[Epigenetic effects of cannabis/tetrahydrocannabinol]. / Les effets épigénétiques du cannabis/tétrahydrocannabinol.

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. Such modifications caused by the tetrahydrocannabinol/THC of cannabis can intervene: either at the level of gametes before procreation, or at different points of the life cycle. These epigenetic modifications are associated with an increase in vulnerability to drug addiction, involving dopamine D2 receptors in the nucleus accumbens, overexpression of enkephalin precursor synthesis, modifications of: CB1 receptors of endocannabinoids, glutamic acid receptors, GABA receptors, proteins involved in synaptic plasticity… These changes can also affect: immune system, cognitive activities, development of psychiatric diseases, related to disturbances of brain maturation. The knowledge that accumulates in this respect is the opposite of the ambient trivialization of this drug. They impose sending an alert to the public authorities and to the public, especially young people, warning on the risks associated with this drug use and abuse.

[A new approach to antischizophrenic therapeutics: D2 dopamine receptor partial agonists]. / Une nouvelle approche de la prise en charge de la schizophrénie : les agonistes partiels des récepteurs D2 de la dopamine.

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.e. their spontaneous activity in the absence of dopamine stimulation). Thus they induce effects which are opposite to those of dopamine. Partial agonists, also called agonists-antagonists, induce intermediate effects between those of full agonists and neutral antagonists. Their intrinsic activity is the following (1>alpha>0>- 1) in the hierarchy: full agonist>partial agonist>neutral antagonist>inverse agonist. These partial agonists moderate the activity of hyperactive dopaminergic neurons (reducing positive expressions: delusion, hallucinations, agitation). They activate deficient dopaminergic transmissions, alleviating at least partly negative expressions. This approach is presently illustrated by aripiprazole: OP 4597. Many other molecules are candidates for such a therapeutic promotion, justified by the search for both antiproductive and antideficit activities, with a low incidence of adverse side effects such as extrapyramidal effects, thermoregulation effects, induction of late dyskinesias, sedation, bulimia, excessive weight, depressive symptoms, incitation to consume addictive drugs, hyperprolactinemia....

[A new pharmacological strategy for schizophrenia: the partial agonists of D2 dopaminergic receptors. The principle characteristics of aripiprazole]. / Nouvelle stratégie pharmacologique dans la schizophrénie : les agonistes partiels des récepteurs dopaminergiques D2. Caractéristiques principales de l'aripiprazole.

The D2 dopamine receptors play a pivotal role in the physiopathology of schizophrenia. Their over-stimulation in the limbic area, resulting from a hyperactivity of the mesolimbic dopaminergic neurones, is linked to positive expressions of the disease, whereas their lack of stimulation in cortical regions, depending on a hypoactivity of mesocortical dopaminergic neurones, underlies the negative expressions of the disease. Concerning the extrapyramidal side effects which emanate from treatments by neuroleptic drugs, they are triggered by the blockade of nigro-striatal dopaminergic transmissions. The ligands of D2 dopamine receptors can be characterized by their intrinsic activity (alpha). Dopamine, which is their physiological ligand, is a full agonist (alpha=1). On the contrary, neuroleptic drugs, by suppressing the constitutive activity of these receptors (spontaneous activity even without occupation by dopamine) are inverse agonists (alpha<0). Thus, they not only oppose the effects of dopamine but they also induce diametrically opposed effects. Between these extremes, are located the partial agonists, the so-called agonists-antagonists (1>alpha>0>-1), illustrated by OPC 14597=aripiprazole. This partial agonist, by stimulating D2 and D3 dopamine autoreceptors, moderates the functioning of hyperactive dopaminergic neurones. In addition, by taking the place of dopamine on D2 post-synaptic receptors, it changes their intense stimulation into a lesser one, which reduces positive expressions (delusions, hallucinations, agitation...). On the other hand, the occupation by aripiprazole of the D2 receptors that are not stimulated by dopamine (on account of an insufficient presynaptic dopaminergic activity) restores a certain amount of stimulation, which partly alleviates negative expressions of schizophrenia. Simultaneously to these actions, both on productive as well as on negative expressions of the disease, this agonist-antagonist is virtually devoid of several adverse effects developed by neuroleptic drugs (extrapyramidal side effects) and new antipsychotic drugs (hyperprolactinemia, sedation, late dyskinesia, modifications in thermoregulation, bulimia, overweight, depression...).

[Illicit drugs, medications and traffic accidents]. / Drogues, médicaments et accidentologie.

