[Cannabis in France, new insights]. / La situation actuelle du cannabis en France.

France holds the record for cannabis use in Europe, especially among adolescents. This drug of abuse is thus mainly used during a very sensitive period of brain development, education, vehicle driving and development of life projects. In addition, synthetic derivatives of tetrahydrocannabinol (THC), which are more noxious than cannabis itself are now appearing on the market. Traficking and cultivation for personnal use have intensified; products proposed for sale are richer in THC; and some methods of consumption (e-cigarettes, vaporizers, water pipes) increase the supply of THC to the lungs and thence to the body and brain. It is in this context that attempts are being made to legalize this drug of abuse. Other attempts are made to disguise it as a medication. Meanwhile, the list of its psychic as well as physical damages grows longer, with some very severe cases of major injuries. This evolution takes place in spite of numerous warnings expressed by the French Academy of Medicine. Subsequently, it is prompted to carefully and vigorously denounce these events. This will be the aim of this thematic session.

[Neurobiology of endocannabinoids and central effects of tetrahydrocannabinol contained in indian hemp]. / Neurobiologie des endocannabinoïdes-- mise en relation avec les effets du tétrahydrocannabinol du chanvre indien.

Tetrahydrocannabinol, the main psychotropic component of Cannabis indica, is an addictive drug with multiple effects including both peripheral and central damages. All these effects are due to interference with endocannabinoidergic transmission. This endocannabinoid system subtly regulates many physiologicalfunctions. This regulation involves various ligands derived from arachidonic acid (anandamide, di-arachidonoylglycerol, virodhamin, noladin ether, N arachidonoyl dopamine, etc.) which stimulate two main types of receptor CB1 in the central nervous system and CB2 in the periphery. CB1 receptors are very numerous and ubiquitous in the brain. They influence various important functions (awakening, attention, delirium, hallucinations, memory, cognition, anxiety, humor stability, motor coordination, brain maturation, etc.). Far from mimicking endocannabinoids, THC caricatures their effects. It affects all brain structures, simultaneously, intensely and durably, inducing down-regulation of CB1 receptors and thereby reducing the effects of their physiological ligands. On account of its exceptional lipophilia, THC accumulates for days and even weeks in the brain. It is not a soft drug but rather a slow drug: its abuse induces long-lasting modifications and deterioration of brain function, potentially leading to various mental and psychiatric disorders.

The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial.

OBJECTIVE: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients. METHODS: Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. RESULTS: The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02). INTERPRETATION: The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined.

[Treatment of insomnia. Pharmacological approaches and their limitations]. / Le traitement de i'insomnie. Les possibilités pharmacologiques et leurs limites.

Far more people complain of inadequate sleep than of true insomnia warranting prescription of a hypnotic drug. The number of available hypnotics has fallen markedly in recent years. Numerous brain areas, transmitters and receptors are involved in sleep. Currently, the main hypnotics (benzodiazepine derivatives and the so-called 4Z group. Zolpidem, Zopiclone, EsZopiclone and Zaleplon) increase GABAergic transmission by acting on components of chloride channels, thereby inducing Cl entry to neurons and resulting in their hyperpolarisation. This pre-eminence of GABAergic transmission should not make us ignore other important transmitters and their receptors as potential targets for new hypnotic drugs; these include histamine (and H1 receptors), dopamine (D1 and D2), norepinephrine (alpha1), serotonin (5HT2), glutamate (NMDA), acetylcholine (nicotinic), hypocretin (OX1 and OX2), melatonin (MLT1 and MLT2), prostaglandin E2 (EP), prostaglandin D2 (DP1), and endocannabinoids (CB1). Knowledge of the pharmacodynamic, pharmacokinetic and clinical characteristics of current hypnotic drugs has allowed us to establish the profile of an ideal hypnotic for the future.

