GABAB Receptor Agonist Research Articles

Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats

BackgroundAlthough abnormal sympathetic nerve system (SNS) activity has been demonstrated in the pathogenesis of ejaculation disorders, few data are available on its underlying mechanism. AimTo investigate whether differences in ejaculatory behavior of rats were associated with the state of SNS activity and gamma-aminobutyric (GABA) receptor expressions in the paraventricular nucleus (PVN) of the hypothalamus and the effects of GABA receptors in the PVN on ejaculatory behavior. MethodsBased on ejaculatory performance, Sprague-Dawley rats were divided into “sluggish,” “normal,” and “rapid” ejaculators. PVN microinjection was performed to evaluate the role of GABA receptors on sexual behavior. OutcomesThe outcomes include differences in expression and distribution of GABA receptors and norepinephrine level among the 3 groups and changes in copulation behavior parameters after PVN microinjection. ResultsCompared with “normal” rats, the “rapid” group ejaculated more times with shorter latency (P < .001, P < .001) and had lower expression and distribution of both GABA-A and GABA-B receptors, while the opposed results appeared in the “sluggish” group. The norepinephrine level was successively increased among “sluggish,” “normal,” and “rapid” rats (P < .001) and correlated with ejaculation frequency (r = 0.896, P < .001) and ejaculation latency (r = −0.835, P < .001). In addition, bilateral microinjection of the GABA-A and GABA-B receptor agonist (isoguvacine and baclofen) into the PVN both significantly prolonged the intromission latency and inhibited ejaculation, which could be blocked by antagonist gabazine and CGP-35348, respectively. Vigabatrin, the GABA-transaminase inhibitor, caused a significantly reduced ejaculation frequency and extended ejaculation latency in rats, which could be offset by simultaneous injections of gabazine and CGP-35348. Clinical ImplicationsOur findings provide new understanding about GABA receptors in the PVN on sexual behavior and enhance the comprehension of neurobiological mechanisms involved in premature ejaculation. Strengths & LimitationsOur results have indicated that GABA receptors in the PVN may inhibit ejaculation through restraining the activity of SNS. However, our study did not analyze the changes of GABA receptors in other brain areas, which needs further study. ConclusionEjaculation behaviors in male rats are associated with SNS activity and could be regulated by GABA receptors in the PVN, which may be of assistance in the treatment of ejaculation disorders in the future.Zhang QJ, Yang BB, Yang J, et al. Inhibitory Role of Gamma-Aminobutyric Receptors in Paraventricular Nucleus on Ejaculatory Responses in Rats. J Sex Med 2020;17:614–622.

Effects of pharmacological inhibition of the centrally-projecting Edinger-Westphal nucleus on ethanol-induced conditioned place preference and body temperature.

Alcohol use disorder is a chronic disease characterized in part by repeated relapsing events. Exposure to environmental stimuli or cues that have previously been associated with the effects of alcohol can promote relapse through the triggering of craving for alcohol. Therefore, identifying and characterizing neuronal populations that may regulate these associations is of the upmost importance. Previous studies have implicated the centrally-projecting Edinger Westphal nucleus (EWcp) in this process, as the EWcp is both sensitive to, and can regulate alcohol intake. To date however, it is unclear if the EWcp is involved in the formation or expression of these alcohol-cue associations. As such, the present studies examined the involvement of the EWcp in male DBA/2J mice in the acquisition and expression of place preference for an alcohol-paired cue using the conditioned place preference (CPP) procedure. Pharmacological inhibition of the EWcp via the GABAA and GABAB receptor agonists muscimol and baclofen did not affect either the acquisition or the expression of CPP. Follow up studies did find however, that pharmacological inhibition of the EWcp increased body temperature and prevented alcohol-induced increases in c-Fos expression in the EWcp. When considered in light of previous studies, the present results indicate that the EWcp may be involved in the regulation of alcohol self-administration, and not conditioned alcohol-seeking. Additionally, the present studies provide further evidence for the involvement of the EWcp in thermoregulation and help elucidate the molecular mechanisms by which alcohol increases c-Fos in the EWcp.

