Involvement Of Gamma-aminobutyric Acid Research Articles

GABA and Executive functions in ASD

Gamma-aminobutyric acid (GABA) is a neurotransmitter critically involved in various psychological and behavioral processes. This review highlights the impact of GABAergic dysfunction within specific brain regions on a range of mental disorders, executive processes, self-control, and behavioral regulation.Reductions in GABAergic neurotransmission within distinct brain regions have been consistently associated with several mental health conditions. Within the context of anxiety disorders, depression, and post-traumatic stress disorder (PTSD), alterations in GABAergic function contribute to symptomatology. GABA plays a pivotal role in anxiety and mood regulation, with its impairment linked to symptoms of depression and mood disorders. Dysfunctional GABAergic transmission also contributes to fear dysregulation and features of PTSD. In terms of executive functions, GABAergic neurotransmission affects working memory, attentional control, and inhibitory regulation. Changes in GABA levels have been linked to decision-making abilities, impulsivity, and attention deficits, especially in conditions like attention deficit hyperactivity disorder (ADHD). GABA further plays a crucial role in self-control mechanisms by regulating impulsivity and prefrontal cortex functionality. Substance use disorders, often accompanied by impaired self-control, are significantly influenced by GABAergic system changes. Additionally, GABA's involvement in anxiety and emotional management affects the control of emotional responses. Behavioral control is modulated by GABAergic action in motor circuitry, where GABA provides inhibitory control for motor actions. Spontaneity, aggression, and stress are influenced by GABAergic dysfunction, impacting behavioral control. In the realm of attentional control, GABAergic neurotransmission influences selective attention and sensory salience, maintaining a balance between neural stimulation and inhibition. The study also explores executive function deficits in individuals with Autism Spectrum Disorder (ASD) in relation to GABA levels within specific brain regions. Moreover, GABA and its network connectivity contribute to individual variations in sensory responsiveness, emphasizing the dynamic role of GABA in the phenotypic heterogeneity of ASD. In summary, this research underscores the critical role of GABAergic neurotransmission within specific brain regions in various psychological disorders, executive functions, self-control, behavioral regulation, and attentional processes. Understanding the directional influence of GABAergic changes on behavior and mental health conditions can pave the way for more targeted interventions in neuropsychiatric disorders.

Nxiolytic Effect of the Hydro-alcoholic Extract of Anethum Graveolens Seed in Adult Female Wistar Rats: Modulation of GABA Receptors

Background: Along with industrial development and the increasing social complexity of societies, anxiety is one of the most prevalent psychological disorders. Medicinal plants are considered as an enrichment source of ingredients with biological activity. Objectives: The aim of this study was to evaluate the anxiolytic effect of Anethum Graveolens seed (AGS) and the possible involvement of Gamma-Aminobutyric Acid (GABA)-ergic system in the AGS effect. Materials & Methods: In the present experimental study, 64 female Wistar rats were divided into eight groups and received various concentrations of hydroalcoholic extract of AGS. To measure the level of anxiety, an elevated plus maze was used in a way that the animal’s head turned to an open arm. Prior to the injections of AGS extract, the GABA receptor antagonist was used. The results were analyzed by one-way analysis of variance using IBM SPSS v. 16. Results: Dose-response experiments showed that the AGS extract significantly decreased the anxiety indices compared to the control group (P<0.05). To analyze locomotor activity, our data showed that AGS extract at 0.1, 1, and 10 mg/kg could significantly increase locomotor activity compared to the control group (P<0.001). Pentylenetetrazol (PTZ (+extract significantly decreased the anxiolytic effect of AGS extract (P<0.01). Conclusion: Considering the anti-anxiety effects of AGS extract and a reduction in this effect caused by PTZ, part of the anti-anxiety effect of extract might be assumed via its interaction with GABA-ergic receptors. Further experimental trials; however, are required for the establishment of the anti-anxiety impact of AGS.