The European Union (EU) has 25 member-states and 455 million inhabitants. Statistics on traffic accidents in the EU show that more than 45,000 people are killed annually, including 5200 in France. At the same time, nearly two million persons in the EU require medical treatment for traffic-accident-related injuries, including 109,000 in France. In addition, traffic accidents are the major cause of death of those individuals aged 15 to 24 years. One third of the EU inhabitants will be hospitalized during their life due to a traffic accident with a cost over 160 billion euro (2-3% of the Gross Domestic Product). An important contributing factor to crashes is the use of alcohol and/or illicit drugs or medication when driving, as they exert negative effects on cognition and psychomotor functions. For illicit drugs, abuse of cannabis with or without alcohol is a major concern for the EU. In fact, three million Europeans use cannabis daily and 80% of them drive after use. A number of French studies since 1999 have underlined the high prevalence of cannabis found in the blood of injured or killed drivers. From medical or judicial observations, it is clear that cannabis use increases the risk of traffic accidents. Many groups outside Europe have also shown the association between drug abuse and crashes. The number of casualties related to certain medicines, especially benzodiazepines remains at a high level, particularly in the elderly. In many countries the prevalence of medicinal drugs associated with car accidents is higher than with cannabis. Annex III of the European Union Council Directive of July the 29th 1991 in fact states that a driving license should not be issued to or renewed for applicants or drivers who are dependent on psychotropic substances or use them regularly. Recently, France has categorized the medicinal drugs available in the country by using three pictograms: level one yellow, "be careful"; level two orange, "be very careful"; level three red, "don't drive". It is an important campaign that increases awareness among the public and the medical professionals about the potential dangerous effects of medicinal drugs when driving. The EU objective of reducing the number of fatalities to 25,000 by 2010 will require strengthening measures against the use of alcohol, illicit and medicinal drugs by not well-informed drivers. It is not only a really great challenge, but also a significant investment towards improving public health in France as well as in Europe.

[Neuropsychopharmacology of delta-9-tetrahydrocannabinol]. / Neuropsychopharmacologie du delta-9-tétrahydrocannabinol (THC).

Today, the main route of introduction of tetrahydrocannabinol (THC), the main active substance of cannabis, into the human body is via the lungs, from smokes produced by combustion of a haschich-tobacco mixture. The use of a water pipe (nargileh-like) intensifies its fast supply to the body. THC reaches the brain easily where it stimulates CB1 receptors; their ubiquity underlies a wide variety of effects. THC disappears from extracellular spaces by dissolving in lipid rich membranes, and not by excretion from the body. This is followed by a slow release, leading to long lasting effects originating from brain areas containing a large proportion of spare receptors ("reserve receptors"). Far from mimicking the effects of endocannabinoids, THC caricatures and disturbs them. It induces both psychical and physical dependencies, but the perception of withdrawal is weak on account of its very slow elimination. THC disturbs cognition. Acutely, it develops anxiolytic- and antidepressant-like effects, which causes a lot of users to abuse THC, thus leading to a tolerance (desensitization of CB1 receptors) making anxiety and depression to reappear more intensely than originally. THC has close relationships with schizophrenia. It incites to tobacco, alcohol and heroine abuses.

[Clinical potentialities and perspectives for the use of aripiprazole in other disorders than its classical indications. A critical analysis of the recent literature]. / Potentialités cliniques et perspectives d'utilisation de l'aripiprazole hors de ses champs classiques d'indication. Analyse critique des données de la littérature récente.

Aripiprazole is indicated for the treatment of schizophrenia in Europe and the United States, and for bipolar disorders in the latter. Nevertheless, a review of recent literature has shown that aripiprazole has been studied in many other disorders, notably resistant depression, anxiety, obsessive-compulsive disorder, borderline personality, Tourette syndrome, addiction, psychotic symptoms in children and adolescents, and neurological and psychiatric disorders in the elderly (late onset delusional disorders, Alzheimer, Parkinson, and delirium). The study of aripiprazole in these numerous indications is motivated by its excellent tolerance and original pharmacological effect (partial agonistic effect on the D2 and 5-HT1A receptors, and antagonistic effect on the 5-HT2A receptors). This paper reviews the recent literature, with particular attention paid to the level of proof provided by these various studies.

[Present data and treatment schedule of aripiprazole in the treatment of schizophrenia]. / Données actuelles et modalités d'utilisation de l'aripiprazole dans le traitement de la schizophrénie.

