Xanthurenic acid: A role in brain intercellular signaling.

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3-hydroxykynurenine (3-HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G-protein-coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+ -dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain-specific properties in balance with its formation and peripheral inputs.

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity.

Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1-0.4 µM in A9 and A10), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.

Mechanisms for the Specific Properties of γ-Hydroxybutyrate in Brain.

γ-Hydroxybutyrate (GHB) is both a natural brain compound with neuromodulatory properties at central GABAergic synapses (micromolar concentration range) and also a drug (Xyrem(R) ) clinically used for the treatment of various neurological symptoms (millimolar dose range). However, this drug has abuse potential and can be addictive for some patients. Here, we review the basic mechanistic role of endogenous GHB in brain as well as the properties and mechanisms of action for therapeutic clinical doses of exogenous GHB. Several hypotheses are discussed with a preference for a molecular mechanism that conciliates most of the findings available. This conciliatory model may help for the design of GHB-like drugs active at lower doses and devoid of major side effects.

Prevalence of undiagnosed psoriatic arthritis among psoriasis patients: Systematic review and meta-analysis.

BACKGROUND: Skin psoriasis precedes the onset of psoriatic arthritis (PsA) in 84% of patients with psoriasis. Dermatologists have an important role to screen psoriasis patients for PsA. The efficiency of PsA screening remains unknown. OBJECTIVE: We sought to determine the point prevalence of undiagnosed PsA in patients with psoriasis using a systematic search of the literature and meta-analysis. METHODS: PubMed, Cochrane, and Embase database searches yielded 394 studies for review. No study aimed to determine the prevalence of undiagnosed PsA in patients with psoriasis. We assumed that the prevalence of newly diagnosed PsA in patients with psoriasis at the time they seek medical care could be a sound estimate of this value. Seven epidemiological studies and 5 studies on PsA screening questionnaires allowed us to clearly identify patients with newly diagnosed PsA and were selected for review. RESULTS: The prevalence of undiagnosed PsA was 15.5% when all studies were considered and 10.1% when only epidemiological studies were considered. LIMITATIONS: Data were obtained from studies not designed to address the question at hand. Heterogeneity was high (I(2) = 96.86%), and therefore a random effects model was used. CONCLUSION: The high prevalence of undiagnosed PsA in patients with psoriasis adds to the recommendation that dermatologists need to screen all patients with psoriasis for PsA.

Monomeric Amyloid Peptide-induced Toxicity in Human Oligodendrocyte Cell Line and Mouse Brain Primary Mixed-glial Cell Cultures: Evidence for a Neuroprotective Effect of Neurosteroid 3α-O-allyl-allopregnanolone.

Amyloid-peptide (Aß) monomeric forms (ABM) occurring in presymptomatic Alzheimer's disease (AD) brain are thought to be devoid of neurotoxicity while the transition/aggregation of ABM into oligomers is determinant for Aß-induced toxicity since Aß is predominantly monomeric up to 3 µM and aggregates over this concentration. However, recent imaging and/or histopathological investigations revealed alterations of myelin in prodromal AD brain in absence of aggregated Aß oligomers, suggesting that ABM may induce toxicity in myelin-producing cells in early AD-stages. To check this hypothesis, here we studied ABM effects on the viability of the Human oligodendrocyte cell line (HOG), a reliable oligodendrocyte model producing myelin proteins. Furthermore, to mimic closely interactions between oligodendrocytes and other glial cells regulating myelination, we investigated also ABM effects on mouse brain primary mixed-glial cell cultures. Various methods were combined to show that ABM concentrations (600 nM-1 µM), extremely lower than 3 µM, significantly decreased HOG cell and mouse brain primary mixed-glial cell survival. Interestingly, flow-cytometry studies using specific cell-type markers demonstrated that oligodendrocytes represent the most vulnerable glial cell population affected by ABM toxicity. Our work also shows that the neurosteroid 3α-O-allyl-allopregnanolone BR351 (250 and 500 nM) efficiently prevented ABM-induced HOG and brain primary glial cell toxicity. Bicuculline (50-100 nM), the GABA-A-receptor antagonist, was unable to block/reduce BR351 effect against ABM-induced HOG and primary glial cell toxicity, suggesting that BR351-evoked neuroprotection of these cells may not depend on GABA-A-receptor allosterically modulated by neurosteroids. Altogether, our results suggest that further exploration of BR351 therapeutic potential may offer interesting perspectives to develop effective neuroprotective strategies.

