials and Methods5xFAD mice were used to evaluate the potential neuroprotective effect of electroacupuncture at Baihui (DU 20) and Dazhui (DU 14) through behavioral testing, immunofluorescence staining, electrophysiology recording, and molecular biology analysis. ResultsFirst, we observed that EA improved memory deficits and inhibitory synaptic protein expression. Second, EA treatment alleviated the decrease of somatostatin-positive interneurons in the dorsal hippocampus. Third, EA attenuated E/I imbalance in 5xFAD mice. Last, EA treatment enhanced theta and gamma oscillation in the hippocampus of 5xFAD mice. ConclusionsEA stimulation at DU20 and DU14 acupoints may be a potential alternative therapy to ameliorate cognitive deficits in AD through the regulation of the function of the GABAergic interneuron.

Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson's disease.

Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

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

Psychiatric Psychobiological Treatment Versus Exclusive Psychological Treatment in Depressive Disorders

Introduction: Scientific information on the antidepressant effectiveness of the varied usual therapeutic interventions is considerable but of poor quality. Objective: To analyse the scientifically well qualified international contributions on the effectiveness of habitual psychobiological psychiatric interventions in depressive disorders. Method: N= 6 structured bibliographic systems have been reviewed in a non-systematic, narrative and synthetic way and N= 75 significant contributions have been selected. Results and discussion: Patients with severe depression are more likely to receive any type of medical attention, but less likely to receive adequate attention. The use of both drugs and psychotherapy is the habitual mixed combined intervention during any ordinary psychiatric treatment. We will call it psychobiological or psychopharmacological intervention. The exclusive psychological intervention without using any medically prescribed drugs, is likely to be less cost/effective. The matter is not only to prioritise but also to adequately combine psychiatric interventions and added psychological interventions when convenient. The intervention on the neurophysiological pathways related with glutamate, the GABAergic, opioidergic, and inflammatory systems as well as on connectome and microbiome are being promoted for future drug antidepressant therapy with encouraging results. Conclusion: The mixed psychiatric option using drugs and psychotherapy, either regulated or not, by the intervening psychiatrist himself or herself is probably the main therapeutic choice for the correctly diagnosed depressive disorders. The psychotherapeutics intervention excluding the psychobiological psychiatric intervention in correctly diagnosed depressions will be insufficient in general. The professional psychological intervention may obviously complement the mixed psychiatric intervention, but can not replace it.