Baclofen is an effective treatment for spasticity. Abrupt cessation of intrathecal (IT) or oral baclofen risks the development of withdrawal symptoms; however, the magnitude of the problem is unknown.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

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 Thus, C57BL/6 mice were submitted to a 6-month alcohol consumption [12% volume/volume (v/v)] and were progressively withdrawn to water before testing.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.

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3β(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system.

One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system.

Our study aims at comparing in C57/Bl male mice, the impact of repeated injections of baclofen (an agonist of GABAB receptor) or diazepam (a benzodiazepine acting through a positive allosteric modulation of GABAA receptor) administered during the alcohol-withdrawal period on hippocampus-dependent memory impairments and brain regional glucocorticoid dysfunction after a short (1-week) or a long (4-week) abstinence. Hence, mice were submitted to a 6-month alcohol consumption (12%v/v) and were progressively withdrawn to water. Then, after a 1- or 4-weeks abstinence, they were submitted to a contextual memory task followed by measurements of corticosterone concentrations in the dorsal hippocampus (dHPC), the ventral hippocampus (vHPC) and the prefrontal cortex (PFC). Results showed that 1- and 4-week withdrawn mice exhibited a severe memory deficit and a significant abnormal rise of the test-induced increase of corticosterone (TICC) in the dHPC, as compared to water-controls or to mice still under alcohol consumption. Repeated daily systemic administrations of decreasing doses of diazepam (ranged from 0.5 to 0.12 mg/kg) or baclofen (ranged from 1.5 to 0.37 mg/kg) during the last 15 days of the withdrawal period, normalized both memory and TICC scores in the dHPC in 1-week withdrawn animals; in contrast, only baclofen-withdrawn mice showed both normal memory performance and TICC scores in the dHPC after a 4-week withdrawal period. In conclusion, the memory improvement observed in 4-week withdrawn mice administered with baclofen stem from the protracted normalization of glucocorticoid activity in the dHPC, a phenomenon encountered only transitorily in diazepam-treated withdrawn mice.

Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates.

Autism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology.

In the present study we compared the clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury. A total of 150 patients were enrolled in the present study and were divided into two groups with 75 patients in each group, receiving baclofen or tolperisone, respectively. We used Modified Ashworth Scale, Medical research council scale, Barthel Index, and Coefficient of efficacy to measure clinical efficacy. After 6-week treatment, both groups demonstrated significant improvement in muscle tone, muscle strength and functional outcome (Group I, 1.55 ± 0.053, 2.79 ± 0.032, 59.31 ± 1.32; Group II, 1.57 ± 0.053, 3.04 ± 0.032, 73 ± 1.32 respectively). There was no significant difference regarding improvement in muscle tone and muscle strength between the two groups (Group I, 1.055 ± 0.053 vs Group II, 1.57 ± 0.053; Group I, 2.79 ± 0.032 vs Group II, 3.04 ± 0.032, p > 0.05). However, the improvement in functional outcomes was greater in group II as compared to that in group I (Group I, 59.31 ± 1.32 vs Group II, 73 ± 1.32, p < 0.05). In addition, overall efficacy coefficient was greater for group II as compared to group I (Group I, 3.6 vs Group II, 2.3, p < 0.05). Group I had more side effects compared to Group II. Compared to baclofen, tolperisone offers greater improvement in activities of daily living compared to baclofen.

Alcohol is the leading psychoactive substance consumed in France, with about 15 million regular consumers. The National institute on Alcohol Abuse and Alcoholism (NIAAA) considers alcohol abuse to be more than 14 units of alcohol a week for men and 7 units for women. The specific complication of alcoholism is the alcohol withdrawal syndrome. Its incidence reaches up to 30 % and its main complications are delirium tremens, restlessness, extended hospital stay, higher morbidity, and psychiatric and cognitive impairment. Without appropriate treatment, delirium tremens can lead to death in up to 50 % of patients.

To characterize musculoskeletal pain intensity, duration, frequency, and interference with activities of daily living in children with cerebral palsy (CP) before and after intrathecal baclofen pump placement.