Regulation of feeding and anxiety by alpha-MSH reactive autoantibodies.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a stress-related neuropeptide involved in the regulation of motivated behavior, appetite and emotion including stimulation of satiety and anxiety. Although autoantibodies (autoAbs) reactive with alpha-MSH have been identified in human subjects and in rats, it remained unknown if these autoAbs are involved in the regulation of feeding and anxiety and if their production is related to stress. Here we show that repeated exposure of rats to anxiolytic mild stress by handling increases the levels and affinity of alpha-MSH reactive IgG autoAbs and that these changes are associated with adaptive feeding and anxiety responses during exposure of rats to a strong stress by food restriction. Importantly, an increase in affinity of alpha-MSH reactive autoAbs was associated with changes of their functional roles from stimulation to inhibition of alpha-MSH-mediated behavioural responses, suggesting that these autoAbs can be a carrier or a neutralizing molecule of alpha-MSH peptide, respectively. Using a model of passive transfer into the brain, we show that alpha-MSH autoAbs affinity purified from blood of rats exposed to repeated mild stress, but not from control rats, are able to increase acutely food intake, suppress anxiety and modify gene expression of hypothalamic neuropeptides in naïve rats. These data provide the first evidence that autoAbs reactive with alpha-MSH are involved in the physiological regulation of feeding and mood, supporting a further role of the immune system in the control of motivated behavior and adaptation to stress.

Synthesis, radiosynthesis and biological evaluation of 1,4-dihydroquinoline derivatives as new carriers for specific brain delivery.

In spite of numerous reports dealing with the use of 1,4-dihydropyridines as carriers to deliver biological active compounds to the brain, this chemical delivery system (CDS) suffers from poor stability of the 1,4-dihydropyridine derivatives towards oxidation and hydration reactions seriously limiting further investigations in vivo. In an attempt to overcome these limitations, we report herein the first biological evaluation of more stable annellated NADH models in the quinoline series as relevant neuroactive drug-carrier candidates. The radiolabeled 1,4-dihydroquinoline [(11)C] was prepared to be subsequently peripherally injected in rats. The injected animals were sacrificed and brains were collected. The radioactivity measured in rat brain indicated a rapid penetration of the carrier [(11)C] into the CNS. HPLC analysis of brain homogenates showed that oxidation of [(11)C] into the corresponding quinolinium salt [(11)C] was completed in less than 5 min. An in vivo evaluation in mice is also reported to illustrate the potential of such 1,4-dihydroquinoline derivatives to transport a neuroactive drug in the CNS. For this purpose, gamma-aminobutyric acid (GABA), well known to poorly cross the brain blood barrier (BBB) was connected to this 1,4-dihydroquinoline-type carrier. After i.p. injection of 1,4-dihydroquinoline-GABA derivative in mice, a significant alteration of locomotor activity (LMA) was observed presumably resulting from an enhancement of central GABAergic activity. These encouraging results give strong evidence for the capacity of carrier-GABA derivative to cross the BBB and exert a pharmacological effect on the CNS. This study paves the way for further progress in designing new redox chemical delivery systems.

Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.

This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.

Evidence for the involvement of the adenosine A(2A) receptor in the lowered susceptibility to pentylenetetrazol-induced seizures produced in mice by long-term treatment with caffeine.

Long-term caffeine intake has been reported to decrease the susceptibility to convulsants in mice. Occurrence of seizures following long-term oral administration of caffeine (0.3g/l) was investigated using adenosine A(2A) receptor knockout (A(2A)R KO) and control (A(2A)R WT) mice. Clonic seizures induced by acute pentylenetetrazol (PTZ, 50mg/kg i.p.) were significantly attenuated in adenosine A(2A)R KO mice drinking only water and reduced by a 14-day caffeine treatment in adenosine A(2A)R WT mice. In addition we showed a protecting effect of a 21-day caffeine treatment in A(2A)R WT mice against kindled seizures induced by PTZ in an increasing dose schedule. Summing up, these protective effects against PTZ-induced seizures occurring when adenosine A(2A)R is absent or chronically blocked by a relevant dose of caffeine may be related to a decreased neuronal excitability.