Phytotherapy as treatment for anxiety: An alternative to minimize addiction and side effects

Objective: To describe the anxiolytic activity and possible mechanisms of action on the central nervous system of plants found in the region known as legal Amazon in the Brazilian territory. Bibliographic Review: For this, five plants popularly used as tranquilizers and to treat insomnia in the forms of teas and extracts were selected, they are: passion fruit, valerian, chamomile, lemon grass and bay leaf. A bibliographic survey of articles, mainly original research, reporting comparative studies of the anxiolytic effects of each plant against control groups, as well as its possible mechanisms of action on the nervous system through preclinical and clinical studies, was performed. Conclusion: All the selected plants exhibited comparable and even superior anxiolytic effects when compared to classes of drugs such as benzodiazepines, with minimization or elimination of side/adverse effects. In addition, all reviewed studies indicated some involvement of gamma-aminobutyric acid (GABA) receptors activation by plant chemical constituents in anxiolytic action. Due to the minimization of adverse effects and the absence of dependence, herbal medicine appears as an important alternative therapy to treat anxiety disorders.

Involvement of Gamma Aminobutyric Acid in the Anticonvulsant Effect of the Leaf Methanol Extract of Ruta graveolens L. (Rutaceae) in Mice

Involvement of Gamma Aminobutyric Acid in the Anticonvulsant Effect of the Leaf Methanol Extract of Ruta graveolens L. (Rutaceae) in Mice

Acupuncture at SI5 attenuates morphine seeking behavior after extinction

Our previous studies have shown that acupuncture attenuates morphine self-administration and sensitization behavior as well as withdrawal signs. The present study was designed to investigate the role of acupuncture in the reinstatement of morphine seeking.Male Sprague-Dawley rats weighing 270–300g were subjected to intravenous catheterization after food training. The animals were trained to self-administer morphine (1.0mg/kg, 3weeks), followed by extinction (1week). Extinction conditions were introduced by substituting saline for morphine. The rats were then tested for reinstatement of morphine self-administration by a priming injection of morphine (0.25mg/kg). To see whether acupuncture can reduce morphine reinstatement, acupuncture was performed at SI5 or LI5 for 1min immediately before a morphine injection. To further test the involvement of gamma aminobutyric acid (GABA) receptors in acupuncture effects, GABA receptor antagonists were injected before acupuncture. In the present results, acupuncture at SI5, but not at control acupoint LI5 attenuated the reinstatement of morphine seeking behavior, which was blocked by the GABA receptor antagonists. It suggests that acupuncture can reduce the reinstatement of morphine seeking, possibly due to the mediation of GABA receptor system.

Effects of angiotensin II and atrial natriuretic peptide on LH release are exerted in the preoptic area: possible involvement of gamma-aminobutyric acid (GABA).

The preoptic/anterior hypothalamic area (PO/AH) contains the majority of LHRH neurons of which the function is regulated by a variety of neurotransmitters and peptides. In this area, numerous estrogen-receptive neurons utilize gammaaminobutyric acid (GABA) as neurotransmitter and these neurons communicate directly with LHRH neurons. Angiotensin II (AII) and atrial natriuretic peptide (ANP) are known to be involved in the regulation of LH secretion. The site of action of these peptides and the mechanisms by which they influence LHRH neurons, are largely unknown. Therefore the effects of intrapreoptic application of AII and ANP on serum LH levels of ovariectomized (ovx) and of ovx estrogen-primed rats were investigated. The peptides were applied into the PO/AH by means of push-pull cannula and in the effluent fractions GABA was measured. In the ovx estrogen-primed rat, prominent LH and prolactin surges were observed. At the time of increased LH levels preoptic GABA release was significantly reduced. At this time application of AII or ANP into the PO/AH was without effect on either LH or prolactin levels in the serum or on preoptic GABA release rates. In ovx, not steroid-primed rats intrapreoptic AII application suppressed serum LH levels significantly and this treatment had a slight stimulatory effect on preoptic GABA release rates. This effect of AII could be antagonized by prior preoptic treatment with saralasin, a specific AII receptor blocking peptide. Preoptic treatment with ANP resulted in a slight increase in serum LH levels which was accompanied by a slight, but significant reduction of preoptic GABA release rates.(ABSTRACT TRUNCATED AT 250 WORDS)

A neuronal mechanism of propofol-induced central respiratory depression in newborn rats.