Among the second generation antipsychotics, aripiprazole presents a new pharmacological profile, basically differentiated by a partial agonist effect on the D2 and D3 dopaminergic receptors. Five short-term efficacy studies, conducted on 1648 patients presenting with schizophrenia or acute relapse of schizoaffective disorders, demonstrated the greater efficacy of aripiprazole than the placebo and comparable efficacy to that of haloperidol and risperidone. The short-term tolerance profile was characterised by a lesser incidence of the extrapyramidal side effects and drowsiness than with haloperidol. Two thousand six hundred and eighty five patients were followed-up over a period of 26 to 52 weeks in five clinical trials versus a placebo and haloperidol, olanzapine, quetiapine and risperiodone: demonstrated efficacy in maintaining the response to treatment and on the delay before relapse was comparable to the other antipsychotics. The classical side effects of antipsychotics decreased in the long-term. Versus olanzapine, a glucid and lipid profile, clearly in favour of aripiprazole, was completed by a lesser incidence of hyperprolactinaemia. Aripiprazole is effective on all the dimensions of schizophrenia: the positive and negative and depressive and anxious symptomatology. It appears to be of interest, notably on the cognitive dimension, which should motivate more in-depth exploration of its place in the treatment in the early stages of schizophrenia. Its therapeutic schedule and the methods of initiation are an essential criterion to the success of treatment, notably during the substitution of other antipsychotics. The clinical and pharmacological originality of aripiprazole would justify the terminology of a "third generation antipsychotic".

Effects of acute or 3-day treatments of Hypericum caprifoliatum Cham. & Schltdt. (Guttiferae) extract or of two established antidepressants on basal and stress-induced increase in serum and brain corticosterone levels.

Since depressive patients present alterations in the hypothalamo-pituitary-adrenal (HPA) axis that are normalised by antidepressants, this HPA axis has been considered as a target of their actions. We have investigated the mechanism of action of a cyclohexane extract of Hypericum caprifoliatum (HCP), which displays antidepressant like activity, by studying, in mice, the influence of HCP and of two established antidepressant drugs, imipramine and bupropion, administered either acutely or semi-chronically (once a day, three consecutive days), on serum and brain cortex corticosterone levels, either in basal conditions or shortly after a forced-swimming session (FSS). Administered acutely, imipramine (20 mg/kg, per os (p.o.)), bupropion (30 mg/kg, p.o.) and HCP (360 mg/kg, p.o.) significantly reduced the immobility time and had no effects on FSS-induced increase of serum and cortical corticosterone levels. Conversely, 3 days repeated treatment with imipramine or bupropion resulted in a significant reduction of immobility time and FSS-induced increase of serum and cortical corticosterone levels. In a different way, repeated treatment with HCP significantly reduced the immobility time and only cortical corticosterone levels in stressed mice. These results indicate that short-term treatments with antidepressants are sufficient to induce modifications in the HPA axis reactivity to stress; and that apparently HCP has an influence on corticosterone levels by a mechanism diverse from the other tested antidepressants.

The reduction in electric footshocks perception interferes with the amnesic effect of scopolamine.

In a passive avoidance paradigm, administration of scopolamine in mice seems to provoke forgetting of electric shocks they received when entering into the black compartment. We observed that, in fact, scopolamine reduced the shocks perception. Since, on the hot plate test, scopolamine did not affect latencies of avoidance reactions, this effect did not correspond to analgesia. Thus, in our experimental conditions, scopolamine effect did not exclusively result from a deficit of passive avoidance learning but likely resulted from its anti-sweating properties, thus reducing the shocks perception.

Influence of glial cells in the dopamine releasing effect resulting from the stimulation of striatal delta-opioid receptors.