Alvorlig delir etter GHB-misbruk

The management of benzodiazepine-resistant GHB withdrawal requires careful consideration of GHB pharmacodynamics. A young woman was admitted with tachycardia, confusion, agitation and delusions the day after attempting to quit a daily, high-dose GHB habit. A total of 225mg of diazepam had no effect. She was sedated with propofol and intubated. An extubation attempt after 24 hours was followed by recurrence of delirium. After reintubation she required high doses of propofol, alfentanil and dexmedetomidine to maintain sedation for two days. Baclofen and diazepam were introduced on the third day, allowing dose reductions in anaesthetic agents the fourth day and extubation on the fifth day with resolution of the delirium. GHB targets the GABAB receptor and downregulates it with abuse. Most anaesthetic agents affect the GABAA receptor. Our report suggests that baclofen, a GABAB receptor agonist, may reduce the need for anaesthetic agents and facilitate recovery.

GABAB Receptors and Alcohol Use Disorders: Preclinical Studies.

Preclinical research over the past several decades has demonstrated a role for the γ-aminobutyric acidB (GABAB) receptor in alcohol use disorder (AUD). This chapter offers an examination of preclinical evidence on the role of the GABAB receptor on alcohol-related behaviors with a particular focus on the GABAB receptor agonist baclofen, for which effects have been most extensively studied, and positive allosteric modulators (PAMs) of the GABAB receptor. Studies employing rodent and non-human primate models have shown that activation of the GABAB receptor can reduce (1) stimulating and rewarding effects of alcohol; (2) signs of alcohol withdrawal in rats made physically dependent on alcohol; (3) acquisition and maintenance of alcohol drinking under a two-bottle alcohol versus water choice procedure; (4) alcohol intake under oral operant self-administration procedures; (5) motivational properties of alcohol measured using extinction and progressive ratio procedures; (6) the increase in alcohol intake after a period of alcohol abstinence (the alcohol deprivation effect or ADE); and (7) the ability of alcohol cues and stress to reinstate alcohol seeking when alcohol is no longer available. Baclofen and GABAB PAMs reduce the abovementioned behaviors across different preclinical models, which provides strong evidence for a significant role of the GABAB receptor in alcohol-related behaviors and supports development of medications targeting GABAB receptors for the treatment of AUD. This chapter highlights the value of examining mechanisms of alcohol-related behaviors across multiple animal models to increase the confidence in identification of new therapeutic targets.

Le baclofène dans le traitement du trouble de l’usage d’alcool : données cliniques

Alcohol used disorder is a serious disease that accounts for almost 4% of the global burden of disease, for which currently available treatments have limited effectiveness. Since the early 2000s, baclofen, GABAB receptor agonist, is increasingly used in France with high-doses to treat alcohol dependence following its high media coverage and in response to patient expectations. Despite some studies demonstrating the effectiveness of baclofen in reducing alcohol consumption and maintaining alcohol abstinence, most randomized clinical trials in this context show conflicting and highly variable results, in some cases associated with serious side effects at high doses. However, because of its limited hepatic metabolism, baclofen is a particularly promising drug for people with liver disease, common in this population. It thus obtained its marketing authorization at the end of 2018 in the treatment of alcohol use disorder patients at the maximum dose of 80 mg/day. However, further studies are needed to better understand the variability of baclofen treatment response and thus to better adjust dosages in the overall management of the patient.

Intoxications par les agonistes des récepteurs GABA : aspects pharmacologiques, toxicologiques et épidémiologiques

γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter of the central nervous system (CNS), binds to two types of receptors: the GABAA and GABAB receptors.GABAA agonists poisonings (ethanol, benzodiazepines) are very common and may induce central nervous system depression. The treatment of ethanol poisoning is symptomatic while there is an antidote for benzodiazepines poisoning, the flumazenil. GABAB receptor agonists (GHB, baclofen) poisonings remain rare but are increasing. GHB poisonings can cause coma frequently associated with bradycardia, respiratory depression, myoclonus and hypothermia. Baclofene poisonings are mainly responsible for neurological complications that may be associated with respiratory and hemodynamic complications. Treatment of GABAB receptor agonists poisonings is symptomatic. After acute GABA agonists poisoning, withdrawal syndrome may occur in chronic users shortly after the resolution of poisoning symptoms.GABAergic agonists are frequently responsibles for acute poisoning. Although GABAA receptor agonists poisonings are well described (ethanol, benzodiazepines), the last twenty years have seen the increase in GABAB receptor agonists poisonings (GHB, baclofen).