The neural mechanisms of propofol-induced central respiratory depression remain poorly understood. In the present study, we studied these mechanisms and the involvement of gamma-aminobutyric acid (GABA)A receptors in propofol-induced central respiratory depression. The brainstem and the cervical spinal cord of 1- to 4-day-old rats were isolated, and preparations were maintained in vitro with oxygenated artificial cerebrospinal fluid. Rhythmic inspiratory burst activity was recorded from the C4 spinal ventral root. The activity of respiratory neurons in the ventrolateral medulla was recorded using a perforated patch-clamp technique. We found that bath-applied propofol decreased C4 inspiratory burst rate, which could be reversed by the administration of a GABAA antagonist, bicuculline. Propofol caused resting membrane potentials to hyperpolarize and suppressed the firing of action potentials in preinspiratory and expiratory neurons. In contrast, propofol had little effect on resting membrane potentials and action potential firing in inspiratory neurons. Our findings suggest that the depressive effects of propofol are, at least in part, mediated by the agonistic action of propofol on GABAA receptors. It is likely that the GABAA receptor-mediated hyperpolarization of preinspiratory neurons serves as the neuronal basis of propofol-induced respiratory depression in the newborn rat.

Molecular pathways of anxiety revealed by knockout mice.

Anxiety is a normal reaction to threatening situations, and serves a physiological protective function. Pathological anxiety is characterized by a bias to interpret ambiguous situations as threatening, by avoidance of situations that are perceived to be harmful, and/or by exaggerated reactions to threat. Although much evidence indicates the involvement of the gamma-aminobutyric acid, serotonin, norepinephrine, dopamine, and neuropeptide transmitter systems in the pathophysiology of anxiety, little is known about how anxiety develops and what genetic/environmental factors underlie susceptibility to anxiety. Recently, inactivation of several genes, associated with either chemical communication between neurons or signaling within neurons, has been shown to give rise to anxiety-related behavior in knockout mice. Apart from confirming the involvement of serotonin, gamma-aminobutyric acid, and corticotrophin-releasing hormone as major mediators of anxiety and stress related behaviors, two novel groups of anxiety-relevant molecules have been revealed. The first group consists of neurotrophic-type molecules, such as interferon gamma, neural cell adhesion molecule, and midkine, which play important roles in neuronal development and cell-to-cell communication. The second group comprises regulators of intracellular signaling and gene expression, which emphasizes the importance of gene regulation in anxiety-related behaviors. Defects in these molecules are likely to contribute to the abnormal development and/or function of neuronal networks, which leads to the manifestation of anxiety disorders.

Bicuculline enhances the corticosterone secretion induced by lipopolysaccharide and interleukin-1 alpha in male rats.

Lipopolysaccharide (LPS)-induced inflammatory stress activates the hypothalamus-pituitary-adrenal (HPA) function. Interleukin-I (IL-1) is one of the key factors during this event; however, the mechanisms mediating IL-1 stimulation of HPA axis are still unclear. The present study evaluated the possible involvement of gamma-aminobutyric acid (GABA) in LPS-induced activation of HPA axis in adult male rats. In addition, the possible existence of diurnal changes of LPS-induced HPA axis activity was also investigated. Bicuculline (0.8 mg/kg BW), a GABA-A receptor antagonist and GABA (1 g/kg BW) were intraperitoneally (ip) injected 15 min before LPS (2 mg/kg BW, ip) or recombinant human IL-1 alpha (microgram/rat) administration in intact rats. Control animals received an equivalent volume of 0.9% saline. Rats were sacrificed at 60 min or 90 min after LPS, or IL-1 alpha or saline injection. Plasma corticosterone levels were measured by radioimmunoassay. Results showed that pretreatment with bicuculline enhanced both LPS- and IL-1-induced corticosterone secretion; while pretreatment with GABA significantly reduced the LPS-stimulated corticosterone release (p < 0.05, vs LPS alone). The effect is dependent on the time of sampling and such effect of bicuculline or GABA was not observed when rats were stimulated in the evening. In addition, the maximal changes of plasma corticosterone following LPS administration in the evening were significantly lower than in the morning (p < 0.01). The present study provides evidence that GABA is involved, at least in part, in the neuroendocrine regulation of LPS/interleukin-1a-induced corticosterone secretion via GABA-A receptor in rats. In addition, the response of plasma corticosterone to LPS has a diurnal variation, which corresponds to a diurnal change of GABAergic modulation of the immunoneuroendocrine response.

