Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential?

Bernasconi, R.; Mathivet, Pascal; Bischoff, Serge; Marescaux, Christian

doi:10.1016/s0165-6147(99)01341-3

Cited by 109 publications

(96 citation statements)

References 34 publications

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“…Of note, the mode of action of the GHB is still uncertain and may involve specific GHB receptors and/or stimulation of GABA-B receptors (Bernasconi et al 1999). In electrophysiological studies, GHB administration decreases dramatically the firing rate of dopaminergic cells and the release of this neurotransmitter in awake animals.…”

Section: Treatment Of Human Narcolepsymentioning

confidence: 99%

“…Disturbed nocturnal sleep can be treated using benzodiazepine hypnotic but this treatment does not alleviate daytime sleepiness. A novel compound, Gammahydroxybutyrate (GHB), is now in clinical trial for the treatment of narcolepsy (Nishino and Mignot 1997;Bernasconi et al 1999). This hypnotic, a former anesthetic agent, is unique as it consolidate nocturnal sleep by increasing deep slow wave sleep and to a less extent REM sleep.…”

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“…Indeed, because of its promoting effect on slow wave sleep, the compound releases Growth Hormone, a property that has made the drug popular in athletes. Other abusers have used the compound as a rape drug or in association with other drugs as an euphoric agent in rave parties.Of note, the mode of action of the GHB is still uncertain and may involve specific GHB receptors and/or stimulation of GABA-B receptors (Bernasconi et al 1999). In electrophysiological studies, GHB administration decreases dramatically the firing rate of dopaminergic cells and the release of this neurotransmitter in awake animals.…”

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confidence: 99%

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A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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Rarely in the history of medicine has scientific discovery moved so quickly from the report of a neurotransmitter system to a disease pathophysiology (Mignot 2001). In 1998, two groups independently identified the same neuropeptide system and called the molecules "hypocretins" and "orexins" respectively (de Lecea et al. 1998;Sakurai et al. 1998). One of the most striking findings of these initial studies was the discrete localization of hypocretin-containing cells within a very discrete region of the lateral hypothalamus. This led one group to call this peptide system "hypocretin", a term derived from hypo thalamus and se cretin (a weak-and contested-homology with secretin was noted by these authors). The established role of the perifornical region in the regulation of appetite, together with the observation that intracerebroventricular injections of the peptides induced food intake in rats, led the other group to coin the term "orexin" (orexis ϭ appetite) for this system.The discovery in 1999 that canine narcolepsy was caused by mutations in the Hypocretin receptor 2 (Hcrtr2) gene is shifting the research emphasis from appetite control to sleep regulation (Lin et al. 1999). This finding was followed by the observation that hypocretin knockout mice have sleep and behavioral abnormalities reminiscent of narcolepsy (Chemelli et al. 1999). Other studies have indicated dense projections to all monoaminergic cell groups and wake-promoting effects of hypocretins when administered centrally (Hagan et al. 1999). More recently, clinical studies have shown that most patients with narcolepsy have undetectable hypocretins in the CSF and a striking decrease in hypocretin immunoreactivity and transcript levels in the perifornical hypothalamus Thannickal et al. 2000). The most fre- quent cause of human narcolepsy is now known to be hypocretin deficiency, most probably as the result of an autoimmune attack against hypocretin-containing cells. In this commentary, I will briefly review the current knowledge regarding this system, speculate on its possible function in sleep regulation and discuss the potential importance of this system for neuropsychiatry. HYPOCRETIN/OREXINS: NEURONATOMY AND RECEPTOR SYSTEMSThe description of this system has been the object of multiple recent reviews ( Kilduff and Peyron 2000;Sutcliffe and de Lecea 2000;Hungs and Mignot 2001;Overeem et al. 2001;Willie et al. 2001) and will only be briefly outlined. Two biologically active peptides encoded by a single two-exon precursor gene, the preprohypocretin (Hcrt) locus, have been described. The precursor gene contains a signal peptide sequence, followed by a first active peptide, hypocretin-1 (or orexin-A), a second active peptide, hypocretin-2 (or orexin-B) and a C-terminal section of unknown biological activity. Endopeptidic cleavage occurs at typical dibasic residue sequences located between the hypocretin peptides and at the C-terminal of the hypocretin-2 sequence. The hypocretin-1 and hypocretin-2 regions but not the C-terminal region of the precursor ...