The Cagliari Statement on baclofen for the treatment of alcohol use disorder: An International Consensus

Alcohol Use Disorder (AUD) is a common mental disorder with severe medical, psychological and social consequences [1] . AUD leads up to 3- and 4-fold increases in the risk of mortality in men and women, respectively [2] . Nevertheless, less than 10% of people with AUD seek and receive treatment for their disorder and less than 4% receive any pharmacological intervention [3] . The identification of new medications is crucial to increase the number of people with AUD who receive effective treatment. Baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, has emerged as a promising drug for AUD [4] . Preclinical studies have provided consistent evidence that baclofen administration dose-dependently reduces alcohol consumption in validated animal models of AUD [5] . On the other hand, clinical studies have yielded less consistent results [6] . Some randomized controlled trials (RCTs) found that AUD patients treated with baclofen significantly reduced alcohol consumption compared to patients treated with placebo, whereas other RCTs found no differences between AUD patients treated with baclofen or placebo [6] . In addition, recent meta-analyses report there is insufficient evidence of effectiveness to support the use of baclofen to treat AUD [7] , [8] , [9] , [10] . Several methodological differences among these RCTs may have contributed to these contrasting results, including (i) the daily dose of baclofen (ranging from 30 to 300 mg), (ii) prescribing regimes (fixed doses or titration until the desired clinical effect was achieved), and (iii) presence/absence of comorbid medical (e.g. liver disease) or psychiatric diseases (e.g. anxiety disorders) [6] , [11] . Nevertheless, baclofen is used off-label to treat AUD in several countries, and in France baclofen was officially approved for AUD treatment in October 2018 [6] . In May 2018, during the GABAB Receptor Conference, held in Cagliari, Italy, a group of international experts in the clinical use of baclofen for AUD met and combined their expertise to provide concise and well-balanced information regarding this controversial topic. This group included 26 researchers and physicians who had contributed to the majority of RCTs (both positive and negative) on baclofen and AUD as well as studies focused on the side effects of baclofen in patients with AUD. A modified Delphi method was used. Each statement was discussed, modified, and rated until consensus was reached by the entire group. The final draft included 18 statements and was recently published as “the Cagliari Statement” in Lancet Psychiatry [12] . This Consensus paper is intended as a helpful tool for clinicians deciding whether or not prescribe baclofen off-label to their patients with AUD and to researchers planning investigations with baclofen. The Cagliari Statement may be particularly useful clinicians in France, where baclofen has been officially approved for AUD treatment [6] .

GABA releases from parvalbumin-expressing and unspecific GABAergic neurons onto CA1 pyramidal cells are differentially modulated by presynaptic GABAB receptors in mouse hippocampus

Hippocampus CA1 pyramidal cells receive γ-aminobutyric acid (GABA) release from multiple GABAergic interneurons. Combining optogenetic strategy and whole-cell recordings, we demonstrate that baclofen, a specific GABAB receptor agonist, depresses monosynaptic GABAA receptor-mediated transmission from parvalbumin (PV)-expressing interneuron terminals onto pyramidal cells with less efficacy than that from the unspecific GABAergic terminals. The depression from PV neuron terminals is mainly mediated by presynaptic P/N type calcium channels. The results suggest that GABAB receptors are widely expressed on GABAergic interneurons, where they exert inhibition onto pyramidal cells by GABA release with different efficacy. The data strengthen the proposal that diverse GABA neurons play different roles in modulating CA1 pyramidal cell excitability.

Comparative Efficacy of GABAA and GABAB Receptor Agonists in Pain Alleviation in a Spinal Cord Injury Model of Neuropathic Pain

We investigated the effectiveness of intrathecal introduction of GABAA and GABAB receptor agonists in reversing pain modalities in a central model of neuropathic pain. In adult male Wistar rats, spinal cord injury was produced by compression of the spinal cord at the T6–T8 level. For drug delivery to the spinal cord, a PE10 catheter was inserted into the subarachnoid space through an intervertebral foramen. Testing was performed three weeks after spinal cord injury. Mechanical and thermal hyperalgesia were estimated using the pressure withdrawal (Randall–Selitto) and heat withdrawal (Hargreaves) tests, respectively. Tactile allodynia was quantitated by testing with the von Frey filaments. Cold allodynia was assessed by the acetone drop test to the hindpaw. The motor function was evaluated using the 21-score scale for locomotion in the open field. At the end of the experiment, animals were anesthetized and transcardially perfused with fixative, and sections of the spinal cord were prepared and stained. Compression injury of the spinal cord produced a cavity in the dorsal horn of the spinal cord and resulted in clear impairment of the motor function of animals. Spinal administration of both abovementioned drugs reduced mechanical hyperalgesia and cold and tactile allodynia. The GABAA agonist muscimol also decreased thermal hyperalgesia, while the GABAB agonist baclofen did not change this phenomenon. Thus, exogenous administration of GABAA agonists can reverse all spinal cord compression-induced sensory disorders. These agents may provide a better therapy of neuropathic pain than GABAB agonists.

