F-phenibut (ß-(4-Fluorophenyl)-GABA), a potent GABAB receptor agonist, activates an outward-rectifying K+ current and suppresses the generation of action potentials in mouse cerebellar Purkinje cells.

The GABA analog phenibut (ß-Phenyl-GABA) is a GABAB receptor agonist that has been licensed for various uses in Russia. Phenibut is also available as a dietary supplement from online vendors worldwide, and previous studies have indicated that phenibut overdose results in intoxication, withdrawal symptoms, and addiction. F-phenibut (ß-(4-Fluorophenyl)-GABA), a derivative of phenibut, has not been approved for clinical use. However, it is also available as a nootropic supplement from online suppliers. F-phenibut binds to GABAB with a higher affinity than phenibut; therefore, F-phenibut may lead to more serious intoxication than phenibut. However, the mechanisms by which F-phenibut acts on GABAB receptors and influences neuronal function remain unknown. In the present study, we compared the potency of F-phenibut, phenibut, and the GABAB agonist (±)-baclofen (baclofen) using in vitro patch-clamp recordings obtained from mouse cerebellar Purkinje cells slice preparations Our findings indicate that F-phenibut acted as a potent GABAB agonist. EC50 of outward current density evoked by the three GABAB agonists decreased in the following order: phenibut (1362 µM) > F-phenibut (23.3 µM) > baclofen (6.0 µM). The outward current induced by GABAB agonists was an outward-rectifying K+ current, in contrast to the previous finding that GABAB agonists activates an inward-rectifying K+ current. The K+ current recorded in the present study was insensitive to extracellular Ba2+, intra- or extracellular Cs+, and intra- or extracellular tetraethylammonium-Cl. Moreover, F-phenibut suppressed action potential generation in Purkinje cells. Thus, abuse of F-phenibut may lead to severe damage by inhibiting the excitability of GABAB-expressing neurons.

An intoxication mimicking brain death: baclofen.

Baclofen is a derivative of gamma-aminobutyric acid, used mainly for the treatment of muscle spasticity. Baclofen overdose can result in severe respiratory depression, autonomic disturbances, seizures and coma. Here we report a 15-year-old girl who was found unresponsive, intubated and admitted to the PICU. On initial presentation, her Glasgow Coma Score was 3, with fixed dilated pupils. EEG revealed cerebral bioelectric activity and ground amplitudes significantly lower than normal. Supportive treatments were administered. On the 2nd PICU day, she regained consciousness and was able to follow commands. She was extubated and discharged on hospital day 3. Conclusively emergency physicians should consider baclofen overdose in children presenting with acute loss of consciousness, flaccidity, and hyporeflexia.

Single-dose baclofen-induced neurotoxicity in a patient with end stage renal disease: case report.

BACKGROUND: Baclofen is a centrally acting GABAB receptor agonist and it is used widely for the treatment of spasticity, persistent hiccups and multiple sclerosis. The renal system is the main route of excretion, thus people with suboptimal renal function are prone to baclofen intoxication. Multiple doses of baclofen have been associated with toxicity, but it is very unusual that single dose can do so. CASE PRESENTATION: A 47 year old female patient with end stage renal disease (ESRD) presented with a sudden onset of altered mental status and state of unconsciousness after the ingestion of one tablet of baclofen 25 mg. All other possible causes were ruled out and a diagnosis of baclofen toxicity was considered. The patient showed dramatic improvement after an extra two sessions of hemodialysis. CONCLUSIONS: We highly recommend that more educational efforts are made for health care professionals about the possible risk of baclofen toxicity among kidney-impaired patients. We also recommend avoiding baclofen use if evidence of chronic renal disease is present and to seek other alternatives for pain management.

Baclofen systemic toxicity: Experimental histopathological and biochemical study.