Involvement of gamma-aminobutyric acid in the stimulatory effect of metoclopramide on gastrointestinal motility

The involvement of gamma-aminobutyric acid (GABA) in the mechanism of action of metoclopramide (MCP) on gastrointestinal (GI) tract was investigated employing guinea-pig myenteric plexus longitudinal muscle preparations. MCP induced a concentration dependent enhancement of electrically induced twitch responses of the myenteric plexus and this effect was further intensified by arecaidine and L-2, 4-diaminobutyric acid (L-DABA; GABA uptake inhibitors) and ethylenediamine (EDA;GABA releasing agent). The facilitatory effect of MCP was reduced by 3-mercaptopropionic acid (3-MPA; GABA synthesis and release inhibitor) and after GABA desensitization but remained unchanged after bicuculline methiodide, a specific GABA receptor antagonist. The MCP induced contraction of the unstimulated preparation was also reduced after GABA desensitization and EDA without affecting responces to exogenous acetylcholine (AHc). The study indicated that GABA plays a role in the facilitatory effect of MCP on both stimulated and unstimulated preparations of guineapig myenteric plexus.

GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids

The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

GABA and the regulation of serotonin N-acetyltransferase activity in amphibian retina—I. Effects of GABA agonists and antagonists

Retinal melatonin biosynthesis is regulated in part by changes in the activity of serotonin N-acetyltransferase (NAT), which increases at night in dark-adapted retinas, but not in light-exposed retinas. Using an in vitro preparation of Xenopus laevis (African clawed frog) eye cups, we have obtained evidence supporting the involvement of gamma-aminobutyric acid (GABA) in the regulation of NAT activity. GABA, the GABA-A receptor agonists muscimol and isoguvacine, and the GABA-B receptor agonist (?)baclofen, in the presence of 3-isobutyl-1-methylxanthine, mimicked dark adaptation by increasing the activity of NAT in light-exposed retinas. The response to GABA agonists was not additive to that observed in darkness. Diazepam increased NAT activity of light-exposed retinas when added in the presence of muscimol, but had no significant effect when added alone. Picrotoxin, an antagonist of the GABA-A receptor-linked Cl(?) channel, blocked both the stimulation caused by dark adaptation and that caused by GABA-A agonists. The increase of NAT activity elicited by muscimol, but not that by baclofen, was blocked by bicuculline methobromide and picrotoxin. The results implicate GABA, acting through GABA-A and possibly GABA-B receptors, in the regulation of NAT activity in retina.

GABA and anterior pituitary function: Anatomical data

Anterior pituitary function is under hypothalamic control through hypophysiotropic hormones released into the hypothalamo-hypophyseal portal blood (Green & Harris, 1947). Several of these hormones have been isolated and identified (Guillemin, 1976; Schally et al., 1978). They have a widespread distribution throughout the central nervous system (Elde & HOkfelt, 1979), and they show more physiological effects than their primary hypophysiotropic property which permitted their isolation (Guillemin, 1978; Moss, 1979). Conversely, the capacity to influence endocrine functions by pharmacological manipulation of known central neurotransmitters, as well as localisation of the latter in appropriate anatomical sites within the hypothalamus and hypophysis, suggested the possible role of various neurotransmitters originally isolated in the peripheral or central nervous system in the control of hypophyseal function. For example, extensive investigations on the biogenic amines since the early visualisation of catecholamines in the hypothalamic median eminence (Carlsson, et aL, 1962; Fuxe, 1964) have led to the identification of dopamine as a prolactin (release) inhibiting factor (MacLeod et al., 1976; Weiner & Ganong, 1978; Lichtensteiger, 1979; Leong e ta l . , 1983). In this context, characterized by the progressive identification of various neuroregulatory messengers in neuroendocrine processes (MtiIler et al., 1977; Krtilich, 1979; Meites & Sonntag, 1981), a possible involvement of gamma-aminobutyric acid (GABA), a recognized inhibitory neurotransmitter in the central nervous system (Curtis & Johnston, 1974; Krnjevic, 1974; Roberts et al., 1976), has emerged (Racagni et al., 1982; Elias et al., 1982; McCann et al., 1982; Tappaz et al., 1982; Mtiller et al., 1983). In the following review, the histochemical findings which provide the anatomical basis for GABAergic control of anterior pituitary function will be considered. They have been obtained through two approaches: autoradiography of GABA high-affinity uptake sites (Makara et al., 1975, 1976; Tappaz et al., 1980) and immunocytochemical visualization of the GABA-biosynthetic enzyme glutamate decarboxylase (GAD), a reliable marker for GABAergic systems (Roberts, 1979; Ribak et al., 1981), first as incidental observations (HOkfelt et al., 1978; Fuxe et al., 1979; Perez de la Mora, 1981; Tappaz et al., 1981) and then in more comprehensive investigations at the light(Vincent et al., 1982) and electronmicroscopic level (Oertel et al., 1982a; Tappaz et al., 1982, 1983). The physiological significance of these findings will be discussed. The illustrations are taken from our work