Multiple aggregated yellow-white globules are a major dermoscopic sign of basal cell carcinoma regardless of their histological subtype.

Multiple aggregated yellow-white globules (MAY globules) have been recently described as dermoscopic structures of high specificity associated with high-risk non-pigmented basal cell carcinoma (BCC). To evaluate the diagnostic accuracy of MAY globules in a cohort of pigmented and non-pigmented BCC of all histological types. This was a retrospective case-control study. Dermoscopic and clinical images were all histopathologically confirmed as BCCs of patients seen consecutively at dermatology consultation. Control cases were benign or malignant tumours randomly selected from the database of 8,250 patients. A total of 389 BCCs were included. MAY globules were present in 192 (49%) cases in the BCC group and in only 25 cases in the control group (6,4%). The odds ratio for the diagnosis of BCC was 14.2 (95% CI: 9.62-20.95]). The presence of MAY globules was significant in three histological subtypes, including superficial BCCs. This study shows that MAY globules are a major dermoscopic sign for the diagnosis of BCC, regardless of their histological subtype and their pigmentation.

Myelin in Alzheimer's disease: culprit or bystander?

Alzheimer's disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid ß (Αß) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals' accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αß peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aß peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.

A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex.

γ-Hydroxybutyrate (GHB) is a natural brain neuromodulator that has its own enzymatic machinery for synthesis and degradation, release, and transport systems and several receptors that belong to the G protein-coupled receptor (GPCR) family. Targeting of this system with exogenous GHB is used in therapy to induce sleep and anesthesia and to reduce alcohol withdrawal syndrome. GHB is also popular as a recreational drug for its anxiolytic and mild euphoric effects. However, in both cases, GHB must be administered at high doses in order to maintain GHB concentrations in brain of ∼800-1,000 µM. These high concentrations are thought to be necessary for interactions with low-affinity sites on GABA(B) receptor, but the molecular targets and cellular mechanisms modulated by GHB remain poorly characterized. Therefore, to provide new insights into the elucidation of GHB mechanisms of action and open new tracks for future investigations, we explored changes of GHB-induced transcriptomes in rat hippocampus and prefrontal cortex by using DNA microarray studies. We demonstrate that a single acute anesthetic dose of 1 g/kg GHB alters a large number of genes, 121 in hippocampus and 53 in prefrontal cortex; 16 genes were modified simultaneously in both brain regions. In terms of molecular functions, the majority of modified genes coded for proteins or nucleotide binding sites. In terms of Gene Ontology (GO) functional categories, the largest groups were involved in metabolic processing for hippocampal genes and in biological regulation for prefrontal cortex genes. The majority of genes modified in both structures were implicated in cell communication processes. Western blot and immunohistochemical studies carried out on eight selected proteins confirmed the microarray findings.

Tryptophan metabolites modify brain Aß peptide degradation: A role in Alzheimer's disease?

Among several processes, a decrease in amyloid-beta (Aß) peptide elimination is thought to be one of the major pathophysiological factors in Alzheimer's disease (AD). Neprilysin (NEP) is a key metalloproteinase controlling the degradation and clearance of Aß peptides in the brain. NEP is induced by several pharmacological substances, amyloid deposits and somatostatin, but the physiological regulation of its expression remains unclear. This situation hampers the exploitation of NEP regulatory factors/mechanisms to develop effective strategies against Aß peptide accumulation-induced brain toxicity. Based on recent data aimed at elucidating this major question, the present paper addresses and critically discusses the role of 5-hydroxyindole-acetic acid (5-HIAA) and kynurenic acid (KYNA) in the regulation of NEP activity/expression in the brain. Both 5-HIAA and KYNA are endogenous metabolites of tryptophan, an essential amino-acid obtained through diet and gut microbiome. By interacting with the aryl hydrocarbon receptor, various tryptophan metabolites modulate several metalloproteinases regulating brain Aß peptide levels under normal and pathological conditions such as AD. In particular, interesting data reviewed here show that 5-HIAA and KYNA stimulate NEP activity/expression to prevent Aß peptide-induced neurotoxicity. These data open promising perspectives for the development of tryptophan metabolite-based therapies against AD.