OBJECTIVE: The present study was designed to highlight the toxic impact of baclofen on both biochemical and histopathological aspects in rats' liver, gastric, lung, kidney, and brain tissues. METHODS: The study was performed on 30 healthy adult male albino rats divided into four groups with 5 rats in each control group, and 10 rats in either experimental groups (two experimental and two control groups). Five rats (negative control) were kept in a quite non-stressful environment, provided with food ad libitum and free access to water. Normal saline (1 ml) was given orally as placebo in the positive control group ( n = 5). Experimental group III, baclofen acute toxicity group (10 rats): Each animal received a single dose of lethal dose (LD50) of baclofen orally by gavage. It equals 145 mg/kg body weight. The rats were observed for acute toxicity manifestations as well as for LD50 deaths. Group IV, (baclofen-dependent group, 10 rats): Each animal received baclofen (1/10th LD50) in gradually increasing doses for 1 month. RESULTS: The levels of blood urea nitrogen, creatinine kinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, cardiac troponin I, and prothrombin time in both baclofen-treated groups showed significant elevation when compared to controls. There were brain, lung, gastric, hepatic, and renal histopathological changes in baclofen-treated rats whose severity varied between the two experimental groups. CONCLUSION AND RECOMMENDATION: Baclofen toxicity is an under diagnosed emergency. Physicians should consider baclofen toxicity in users having hepatorenal dysfunction, presenting with altered mental status, bradycardia, and hypotension.

Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood.

The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0mg/kg) or antagonist phaclofen (0.3mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.

Acute onset rhythmic hiccup-like respirations secondary to oral baclofen toxicity.

OBJECTIVE: Baclofen toxicity has been associated with seizures, coma, apnea, autonomic disturbances, and cardiac conduction abnormalities. It has not been associated with rhythmic hiccup-like respirations. METHOD: We report a patient with suspected baclofen toxicity. RESULTS: Our patient is a 19-year-old girl with cerebral palsy secondary to prematurity and repaired tetralogy of Fallot who had started oral baclofen 8 months before to diminish spasticity. Her main concern was the acute onset of rhythmic, deep, continual, hiccup-like breaths every few seconds, increasing in frequency with exhaustion, and disappearing in sleep. The night after her evaluation, her symptoms significantly worsened. She presented at the Johns Hopkins pediatric emergency room where her symptoms were only somewhat responsive to a benzodiazepine; she was discharged without a clear etiology. After discussion the next day, her baclofen dose was reduced. Within 12 hours, her abnormal respirations disappeared without recurrence. CONCLUSIONS: Respiration involves glutamatergic excitatory synaptic input to medullary inspiratory γ-aminobutyric acid-mediated pacemaker neurons. Baclofen acts on presynaptic γ-aminobutyric acid B receptors on glutamate axons; derangement of this system may explain the irregular respirations in our patient in a dose-dependent fashion.

Activation but not blockade of GABAB receptors during early-life alters anxiety in adulthood in BALB/c mice.

Although the underlying pathophysiology of anxiety disorders is unknown it is clear that a combination of genetic and environmental factors in early life predispose to disease risk. Preclinical research increasingly suggests an important role for the GABAB receptor in modulating anxiety behaviour, with GABAB receptor deficient mice having increased anxiety behaviour. Previous studies have highlighted critical windows during development where adult anxiety behaviour is primed. However, little is known regarding the role played by the GABAB receptors in the developmental processes that underlie adult anxiety behaviour. To this end, we treated male BALB/c mouse pups with the either the selective GABAB receptor agonist, R-baclofen (2 mg/kg, s.c), the GABAB receptor antagonist CGP 52432 (10 mg/kg and 30 mg/kg) or vehicle from postnatal days (P) 14-28. The anxiety behaviour of these mice was then assessed in adulthood (P62 onwards) in a battery of behavioural tests comprising; the stress induced hyperthermia (SIH) test, defensive marble burying (DMB), elevated-plus maze (EPM) and the forced swim test (FST). Postnatal R-baclofen treatment resulted in increased anxiety-like behaviour in the EPM as shown by approach-avoidance and ethological measures. Other behavioural measures were not significantly altered. Interestingly, blockade of GABAB receptors with CGP52432 in early life caused no alterations in emotional behaviour. These data suggest that during early life GABAB receptor signalling can play a functional role in programing anxiety behaviour in adulthood. The underlying neurodevelopmental processes underlying these effects remain to be discovered.