Unique and independent role of the GABAB1 subunit in embryo implantation and uterine decidualization in mice

Embryo implantation and decidualization are crucial for successful pregnancy, which include multiple genes and signaling pathways, while the precise mechanism regarding embryo implantation and decidualization has yet to be explored. The GABA which activates GABAA or GABAB receptors has been found playing an important role in early pregnancy. Here we seek to investigate whether GABAB receptors participate in embryo implantation in mice. This study first characterized the spatiotemporal expression pattern of GABAB receptors in the uterus during the peri-implantation period and found that GABAB1 expression was drastically upregulated in stromal cells on days 4–6, a period of embryo implantation and early stages of decidualization. Embryo delayed implantation and oil-induced decidualization models were further used to confirm that the GABAB1 was associated with embryo implantation and decidualization. We also found estrogen or progesterone had no directly effect on expression of GABAB1 in ovariectomized model. Because we were unable to detect significant GABAB2 which couples with GABAB1 to form whole GABAB receptors, and the agonist and antagonist of whole GABAB receptors had weak effect on the proliferation and differentiation of stromal cells as well, we excluded the possibility whole GABAB receptors function, and concluded it should be non-classical signals of GABAB1 involving in embryo implantation and decidualization. Future studies should focus on investigating the roles and mechanisms of GABAB1 during embryo implantation and decidualization.

In silico structure-based design of GABAB receptor agonists using a combination of docking and QSAR.

The study of γ-aminobutyric acid B receptor (GABAB ) activation is of great interest for several brain disorders. The search of new GABAB receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABAB receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABAB receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABAB receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABAB receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (ELUMO and T(N…O)) and the energy interaction with GABAB receptor (ETRP278 ). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the QLOO , QASYM , and rules. Finally, six new compounds are proposed (35-40) with high potential to be used as GABAB receptor agonists.

Pharmacological mechanisms of interhemispheric signal propagation: a TMS-EEG study.

Interhemispheric connections across the corpus callosum have a predominantly inhibitory effect. Previous electrophysiology studies imply that local inhibitory circuits are responsible for inducing transcallosal inhibition, likely through inhibitory GABAB-mediated neurotransmission. We investigated the neurochemical mechanisms involved in interhemispheric connectivity by measuring transcranial magnetic stimulation (TMS)-induced interhemispheric signal propagation (ISP) in the motor cortex and dorsolateral prefrontal cortex (DLPFC) with electroencephalography (EEG) recordings under the pharmacological effects of baclofen, L-DOPA, dextromethorphan, and rivastigmine. We hypothesized that for both stimulated regions, GABAB receptor agonist baclofen would decrease ISP when compared against baseline while drugs that target other neurotransmitter systems (dopaminergic, acetylcholinergic, and glutamatergic systems) would have no effect on ISP. Twelve right-handed healthy volunteers completed this study and underwent TMS across five sessions in a randomized order. In the motor cortex, participants showed a significant decrease in ISP under baclofen, but not in the other drug conditions. There were no drug-induced changes in ISP in the DLPFC and baseline ISP did not differ across experimental sessions for both brain regions. Together, our results suggest that the inhibitory effects observed with interhemispheric signal transmission are mediated by a population of interneurons involving GABAB receptor neurotransmission. Inhibitory mechanisms of ISP may be more salient for motor-related functions in the motor cortex than for cognitive control in the DLPFC. These findings are a fundamental step in advancing our understanding of interhemispheric connectivity and may be used to identify treatments for disorders in which transcallosal transmission is dysfunctional.

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

Neural Networks in Generalized Epilepsy and Novel Antiepileptic Drugs.