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis.

Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-ß (Aß). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aß levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Xanthurenic acid distribution, transport, accumulation and release in the rat brain.

Tryptophan metabolism through the kynurenine pathway leads to several neuroactive compounds, including kynurenic and picolinic acids. Xanthurenic acid (Xa) has been generally considered as a substance with no physiological role but possessing toxic and apoptotic properties. In the present work, we present several findings which support a physiological role for endogenous Xa in synaptic signalling in brain. This substance is present in micromolar amounts in most regions of the rat brain with a heterogeneous distribution. An active vesicular synaptic process inhibited by bafilomycin and nigericin accumulates xanthurenate into pre-synaptic terminals. A neuronal transport, partially dependant on adenosine 5'-triphosphate (ATP), sodium and chloride ions exists in NCB-20 neurons which could participate in the clearance of extracellular xanthurenate. Both transports (neuronal and vesicular) are greatly enhanced by the presence of micromolar amounts of zinc ions. Finally, electrical in vivo stimulation of A10-induced Xa release in the extracellular spaces of the rat prefrontal cortex. This phenomenon is reproduced by veratrine, K+ ions and blocked by EGTA and tetrodotoxin. These results strongly argue for a role for Xa in neurotransmission/neuromodulation in the rat brain, thus providing the existence of specific Xa receptors.

Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain.

Two parent clones of a gamma-hydroxybutyrate (GHB) receptor, C12K32 and GHBh1, were isolated from a human frontal cortex cDNA library. The two clones differ by a deleted cytosine in C12K32. CHO cells transfected with either C12K32 or GHBh1 responded positively to submicromolar GHB stimulation. However, unlike C12K32, GHBh1 desensitizes rapidly on application of low concentrations of GHB. GHB receptor properties were then studied on C12K32 expressed in CHO cells. C12K32 bound GHB with a Kd of 114 nM and has no affinity for GABA or glutamate. GHB and NCS-382 displaced [3H]GHB with an IC50 of 53 +/- 8 and 120 +/- 18 nM, respectively. In patch-clamp experiments, GHB induced a dose-dependent response with an EC50 of 130 nM. This response was antagonized by NCS-382, was not reproduced by GABA, and was sensitive to the addition of GTP-gamma-S in the recording pipette. CHO cells transfected with C12K32 exhibited GTPgamma-35S binding with an EC50 of 462 nM for GHB and an IC50 of 2.9 microM for NCS-382. The present data led to the conclusion that both C12K32 and GHBh1 are two closely related isoforms of a human GHB receptor, GHBh1, that is described in the databank as the GPCR 172A.

5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a mouse model for Alzheimer's disease.

Serotoninergic activation which decreases brain Aß peptides is considered beneficial in mouse models for Alzheimer's disease (AD), but the mechanisms involved remain unclear. Because growing evidence suggested that the stimulation of proteases digesting Aß, especially the endopeptidase neprilysin (NEP) may be effective for AD therapy/prevention, we explored the involvement of serotonin precursors and derivatives in NEP regulation. We found that 5-hydroxyindolacetic acid (5-HIAA), the final metabolite of serotonin, considered until now as a dead-end and inactive product of serotonin catabolism, significantly reduces brain Aß in the transgenic APPSWE mouse model for AD-related Aß pathology and in the phosphoramidon-induced cerebral NEP inhibition mouse model. 5-HIAA treatment improves memory performance in APPSWE mice. Furthermore, 5-HIAA and its precursors increase NEP level in vivo and in neuroblastoma cells. Inhibition of ERK 1/2 cascade by 5-HIAA or SCH772984 enhanced NEP levels, suggesting MAP-kinase pathway involvement in 5-HIAA-induced regulation of NEP expression. Our results provide the first demonstration that 5-HIAA is an active serotonin metabolite that increases brain Aß degradation/clearance and improves symptoms in the APPSWE mouse model for AD.