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Section: Treatment Of Human Narcolepsymentioning

confidence: 99%

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A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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“…Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter (Bernasconi et al 1999;Maitre 1997). Administered peripherally, GHB penetrates freely into the brain and produces doserelated pharmacological effects including euphoria, antidepressant, and anxiolytic effects, sedation, sleep, anesthesia (Agabio and Gessa 2002;Colombo et al 1998;De Couedic and Voisse 1964;Laborit et al 1960;Rinaldi et al 1967;Schmidt-Mutter et al 1998).…”

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Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Cammalleri

Brancucci

Berton

et al. 2002

Neuropsychopharmacology

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Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter, derived from gammaaminobutyric acid (GABA). At micromolar concentrations GHB binds to specific high and low affinity binding sites present in discrete areas of the brain, while at millimolar concentrations GHB also binds to GABA B receptors. Previous studies indicated that GHB inhibits bothGamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter (Bernasconi et al. 1999;Maitre 1997). Administered peripherally, GHB penetrates freely into the brain and produces doserelated pharmacological effects including euphoria, antidepressant, and anxiolytic effects, sedation, sleep, anesthesia (Agabio and Gessa 2002;Colombo et al. 1998;De Couedic and Voisse 1964;Laborit et al. 1960;Rinaldi et al. 1967;Schmidt-Mutter et al. 1998). GHB has been used clinically as a general anesthetic and as a sleep inducer in the treatment of narcolepsy (Agabio and Gessa 2002;Broughton and Mamelak 1979). GHB is currently marketed in Italy and Austria for the treatment of alco- Gallimberti et al. 1989Gallimberti et al. , 2000. However, GHB has also gained popularity in the illicit market in the United States, being abused for its euphoriant action, which reportedly resembles that of alcohol and ecstasy (Boyce et al. 2000;Kam and Yoong 1998;Nicholson and Balster 2001). However, GHB is also synthesized and released by specific neurons in the brain and possesses most of the properties required to be classified as a neurotransmitter and/or neuromodulator. In fact, synthesis, release, uptake mechanisms, and specific binding sites for GHB have been identified in the mammalian brain (Benavides et al. 1982a,b;Hechler et al. 1985Hechler et al. , 1992Maitre et al. 1983;Rumigny et al. 1981;Snead and Liu 1984;Vayer et al. 1988). GHB binding sites exhibit high (Kd 30-580 nM) and low (about 20 M) affinity for GHB (Benavides et al. 1982a) and are sensitive to pertussis toxin, suggesting that these sites could represent G protein coupled receptors (Kemmel et al. 1998;Rotomponirina et al. 1995). GHB binding sites have a discrete brain distribution including the frontal cortex, nucleus accumbens, amygdala, hypothalamus, and, with highest density, the hippocampus (Hechler et al. 1992;Maitre et al. 2000;Snead et al. 1990). The synthetic structural analog of GHB, 6,7,8, (Maitre et al. 2000). In vivo, NCS-382 diminishes the sedative effect and the petit mal seizures induced by GHB (Hu et al. 2000;Schmidt et al. 1991;Schmidt-Mutter et al. 1998) and suppresses GHB-intravenous self-administration in mice (Martellotta et al. 1998). Moreover, NCS-382 inhibits GHB-induced increase in Guanosine 3 Ј ,5 Ј -cyclic monophosphate (cGMP) levels and inositol phosphate turnover in the hippocampus both in vivo and in vitro Snead 2000). At millimolar concentrations GHB displaces [ 3 H] baclofen from GABA B (gammaaminobutyric acid) receptors (Mathivet et al. 1997;Snead 1996). GHB action on GABA B receptors appears to mediate some of the pharmacological actions of GHB...

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“…Subsequent experiments tested the interactions between PCP and the serotonergic agents, LSD, DOM, psilocybin, and buspirone. In addition, interactions with PCP were tested with the dopaminergic/serotonergic drugs, d-amphetamine and MDMA, as well as with GHB, a drug thought to act via non-serotonergic mechanisms (Bernasconi et al 1999;Carter et al 2004;Winter, 1981).…”

Section: Introductionmentioning

confidence: 99%

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

2008

Pharmacology Biochemistry and Behavior

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It has been observed that agents with agonist activity at 5-HT 2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.

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Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential?

Cited by 109 publications

References 34 publications

A Commentary on the Neurobiology of the Hypocretin/Orexin System

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Gamma-hydroxybutyrate Reduces GABAA-mediated Inhibitory Postsynaptic Potentials in the CA1 Region of Hippocampus

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

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