The present study explored the antinociceptive effects of H₃ (R-methylhistamine) and GABA(B) (baclofen) receptor ligands in an orofacial model of pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (50 μl, 5 %) in the upper lip region, and the number of jumps and time spent face rubbing was recorded for 40 min. Formalin produced a marked biphasic pain response; first phase, 0-10 min (jumps), and second phase, 15-40 min, (rubbing). Baclofen (50 μg) injected into the rat wiskerpad 5 min before formalin administration suppressed both phases of pain whereas R-alpha-methylhistamine (12.5 μg) abolished the first phase only. Brains were taken immediately after behavioral testing was completed. HPLC/ED analysis showed that 5-hydroxytryptamine (5-HT) turnover was increased in hippocampus, thalamus, and brain stem of all formalin groups, excepting the baclofen group in which the balance of 5-HT metabolism was restored to control values. These findings demonstrate that GABA(B) receptors represent peripheral targets for analgesia. Consequently, locally administered baclofen may be a useful approach in treating inflammatory trigeminal pain.

To develop an algorithm for the selection of adults with disabling spasticity for treatment with intrathecal baclofen (ITB) and/or botulinum toxin type A (BoNT A).

Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear.

Intrathecal baclofen (ITB) treatment is used with increasing frequency in the cerebral palsy population. We describe the complications of ITB treatment, the incidence of complications, and our experience with their treatment.

A previous study from our laboratory showed that baclofen (BAC, GABAB receptor agonist) was able to prevent the behavioral expression of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying this effect, we conducted this study, with the aims of analyzing α4β2 nicotinic receptor density during NIC withdrawal and, in case we found any changes, of determining whether they could be prevented by pretreatment with BAC. Swiss Webster albino mice received NIC (2.5 mg/kg, s.c.) 4 times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and brain autoradiography with [(3)H]epibatidine was carried out at five different anatomical levels. Autoradiographic mapping showed a significant increase of α4β2 nicotinic receptor labeling during NIC withdrawal in the nucleus accumbens shell (AcbSh), medial habenular nucleus (HbM), thalamic nuclei, dorsal lateral geniculate (DLG) nucleus, fasciculus retroflexus (fr), ventral tegmental area, interpeduncular nucleus and superior colliculus. BAC pretreatment prevented the increased α4β2 nicotinic receptor binding sites in the AcbSh, MHb, thalamic nuclei, DLG nucleus and fr. The present results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in α4β2 nicotinic receptor labeling, evidenced in specific brain areas in NIC withdrawn animals.

This study will explore the efficacy and safety of intrathecal baclofen bolus (IBB) on neuropathic pain (NPP) in patients with spinal cord injury (SCI).

The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder.

Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30-80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

One important function of GABA B receptors is the control of neuronal activity to prevent overexcitation and thereby excitotoxic death, which is a hallmark of cerebral ischemia. Consequently, sustained activation of GABA B receptors with the selective agonist baclofen provides neuroprotection in in vitro and in vivo models of cerebral ischemia. However, excitotoxic conditions severely downregulate the receptors, which would compromise the neuroprotective effectiveness of baclofen. On the other hand, recent work suggests that sustained activation of GABA B receptors stabilizes receptor expression. Therefore, we addressed the question whether sustained activation of GABA B receptors reduces downregulation of the receptor under excitotoxic conditions and thereby preserves GABA B receptor-mediated inhibition. In cultured neurons subjected to oxygen and glucose deprivation (OGD), to mimic cerebral ischemia, GABA B receptors were severely downregulated. Treatment of the cultures with baclofen after OGD restored GABA B receptor expression and reduced loss of neurons. Restoration of GABA B receptors was due to enhanced fast recycling of the receptors, which reduced OGD-induced sorting of the receptors to lysosomal degradation. Utilizing the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia, we verified the severe downregulation of GABA B receptors in the affected cortex and a partial restoration of the receptors after systemic injection of baclofen. Restored receptor expression recovered GABA B receptor-mediated currents, normalized the enhanced neuronal excitability observed after MCAO and limited progressive loss of neurons. These results suggest that baclofen-induced restoration of GABA B receptors provides the basis for the neuroprotective activity of baclofen after an ischemic insult. Since GABA B receptors regulate multiple beneficial pathways, they are promising targets for a neuroprotective strategy in acute cerebral ischemia.