A compound heterozygote case of isolated sulfite oxidase deficiency.

We report an isolated sulfite oxidase deficiency in the first child boy of a non-consanguineous Caucasian family. He's a compound heterozygote for the sulfite oxidase gene, presenting low cystine, undetectable homocysteine and normal uric acid blood concentrations and undetectable sulfite oxidase activity in his cultured fibroblasts. Both mutations are not reported yet. The clinical presentation was typical and severe, with generalized status epilepticus and premature death.

A peel-off facial mask comprising myoinositol and trehalose-loaded liposomes improves adult female acne by reducing local hyperandrogenism and activating autophagy.

BACKGROUND: Hyperandrogenism and reduced skin autophagy have been implicated in the pathogenesis of adult female acne (AFA). Here, we tested whether a ready-to-use peel-off facial mask containing myoinositol (an androgen inhibitor) and trehalose-loaded liposomes (as activators of cutaneous autophagy) applied overnight every other day for 60 days can improve AFA. We also sought to investigate the molecular mechanisms underlying the clinical effects. OBJECTIVES: We conducted an uncontrolled, open-label clinical study in 40 cases of AFA to investigate the effect of the facial mask on lesion count, sebum production (measured with the Sebutape® technique), and Global Acne Grading System (GAGS) scale. We also investigated the changes from baseline to the end of treatment in androgen and beclin-1 levels (as a marker of authophagy) in skin biopsy supernatants. METHODS: Forty Caucasian patients with AFA were enrolled. Changes in clinical and molecular endpoints before and after treatment were investigated. RESULTS: The mean counts of comedones, papules, pustules, and nodular lesions decreased significantly (all P<.001). The mean Sebutape® score was reduced from 3.4±0.6 to 1.8±0.2 (P<.001), whereas the mean GAGS scale score decreased from 16.8±5.3 at baseline to 9.8±4.6 after treatment (P<.001). A significant decrease in testosterone and dehydroepiandrosterone sulfate in skin biopsy supernatants was observed, whereas beclin-1 levels increased significantly (P<.001). CONCLUSION: A ready-to-use peel-off facial mask containing myoinositol and trehalose-loaded liposomes improved the cosmetic appearance of AFA by reducing cutaneous androgen content and promoting skin autophagy.

Immunohistochemical localization of a GHB receptor-like protein isolated from rat brain.

Gamma-hydroxybutyrate (GHB) is a substance derived from the metabolism of GABA and is heterogeneously distributed in various regions of the brain. This compound possesses a neuromodulatory role on several types of synapses, particularly those using GABA as a neurotransmitter. At physiological concentrations, this effect of GHB is mediated via specific receptors that induce neuronal hyperpolarization and bind radioactive GHB with a specific distribution, ontogenesis, kinetics, and pharmacology. A membrane protein that possesses six to seven transmembrane domains and which binds and is activated by micromolar amounts of GHB was recently cloned from rat brain hippocampus. In order to study the regional and cellular distribution of this receptor in rat brain, we selected several specific peptides belonging to the extracellular domains of the receptor to be used as specific immunogens to raise polyclonal antibodies in the rabbit. Among the antisera obtained, one of them gave particularly good results in terms of specificity and reactivity at high dilution. Immunohistochemical analyses, both at the confocal and electron microscopic level, showed receptor protein distribution closely resembling the distribution of GHB high-affinity binding sites, except for cerebellum, where GHB receptor(s) of lower affinity exist(s). In all regions studied the GHB receptor-like protein labeling appears to be distributed specifically in neurons and not in glial cells. At the cellular level the antibody specifically labels dendrites, and no immunoreactivity was detected in presynaptic endings or in axons. Accordingly, electron microscopy reveals strong labeling of postsynaptic densities and of neuronal cytosol.

