[Epigenetic effects of cannabis/tetrahydrocannabinol].

The almost pandemic spread of cannabis among adolescents and young adults, especially in France, justifies the attention given to the consequences, not only acute but also delayed, of this intoxication. In the latter case, epigenetic mechanisms occur. We will first recall various types of epigenetic modifications involving either chromatin histones, mainly methylations or acetylations, either DNA, by methylation of cytosines.

[Neurobiology of endocannabinoids and central effects of tetrahydrocannabinol contained in indian hemp].

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.

[Cannabis in France, new insights].

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.

Differential involvement of anxiety and novelty preference levels on oral ethanol consumption in rats.

Rationale: Drug addiction is defined as a recurring cycle of intoxication, abstinence and relapse. The behavioural trait of novelty seeking is frequently observed in alcohol abusers. Moreover, converging evidence indicates that anxious individuals are also predisposed to alcohol abuse.

Acute and subchronic treatments with selective serotonin reuptake inhibitors increase Nociceptin/Orphanin FQ (NOP) receptor density in the rat dorsal raphe nucleus; interactions between nociceptin/NOP system and serotonin.

Nociceptin/Orphanin FQ is the endogenous ligand of NOP receptor, formerly referred to as the Opioid Receptor-Like 1 receptor. We have previously shown that NOP receptors were located on serotonergic neurons in the rat dorsal raphe nucleus, suggesting possible direct interactions between nociceptin and serotonin in this region, which is a target for antidepressant action. In the present study, we investigated further the link between Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant treatments and the nociceptin/NOP receptor system.

[Treatment of insomnia. Pharmacological approaches and their limitations].

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.

Rational design of a low molecular weight, stable, potent, and long-lasting GPR103 aza-β3-pseudopeptide agonist.

26RFa, a novel RFamide neuropeptide, is the endogenous ligand of the former orphan receptor GPR103. Intracerebroventricular injection of 26RFa and its C-terminal heptapeptide, 26RFa((20-26)), stimulates food intake in rodents. To develop potent, stable ligands of GPR103 with low molecular weight, we have designed a series of aza-β(3)-containing 26RFa((20-26)) analogues for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca(2+)](i) in GPR103-transfected cells.

Influence of corticostriatal δ-opioid receptors on abnormal involuntary movements induced by L-DOPA in hemiparkinsonian rats.

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease induces in time numerous side effects, such as abnormal involuntary movements called L-DOPA-induced dyskinesias (LIDs). An involvement of glutamate transmission, dopamine transmission and opioid transmission in striatal output pathways has been hypothesized for the induction of LIDs. Interestingly, our previous experiments indicated that some striatal δ-opioid receptors are located on terminals of glutamatergic corticostriatal neurons and that stimulation of these receptors modulates the release of glutamate and dopamine.

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs.

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.

Effect of potent endomorphin degradation blockers on analgesic and antidepressant-like responses in mice.

The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs.

Structure-activity relationships of a series of analogues of the RFamide-related peptide 26RFa.

26RFa is a new member of the RFamide peptide family that has been identified as the endogenous ligand of the orphan GPCR GPR103. As the C-terminal heptapeptide (26RFa((20-26))) mimics the action of the native peptide on food intake and gonadotropin secretion in rodents, we have synthesized a series of analogues of 26RFa((20-26)) and measured their potency to induce [Ca(2+)](i) mobilization in Gα(16)-hGPR103-transfected CHO cells. Systematic replacement of each residue by an alanine (Ala scan) and its D-enantiomer (D scan) showed that the last three C-terminal residues were very sensitive to the substitutions while position 23 tolerated rather well both modifications.

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.

Erythrocytes catechol-o-methyl transferase activity is up-regulated after a 3-month treatment by entacapone in parkinsonian patients.

Objectives: Entacapone is a highly potent, reversible, peripherally acting catechol-O-methyl transferase (COMT) inhibitor that is used as an adjunct to L-dopa in the treatment of patients with Parkinson disease (PD). Nevertheless, the consequence of the long-lasting inhibition of COMT by entacapone has never been investigated. We assessed the variation of the soluble red blood cell (S-RBC)-COMT activity after 3 months of chronic treatment by entacapone.

Structural and pharmacological characteristics of chimeric peptides derived from peptide E and beta-endorphin reveal the crucial role of the C-terminal YGGFL and YKKGE motifs in their analgesic properties.

Peptide E (a 25-amino acid peptide derived from proenkephalin A) and beta-endorphin (a 31-amino acid peptide derived from proopiomelanocortin) bind with high affinity to opioid receptors and share structural similarities but induce analgesic effects of very different intensity. Indeed, whereas they possess the same N-terminus Met-enkephalin message sequence linked to a helix by a flexible spacer and a C-terminal part in random coil conformation, in contrast with peptide E, beta-endorphin produces a profound analgesia. To determine the key structural elements explaining this very divergent opioid activity, we have compared the structural and pharmacological characteristics of several chimeric peptides derived from peptide E and beta-endorphin.

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.

[A new approach to antischizophrenic therapeutics: D2 dopamine receptor partial agonists].

Since chlorpromazine was described, antischizophrenic therapeutics have been enriched with various other D2 dopamine receptors antagonists, either neuroleptics (which develop extrapyramidal side effects) or non neuroleptic antipsychotics (devoid of extrapyramidal side effects when used at effective doses against psychotic expressions). The latter drugs display such properties on account of several associated pharmacological activities (D3 receptors antagonism more efficient than D2 antagonism; antagonism at cholinergic muscarinic receptors; antagonism at 5HT2 serotonin receptors). All these antipsychotic drugs are not, as initially described, neutral antagonists of D2 receptors, but are in fact inverse agonists (alpha<0), because they suppress the constitutive activity of these receptors (i.

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.