Mecanismes de synthese de novo de choline par methylations sequentielles de l'ethanolamine et de ses composes, dans le tissu nerveux

SIGLEINIST T 72000 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Mécanismes d’action d’un médicament détourné : le γ-hydroxybutyrate

Le γ-hydroxybutyrate (GHB), synthétisé dans les années 1960 pour ses propriétés GABAergiques (GABA, acide γ-amino-butyrique), est une substance qui pénètre facilement et rapidement dans le cerveau. Il induit un sommeil proche du sommeil physiologique, avec un réveil de bonne qualité, et possède des indications en anesthésiologie et dans le traitement des troubles narcoleptiques et de l’addiction à l’alcool. Ses propriétés sédatives, anxiolytiques et euphorisantes ont détourné ce composé de ses indications en thérapeutique, pour une utilisation à des fins récréatives et une consommation illicite. Le GHB à doses pharmacologiques interagit avec les récepteurs GABAB cérébraux et avec une famille de récepteurs spécifiques, exprimés principalement par le système nerveux central. Cette dernière famille représente l’un des constituants essentiels d’un système GHB endogène qui aurait comme rôle principal de contrôler l’activité de certaines synapses GABA du système nerveux central.γ-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

Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system

The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABA(B) receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC(50)) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABA(B) receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits

RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area

Agonists of GABA(B) receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABA(B) receptor agonists such as gamma-hydroxybutyrate (GHB) and its derivatives. Here we show that, in DA neurons of mice, the low coupling efficiency reflects the selective expression of heteromeric GIRK2/3 channels and is dynamically modulated by a member of the regulator of G protein signaling (RGS) protein family. Moreover, repetitive exposure to GHB increases the GABA(B) receptor-GIRK channel coupling efficiency through downregulation of RGS2. Finally, oral self-administration of GHB at a concentration that is normally rewarding becomes aversive after chronic exposure. On the basis of these results, we propose a mechanism that might underlie tolerance to GHB