Recent data indicate that striatal dopamine release induced by stimulation of delta-opioid receptors is a consequence of glutamate release. However, glial cells, which mainly support glutamate uptake and are involved in glutamate signaling and potentially express delta-opioid receptors, could participate to this effect. The present study investigates the contribution of glial cells in the releasing effects of [d-Pen2, d-Pen5]-enkephalin (DPDPE) by using the gliotoxin l-alpha-aminoadipate (l-alpha AA). Initially, we evaluated the early influence of l-alpha AA local infusion (10 microg/microL) on dialysate levels of glutamate and dopamine under basal or DPDPE treatment conditions. l-alpha AA produced a significant increase of glutamate and dopamine in dialysates (+76% and +50% respectively) and the concomitant infusion of DPDPE (10 microM) significantly enhanced this effect in an additive manner (+110% and +44% respectively). Secondly, we assessed the DPDPE effects on striatal glutamate and dopamine dialysate levels, 2 days after an intra-striatal injection of l-alpha AA which produced destruction of glial cells. This lesion, decreasing the basal glutamate dialysate level as well as its tissue content (by 55% and 36% respectively), prevented the increase in glutamate and dopamine extracellular levels induced by DPDPE. This result confirmed that the DPDPE-induced dopamine release requires an initial glutamate release. However, this effect could reflect a major disruption of glutamatergic transmission caused by the toxin, as suggested by the local infusion of glutamine (2.5 mM) which, in lesioned rats, prevented the decrease in the basal extracellular content of glutamate and restored the DPDPE-induced increase in glutamate and dopamine dialysate levels. Therefore, these results indicate that, although glial cells are essential to maintain functional glutamatergic neurotransmission, they are not directly involved in the process by which stimulation of striatal delta-opioid receptors induces extracellular glutamate release and, consecutively, dopamine release.

Comparisons between bupropion and dexamphetamine in a range of in vivo tests exploring dopaminergic transmission.

BACKGROUND AND PURPOSE: In the present study we investigated, in a range of in vivo tests whether the antidepressant bupropion, and its metabolites shared the dopamine releasing effect of the chemically related dexamphetamine. EXPERIMENTAL APPROACH: We compared bupropion and dexamphetamine in different neurochemical (microdialysis, DOPAC and HVA contents) and behavioural tests, assessing their effects in animals pretreated with a variety of agents (reserpine, sodium hydroxy-4-butyrate or haloperidol) known to modify dopaminergic transmission. KEY RESULTS: In mice, dexamphetamine, like bupropion, increased at low doses and reduced at high doses, locomotor activity. Dexamphetamine restored the locomotor activity in mice made akinetic by either sodium hydroxy-4-butyrate or reserpine, whereas bupropion did not. Moreover, bupropion prevented the dexamphetamine-induced reversal of akinetic effects of reserpine. Haloperidol abolished the locomotor-stimulant effects of dexamphetamine but did not suppress stimulation by bupropion. In microdialysis experiments, in chloral hydrate anesthetized rats, low doses of dexamphetamine (1 mg kg(-1)) markedly increased the extracellular dopamine concentration in striatum (340%), while bupropion (100 mg kg(-1)) produced only a moderate increase (150%). Finally, in rat striatum, as well as in the nucleus accumbens, bupropion increased the effect of haloperidol on DOPAC and HVA concentrations, whereas dexamphetamine reduced these haloperidol effects. CONCLUSIONS AND IMPLICATIONS: Considering only dopaminergic transmission, our results demonstrated that bupropion and metabolites displayed in vivo, as did bupropion in vitro, an inhibition of dopamine uptake and, contrast to dexamphetamine, were devoid of dopamine releasing effects.

[Neurobiology of cannabis--recent data enlightening driving disturbances]. / Le cannabis--données neurobiologiques récentes éclairant les perturbations de la conduite des véhicules.

During the last decades a new landscape of cannabis has been designed on account of: the increase in its use the greater youth of its users; the increase in the content of its main active constituent tetrahydrocannabinol (THC) and a lot of new epidemiological and neurobiological data. THC displays an exceptional lipophilicity, allowing its cerebral storage, leading to long lasting effects, by far more lasting than its presence in blood, and beyond the period throughout the intoxicated people feel a disablement. This is linked to its slow release from brain areas in which large proportion of spare receptors exists (reserve receptors). THC disturbs cognition and various skills required in driving. It may be responsible for psychiatric troubles: anxiety, depression, suicide attempt, psychotic attack, triggering of schizophrenia. It potentiates the alcohol effects and incites to alcohol drinking. It displays close relationships with dependence to heroin. This new landscape of cannabis urges to make a radical alteration in the public communication about this drug of abuse as it has yet collected so many troubles, accidents or tragedies.

Novel endomorphin-2 analogs with mu-opioid receptor antagonist activity.