Possible involvement of gamma-aminobutyric acid in growth hormone release induced by a Met5-enkephalin analog in conscious rats.

The interaction between opioid peptides and gamma-aminobutyric acid (GABA) in regulating GH secretion was studied in unanesthetized male rats with chronically implanted intraatrial catheters. GH secretion was pulsatile with GH bursts (mean +/- SE, 259.1 +/- 70.3 ng/ml) occurring at regular intervals (mean +/- SE, 3.6 +/- 0.2 h) in control rats. When a potent met5-enkephalin analog, FK 33-824 ([D-Ala,MePhe4,Met(O)-ol]enkephalin; 10 micrograms/100 g BW), was injected iv in the interval between two anticipated spontaneous GH bursts, plasma GH abruptly increased to a peak value of 716.0 +/- 144.9 ng/ml 20 min after the injection, and the following spontaneous GH burst appeared at longer intervals than expected (5.0 +/- 0.4 h, P less than 0.025 vs. control). The plasma GH increase induced by FK 33-824 was blunted by a specific opiate antagonist, naloxone (125 micrograms/100 g BW, iv), and the following spontaneous GH bursts occurred at the same time as in controls. The plasma GH response to FK 33-824 was significantly inhibited by two GABA antagonists, picrotoxin (0.3 mg/100 g BW, iv) and bicuculline (60 micrograms/100 g BW, iv), with peak GH values of 24.6 +/- 6.4 and 136.4 +/- 35.2 ng/ml, respectively (P less than 0.01 vs. FK 33-824 alone). The following natural GH bursts were also inhibited by these GABA antagonists (50.1 +/- 21.3 and 35.3 +/- 9.6 ng/ml; P less than 0.01 vs. control). These findings suggest the possible involvement of GABA in GH release induced by opioid peptides in the rat.

Involvement of gamma-amino butyric acid (GABA) in the anticonvulsant action of methaqualone.

The effects of methaqualone on isonicotinic acid hydrazide, 6-mercapto propionic acid, picrotoxin, and strychnine-induced convulsion were studied in mice and the results compared with diazepam. Methaqualone, like diazepam, was found to be a selective antagonist of isoniazid-induced convulsion and a much less effective inhibitor of strychnine convulsion. Methaqualone elicits muscle-relaxant, sedative, and anticonvulsant effects at different dose levels. At low, nonsedative doses the drug produces anticonvulsant effects, and at higher doses, muscle-relaxant and sedative effects. It appears that the mechanism(s) of action of methaqualone in on GABA deficiency or receptor blockade, rather than on glycine receptors.

The involvement of gamma-aminobutyric acid in the organization of cat retinal ganglion cell receptive fields. A study with picrotoxin and bicuculline.

The effects of picrotoxin and bicuculline upon the discharge pattern of center-surround organized cat retinal ganglion cells of X and Y type were studied. All experiments were carried out under scotopic or possibly low mesopic conditions; mostly but not exclusively on-center cells were studied. Stimuli were chosen so that responses were either; (a) "purely" central; (b) surround dominated; or (c) clearly mixed but center dominated. In each case a pre-drug control response was estaboished, the drug was administered intravenously, and its subsequent effect upon the response was observed. In Y cells both picrotoxin and bicucullin caused the center-driven component of the response to become somewhat reduced in magnitude, while the surround component was substantially reduced. There was thus a change in center-surround balance in favor of the center-driven component. Responses of X cells remained virtually unaffected by both picrotoxin and bicuculline.