A proposed preventive role for Gamma-hydroxybutyrate (Xyrem(R)) in Alzheimer's disease.

Gamma-hydroxybutyrate (GHB or Xyrem(R)) is frequently used in humans for several clinical indications, including anesthesia, narcolepsy/cataplexy, and alcohol-withdrawal symptoms. Pharmacological effects induced in the brain by therapeutic doses of Xyrem(R) are generally GABAergic-dependent. These effects allow sedation, stress/anxiety reduction, deep sleep induction, decrease of neuroinflammation, and neuroprotection. Furthermore, Xyrem(R) promotes the expression of pivotal genes reducing toxic proteinopathies, as demonstrated in laboratory animal models. Altogether, these data represent additional evidence to suggest that Xyrem(R) may be tested during repeated short periods in populations at risk for Alzheimer's disease.

Xanthurenic acid is localized in neurons in the central nervous system.

Kynurenine pathway metabolites (KPM) are thought to be synthesized mainly by non-neuronal cells in the mammalian brain. KPM are of particular interest because several studies demonstrated their implication in various disorders of the nervous system. Among KPM is xanthurenic acid (XA) deriving from the catabolism of 3-hydroxykynurenine. Based on its chemical structure, XA appears as a close analog of kynurenic acid which has been extensively investigated and is considered as a potent neuroprotective compound. Contrary to kynurenic acid (KYNA), XA has received little attention and its role in the brain remains not elucidated. We have previously described several characteristics of XA, suggesting its possible involvement in neurotransmission. XA is also proposed as a potential modulator at glutamatergic synapses. Here, we used a selective antibody against XA and various neuronal, glial and synaptic markers to show that XA is essentially localized in the soma and dendrites of brain neurons, but is absent from axonal compartments and terminal endings. Our results also reveal that XA-like immunoreactivity is not expressed by glial cells. To double-check our findings, we have also used another XA antibody obtained from a commercial source to confirm the neuronal expression of XA. Together, our results suggest that, differently to several other KPM produced by glial cells, XA exhibits a neuronal distribution in the mouse brain.

Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB).

Gamma-hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven-transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABA(B) receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch-clamp experiments, transfected CHO cells revealed a functional G-protein-coupled receptor as demonstrated by GTP-gamma-S-induced irreversible activation. Application of 0.1-15 microM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 microM). CGP-55845, a GABA(B) receptor antagonist, did not inhibit the GHB-induced response nor did the GHB receptor antagonist NCS-382, suggesting that the GHB receptor system includes several subtypes.

[A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]. / Mécanismes d'action d'un médicament détourné: le gamma-hydroxybutyrate.

Gamma-hydroxybutyrate (GHB) is mainly known because of its popularity as a drug of abuse among young individuals. However this substance increases slow-wave deep sleep and the secretion of growth hormone and besides its role in anaesthesia, it is used in several therapeutic indications including alcohol withdrawal, control of daytime sleep attacks and cataplexy in narcoleptic patients and is proposed for the treatment of fibromyalgia. GHB is also an endogenous substance present in several organs, including brain where it is synthesized from GABA in cells containing glutamic acid decarboxylase, the marker of GABAergic neurons. GHB is accumulated by the vesicular inhibitory aminoacid transporter (VIAAT) and released by depolarization via a Ca2+ dependent-mechanism. A family of GHB receptors exists in brain which possesses hyperpolarizing properties through Ca2+ and K+ channels. These receptors--one of them has been recently cloned from rat brain hippocampus--are thought to regulate GABAergic activities via a subtle balance between sensitized/desensitized states. Massive absorption of GHB desensitize GHB receptors and this modification, together with a direct stimulation of GABAB receptors by GHB, induce a perturbation in GABA, dopamine and opiate releases in several region of the brain. This adaptation phenomenon is probably responsible for the therapeutic and recreative effects of exogenous GHB.