A series of position 4-substituted endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) analogs containing 3-(1-naphthyl)-alanine (1-Nal) or 3-(2-naphthyl)-alanine (2-Nal) in L- or D-configuration, was synthesized. The opioid activity profiles of these peptides were determined in the mu-opioid receptor representative binding assay and in the Guinea-Pig Ileum assay/Mouse Vas Deferens assay (GPI/MVD) bioassays in vitro, as well as in the mouse hot-plate test of analgesia in vivo. In the binding assay the affinity of all new analogs for the mu-opioid receptor was reduced compared with endomorphin-2. The two most potent analogs were [D-1-Nal(4)]- and [D-2-Nal4]endomorphin-2, with IC50 values 14 +/- 1.25 and 19 +/- 2.1 nM, respectively, compared with 1.9 +/- 0.21 nM for endomorphin-2. In the GPI assay these analogs were found to be weak antagonists and they were inactive in the MVD assay. The in vitro GPI assay results were in agreement with those obtained in the in vivo hot-plate test. Antinociception induced by endomorphin-2 was reversed by concomitant intracerebroventricula (i.c.v.) administration of [D-1-Nal4]- and [D-2-Nal4]-endomorphin-2, indicating that these analogs were mu-opioid antagonists. Their antagonist activity was compared with that of naloxone. At a dose 5 microg per animal naloxone almost completely inhibited antinociceptive action of endomorphin-2, while [D-1-Nal4]endomorphin-2 in about 46%.

Binding of endomorphin-2 to mu-opioid receptors in experimental mouse mammary adenocarcinoma.

Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) binds with high affinity and selectivity to the mu-opioid receptor. In the present study, [125I]endomorphin-2 has been used to characterize mu-opioid-binding sites on transplantable mouse mammary adenocarcinoma cells. Cold saturation experiments performed with [125I]endomorphin-2 (1 nM) show biphasic binding curves in Scatchard coordinates. One component represents high affinity and low capacity (K(d) = 18.79 +/- 1.13 nM, B(max) = 635 +/- 24 fmol/mg protein) and the other shows low affinity and higher capacity (K(d) = 7.67 +/- 0.81 microM, B(max) = 157 +/- 13 pmol/mg protein) binding sites. The rank order of agonists competing for the [125I]endomorphin-2 binding site was [d-1-Nal3]morphiceptin > endomorphin-2 >> [d-Phe3]morphiceptin > morphiceptin > [d-1-Nal3]endomorphin-2, indicating binding of these peptides to mu-opioid receptors. The uptake of 131I-labeled peptides administered intraperitoneally to tumor-bearing mice was also investigated. The highest accumulation in the tumor was observed for [d-1-Nal3)morphiceptin, which reached the value of 8.19 +/- 1.14% dose/g tissue.

[Assessment of the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL)]. / Recherche d'une toxicité du 3,4-dihydroxyphénylacétaldéhyde (DOPAL) in vitro et in vivo.

This work was carried out in order to evaluate the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL). This aldehyde is formed from dopamine (DA) by monoamine oxidases (MAO) and is mainly oxidised to 3,4-dihydroxyphenylacetic acid by brain aldehyde dehydrogenases (ALDH), or eventually reduced to 3,4-dihydroxyphenylethanol by aldose/aldehyde reductases. In vitro, catecholaminergic SH-SY5Y cells were incubated with DA and disulfiram (DSF), an irreversible inhibitor of ALDH. As evidenced by MTT assays, a 24-h treatment with 10(-4) M DA and/or 10(-6) M DSF followed by a 24-h incubation in a drug-free medium evidenced that the toxicity of each of these drugs was potentiated by the second drug. HPLC measurements demonstrated that this drug association induced an early DOPAL production that could result in a delayed cell toxicity. For in vivo studies, male Sprague-Dawley rats were treated with L-DOPA-benserazide, which increases the production of DOPAL by MAO, and DSF. An acute injection of DSF (100mg/kg i.p.) and L-DOPA/benserazide (100mg/kg+25mg/kg, 24h later) significantly increased the DOPAL striatal level. However, a 30-day treatment with DSF (100mg/kg i.p., once every two days) and L-DOPA/benserazide (100mg/kg+25mg/kg, twice a day) did not affect both indexes used to assess the integrity of the nigro-striatal dopaminergic terminals (i.e. the striatal content in DA and the binding to the vesicular monoamine transporter on striatal membranes). These results do not support the hypothesis of a DOPAL toxicity and argue against the toxicity of L-DOPA therapy.

[Comments on an animal model of depression]. / A propos d'un modèle animal de la dépression.

Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its pathophysiology relies on the availability of experimental models potentially mimicking the disease. Here is presented a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increase pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal serum corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin1A autoreceptor stimulation induced greatest hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.