Disinhibition Is an Essential Network Motif Coordinated by GABA Levels and GABA B Receptors.

Network dynamics are crucial for action and sensation. Changes in synaptic physiology lead to the reorganization of local microcircuits. Consequently, the functional state of the network impacts the output signal depending on the firing patterns of its units. Networks exhibit steady states in which neurons show various activities, producing many networks with diverse properties. Transitions between network states determine the output signal generated and its functional results. The temporal dynamics of excitation/inhibition allow a shift between states in an operational network. Therefore, a process capable of modulating the dynamics of excitation/inhibition may be functionally important. This process is known as disinhibition. In this review, we describe the effect of GABA levels and GABAB receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations.

GABAB receptors blockage modulates somatic and aversive manifestations induced by nicotine withdrawal.

There is substantial evidence that GABAB agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABAB receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABAB receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4ß2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4ß2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABAB receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABAB receptors to treat tobacco addiction in humans.

Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

Participação de receptores GABA B na modulação do consumo etílico em ratos Wistar / Involvement of GABA B receptor on ethylic consumption modulation in Wistar rats

Introdução: o baclofeno, uma droga agonista seletivo de GABA B, tem sido apontado como uma nova opção de tratamento do etilismo. Neste estudo avaliou-se o efeito do baclofeno no consumo etílico em ratos Wistar. Materiais e Métodos: o experimento ocorreu em quatro fases: exposição, abstinência, reexposição e tratamento. Os animais foram alocados em grupos: 1, 2, 3 e 4 (n=5 por grupo), expostos à água pura, solução hidroalcoólica (SHA) 5% e SHA 10%; grupo 5 (subdividido em A, B e C N =5 por subgrupo) e grupo 6 (n=5), ambos expostos a apenas água pura. A administração de baclofeno via intraperitoneal destinou aos grupos 1, 2, 3 e 5 em diferentes doses. Nos demais grupos, administrou-se placebo. Aferiu-se o consumo das soluções em todas as fases, para fins comparativos. Resultados: o baclofeno, na dose de 1mg/Kg, reduziu o consumo de SHA 10% no grupo 1, que apresentou maior consumo etílico durante o experimento. Os demais grupos apresentaram menor consumo das SHA ofertadas, sem redução da ingesta etílica após administração da droga nas doses de 2 e 3mg/Kg. Conclusão: baclofeno reduziu etilismo apenas em animais com maior consumo etílico prévio à sua administração. O peso dos animais não foi fator determinante na resposta à droga. A dose efetiva no tratamento dos efeitos da privação alcoólica foi a de menor concentração (1mg/kg).

Introduction: Baclofen, a GABA B agonist, has been pointed as a new drug on the alcohol consumption treatment. This study has evaluated baclofen ́s effect on ethanol consumption in Wistar rats. Materials and Methods: four phases protocol: exposure, abstinence, re-exposure and treatment. Animals were allocated into groups: 1, 2, 3 and 4 (n=5 per group), exposed to pure water, 5% ethanol solution and 10% ethanol solution. Group 5 (subdivided into A, B and C, n=5 by subgroup) and group 6 (n=5), exposed to pure water. Baclofen intraperitoneal administration was destined to groups 1, 2, 3 and 5 (A, B and C) in different doses. The remaining groups received saline solution as control. Solutions consumption was assessed in all phases for comparative purposes. Results: Baclofen at 1mg/Kg reduced the 10% (vv) water-alcohol consumption in animals from Group 1, which also presented greater ethanol consumption during the experiment. The other groups showed a lower water - alcohol consumption and did not show an ethanol intake reduction after the drug administration in both 2 and 3mg/Kg doses. Conclusion: Baclofen only reduces alcoholism in animals with higher ethanol consumption. Animals weight is not a determining factor in ethanol consumption or in baclofen response. The effective baclofen dose in treating the deprivation alcohol effects was observed in the lowest concentration, corresponding to 1mg/Kg dose.

Lack of GABAB receptors modifies behavioural and biochemical alterations induced by precipitated nicotine withdrawal.

The nicotine (NIC) withdrawal syndrome is considered to be a major cause of the high relapse rate among individuals undergoing smoking cessation. The aim of the present study was to evaluate a possible role of GABAB receptors in NIC withdrawal, by comparing GABAB1 knockout mice and their wild-type littermates. We analysed the time course of the global withdrawal score, the anxiety-like effects, monoamine concentrations, the brain-derived neurotrophic factor (BDNF) expression, the corticosterone plasmatic levels and [(3)H]epibatidine binding sites during NIC withdrawal precipitated by mecamylamine, a nicotinic receptor antagonist (MEC). In NIC withdrawn wild-type mice, we observed a global withdrawal score, an anxiety-like effect in the elevated plus maze, a decrease of the striatal dopamine and 3,4-dihydroxyphenylacetic acid concentrations, an increase of corticosterone plasma levels, a reduction of BDNF expression in several brain areas and an increase of [(3)H]epibatidine binding sites in specific brain regions. Interestingly, the effects found in NIC withdrawn wild-type mice were absent in GABAB1 knockout mice, suggesting that GABAB1 subunit of the GABAB receptor is involved in the regulation of the behavioural and biochemical alterations induced by NIC withdrawal in mice. These results reveal an interaction between the GABAB receptors and the neurochemical systems through which NIC exerts its long-term effects.

Involvement of GABAB receptors in biochemical alterations induced by anxiety-related responses to nicotine in mice: genetic and pharmacological approaches.

Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.