In previous works, alterations of neurotransmitters and neuropeptides in the brain areas involved in generalized epilepsy have been reported. We reviewed the alterations of these neurotransmitters and neuropeptides in the following brain areas involved in generalized epilepsy: hippocampus, hypothalamus, thalamus and cerebral cortex. In these brain areas, the neural networks are also actualized. The mechanisms of action of newer antiepileptic drugs in the treatment of generalized epilepsy are also discussed. Up-dating the neurotransmitter and neuropeptide alterations, we found that hippocampal GABAergic neurons presynaptically inhibit epileptogenic neurons via GABAB receptors. Epilepsy modulating neuropeptides (galanin, neuropeptide Y, dynorphin) are also involved. GABA deficiency, serotonin hyperactivity, dopamine hyperactivity and glutamate excitotoxicity can enhance ictogenesis: neurons containing these neurotransmitters form the main neural circuit. An increased excitability occurs when the alteration of these neurotransmitters is permanent. In preclinical studies, the GABAB receptor agonist GS 39,783 exerted a good antiepileptic effect. Perampanel, an AMPA receptor antagonist, showed good clinical effects in the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. In this treatment, perampanel can be combined with other antiepileptic drugs. Brivaracetam, which shows a high affinity for the synaptic vesicle 2A, exerted a good efficacy in the treatment of adult focal seizures and secondarily generalized tonic-clonic seizures.

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception.

While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain. It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.

GABAB receptor activation ameliorates spatial memory impairments in stress-exposed rats.

Objective: Due to the prevalence of stress in modern life and its impact on spatial memory, the role of inhibitory systems in brain areas such as the nucleus accumbens (NAc) in reducing stress is important. The current study aimed to examine the response of NAc shell GABAB receptors to stress and the role of intraperitoneally (i.p.) and intra-NAc injection of the GABAB receptor agonist baclofen on spatial memory impairments in stress-exposed rats.Methods: Eighty adult male Wistar rats were randomly divided into ten groups (n=8): two were control groups for intra-NAc and i.p baclofen; two groups were subjected to stress and injected with saline (baclofen vehicle); three groups were given baclofen (1, 5, and 10 µg/rat) intra-NAc 5 mins before stress was induced; and three groups received baclofen (1, 5, and 10 mg/kg/i.p.) 30 mins before being subjected to stress. Foot-shock stress was applied for 7 consecutive days. Behavioral assays using the Barnes maze were performed 24 hrs after the last baclofen injection.Results: Both the intra-NAc and the i.p administration of baclofen dose-dependently reduced escape latency and total distance and increased velocity in the treatment groups in the training trials. In the probe test, the rats that had received 5 mg/kg of baclofen had the highest target frequency, but there no significant differences were observed in velocity, duration, or distance to the target between the groups.Conclusion: According to the findings, baclofen can dose-dependently improve spatial memory, and GABAB receptor in the NAc plays an important role in spatial memory.

Baclofen but Not Diazepam Alleviates Alcohol-Seeking Behavior and Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Stressed Withdrawn Mice.

This study compares the impact of repeated injections of baclofen (an agonist of GABAB receptors) or diazepam (a benzodiazepine having an agonist action on GABAA receptors) given during the alcohol-withdrawal period on the stress-induced restoration of alcohol-seeking behavior and hypothalamic–pituitary–adrenal (HPA) axis dysfunction after a long (4 weeks) abstinence. Thus, C57BL/6 mice were submitted to a 6-month alcohol consumption [12% volume/volume (v/v)] and were progressively withdrawn to water before testing. Diazepam (Valium®, Roche) and baclofen (Baclofen®, Mylan) were administered intraperitoneally for 15 consecutive days (1 injection/day) during the withdrawal period at decreasing doses ranging from 1.0 mg/kg (Day 15) to 0.25 mg/kg (Day 1) for diazepam and from 1.5 mg/kg (Day 15) to 0.37 mg/kg (Day 1) for baclofen. Alcohol-seeking behavior was evaluated by alcohol-place preference in an odor recognition task. In the stress condition, mice received three electric footshocks 45 min before behavioral testing. Blood was sampled immediately after behavioral testing, and plasma corticosterone concentrations were measured by commercial enzyme immunoassay kits. Results showed that non-stressed withdrawn mice did not exhibit alcohol-place preference or alteration of plasma corticosterone concentrations relative to water controls. After stress, however, withdrawn mice exhibited a significant alcohol-place preference and higher circulating corticosterone concentrations as compared to stressed water controls. Interestingly, repeated administration during the withdrawal phase of baclofen but not diazepam suppressed both the alcohol-place preference and normalized corticosterone levels in stressed withdrawn animals. In conclusion, this study evidences that a pre-treatment with baclofen but not with diazepam during the withdrawal phase normalized, even after a long period of abstinence, the HPA axis response to stress, which contributes to the long-term preventing effects of this compound on alcohol-seeking behavior.

Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial.

Increasing evidence suggests that the function of the GABAergic system is abnormally low in autism spectrum disorder (ASD). Baclofen, which functions as a selective agonist for GABAB receptors, does appear promising for the treatment of ASD. We conducted a 10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD. Sixty-four children (3-12years) with moderate-to-severe irritability symptoms of ASD were included. We used the Aberrant Behavior Checklist-Community Edition (ABC-C) for the outcome measures on each of the follow-up visits (weeks 0, 5, and 10). Analysis of the combined data revealed significant improvement for all the ABC subscales (irritability: F = 51.644, df = 1.66, p < 0.001, lethargy: F = 39.734, df = 1.38, p < 0.001, stereotypic behavior: F = 25.495, df = 1.56, p < 0.001, hyperactivity: F = 54.135, df = 1.35, p < 0.001, and inappropriate speech: F = 19.277, df = 1.47, p = 0.004). Combined treatment with baclofen and risperidone exerted a greater effect on improvement of hyperactivity symptoms at both midpoint [Cohen's d, 95% confidence interval (CI) = - 3.14, - 5.56 to - 0.72] and endpoint (d, 95% CI = - 4.45, - 8.74 to - 0.16) when compared with treatment with placebo plus risperidone. The two treatments achieved comparable results for other outcome measures. Our data support safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD.

Antiallodynic effects of the selective NaV1.7 inhibitor Pn3a in a mouse model of acute postsurgical pain: evidence for analgesic synergy with opioids and baclofen.

Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically, postsurgical pain continues to be a frequent and undermanaged condition. Here, we investigate the analgesic potential of pharmacological NaV1.7 inhibition in a mouse model of acute postsurgical pain, based on incision of the plantar skin and underlying muscle of the hind paw. We demonstrate that local and systemic treatment with the selective NaV1.7 inhibitor μ-theraphotoxin-Pn3a is effectively antiallodynic in this model and completely reverses mechanical hypersensitivity in the absence of motor adverse effects. In addition, the selective NaV1.7 inhibitors ProTx-II and PF-04856264 as well as the clinical candidate CNV1014802 also reduced mechanical allodynia. Interestingly, co-administration of the opioid receptor antagonist naloxone completely reversed analgesic effects of Pn3a, indicating an involvement of endogenous opioids in the analgesic activity of Pn3a. In addition, we found superadditive antinociceptive effects of subtherapeutic Pn3a doses not only with the opioid oxycodone but also with the GABAB receptor agonist baclofen. Transcriptomic analysis of gene expression changes in dorsal root ganglia of mice after surgery did not reveal any changes in mRNA expression of endogenous opioids or opioid receptors; however, several genes involved in pain, including Runx1 (Runt related transcription factor 1), Cacna1a (CaV2.1), and Cacna1b (CaV2.2), were downregulated. In summary, these findings suggest that pain after surgery can be successfully treated with NaV1.7 inhibitors alone or in combination with baclofen or opioids, which may present a novel and safe treatment strategy for this frequent and poorly managed condition.

Effects of gamma-hydroxybutyrate on neurophysiological correlates of performance and conflict monitoring

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. Both ERPs originate in the anterior cingulate cortex (ACC) and PM specifically has been shown to be susceptible to gamma-aminobutyric acid (GABA) A receptor activation. Contrarily, the specific effects of GABAB receptor (GABABR) stimulation on PM and CM are unknown. Thus, the effects of gamma-hydroxybutyrate (GHB; 20 and 35 mg/kg), a predominant GABABR agonist, on behavioral and electrophysiological correlates of PM and CM were here assessed in 15 healthy male volunteers, using the Eriksen–Flanker paradigm in a randomized, double-blind, placebo-controlled, cross-over study. Electroencephalographic (EEG) data were analyzed in the time and time-frequency domains. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neural oscillations in the theta/alpha1 range. Similarly, neural oscillations associated with the N2 were reduced in the theta/alpha1 range, while N2 amplitude was conversely increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM. Reduced ERN likely derives from a GABABR-mediated increase in dopaminergic signaling, disrupting the generation of prediction errors, whereas an enhanced N2 suggests an increased susceptibility towards external stimuli. Conclusively, GHB is the first drug reported, thus far, to have opposite effects on PM and CM, underlined by its unique electrophysiological signature.