[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 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...).

[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....

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.

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.

[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".

[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.

[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.

[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.

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.

A different balance in the sensitivity of D1 and D2 dopamine receptors accounts for differences in apomorphine-induced hypothermic effects in Swiss and C3H mice.

In several strains of mice: Swiss CD1, BALB, DBA2, C57, the mixed D1/D2 direct dopamine receptor agonist, apomorphine, elicited a marked and virtually similar hypothermic effect. By contrast, in C3H mice, this effect was obviously less and shorter. Similarly, the hypothermic effects of two direct D2 dopamine agonists RU 24926 and piribedil were respectively lesser or absent in C3H, compared to Swiss CD1 mice. On the contrary, the hyperthermic effect of the D1 dopamine agonist SKF 38393 was greater in C3H than in Swiss CD1 mice. This unbalanced sensitivity of D1 and D2 dopamine receptors, involved in thermoregulation, likely accounts for the low responsiveness of C3H to the apomorphine-induced hypothermic effect.

Rapid and long lasting reduction of the hypothermic effect of a D2 dopamine agonist after an intracerebroventricular injection of 6-hydroxydopamine.

In mice pretreated intracerebroventricularly (i.c.v.) with 6-hydroxydopamine (6OHDA) (50 micrograms per mouse), as soon as the hypothermia elicited by the neurotoxin had vanished (3 hr), the hypothermic effect induced by the direct D2 dopamine receptor agonist RU 24926 (1 mg/kg, s.c.), was almost completely suppressed. This reduction in hypothermic effect was observed more than 1 month after the 6OHDA injection. On the 3rd day after 6OHDA injection, this reduction was observed for all tested doses of RU 24926 (0.25-2 mg/kg). It was prevented when an i.p. administration of the norepinephrine uptake inhibitor desipramine (20 mg/kg) was performed 30 min before the 6OHDA i.c.v. injection. It was not modified when an i.p. administration of the dopamine uptake inhibitor GBR 12783 (20 mg/kg) was performed 30 min before the 6OHDA i.c.v. injection. The 6OHDA i.c.v. injection modified significantly neither the dopamine nor the serotonin hypothalamic contents. On the contrary it resulted in a marked decrease (-73%) of the norepinephrine hypothalamic content, which was unchanged by the administration of GBR 12783 (20 mg/kg, i.p.) 30 min before 6OHDA, but completely prevented by desipramine (20 mg/kg, i.p.) 30 min before 6OHDA i.c.v. injection. It is concluded that the hypothermic effect resulting from the stimulation of D2 dopamine receptors involves a central norepinephrine transmission, which is very rapidly altered after 6OHDA administration.

The discriminant dopamine antagonist property of benzamides is observed at various times after their systemic or intracerebroventricular administration.

The cataleptogenic effect or the antagonism of apormorphine-induced behaviour (climbing, sniffing, licking and yawning) shown by haloperidol, (+/-)sulpiride and (+/-)amisulpride were determined at different times after their intraperitoneal or intraventricular administration. After intraperitoneal injection, the ED50 or ID50 of haloperidol was similar for all the behavioural responses. On the other hand, sulpiride and amisulpride were effective on climbing and yawning in smaller doses than on sniffing, licking and catalepsy. The property of amisulpride to antagonize climbing at smaller doses than sniffing was still found whether this benzamide derivative was injected 30, 90, 150 or 240 min before testing. After the intraventricular administration of neuroleptics, a dissociated antagonist efficacy appeared for haloperidol, but that of sulpiride and amisulpride became much more marked than after their intraperitoneal injection. Amisulpride antagonized climbing in smaller doses than sniffing, whether administered intraventricularly 15, 30 or 120 min before testing. These results indicate that the dissociated dopamine antagonist efficacy of benzamides is long lasting and is observed even when the passage across the blood-brain barrier is avoided (i.c.v. route).

Histamine-induced rise in core temperature of chloral-anaesthetized rats: mediation by H2-receptors located in the preopticus area of hypothalamus.

Intracerebroventricular (i.c.v.) administration of histamine in chloral anaesthetized rats exposed to an ambient temperature of 22 C elicited a rise in their colonic temperature associated with a shivering. This effect was shared by the H2 receptor agonists dimaprit and impromidine. Impromidine is, in this respect, a partial agonist with an ED50 much lower than histamine. The histamine-induced rise in core temperature was antagonized by cimetidine administered either centrally (in doses of 25-40 micrograms, i.c.v.) or peripherally (large doses greater than or equal to 50 mg/kg i.p.) This constitutes an indication for the crossing of the blood-brain barrier by cimetidine. The H2 histamine receptors involved in this effect seem to be located mainly in the preopticus medialis nucleus (p.o.m.n.) of the hypothalamus since bilateral microinjections of histamine (5 ng) into this nucleus induced the effect, whereas cimetidine injected into the p.o.m.n., antagonised the relative hyperthermia elicited by an intracerebroventricular administration of histamine.

Mechanism of the hypothermic effect of MPP+ administered centrally in mice.

The neurotoxin methyl phenyl pyridinium (MPP+) was administered intracerebroventricularly (i.c.v.) to mice. From the 1.25 microg dose per mouse, MPP+ elicited a dose-dependent hypothermic effect from doses as low as 1.25 microg per mouse. The minimal lethal dose was determined to be between 17.5 and 20 microg per mouse. The hypothermia induced by 2.5 microg MPP+ was unaffected by pretreatment with propranolol (8 mg/kg, i.p.), scopolamine (5 mg/kg, s.c.) and haloperidol (250 microg/kg, i.p.). It was decreased by yohimbine (4 mg/kg, s.c.), idazoxan (5 mg/kg, s.c.) and desipramine (20 mg/kg, i.p.). In mice injected i.c.v. with 6 hydroxydopamine (50 microg, 8 days before testing with MPP+ 2.5 microg), a significant reduction in the hypothermic effect of MPP+ was observed. A similar 6 OHDA injection has been shown previously to reduce by about 40% the DA striatal content of DA and by about 70% the hypothalamic content of NE. On the contrary, in mice injected with MPP+ (17.5 microg, 8 days before testing with 50 microg 6 OHDA) there was no modification in the hypothermic effect of 6 OHDA (50 microg). This injection of MPP+ reduced by about 40% the striatal content of DA but did not affect the hypothalamic content of NE. It is concluded that MPP+ decreases body temperature, at least in part, by acting as an indirect NE agonist, which stimulates alpha2 adrenoreceptors. In contrast, this agent in the present experimental conditions, does not destroy NE neurons in opposition to its action on DA neurons.

Antagonism of the apomorphine-induced yawning by "atypical" neuroleptics.

In relatively small doses, the four "atypical" neuroleptics, sulpiride, clozapine, thoiridazine and mezilamine were effective antagonists of apomorphine-induced yawning in rats. Of the four drugs, used in doses which inhibited apomorphine-induced yawning almost completely, only clozapine also antagonized yawning induced by physostigmine. Therefore it appears that the antagonism of this effect of apomorphine, already reported for classical neuroleptic agents, is also shown by "atypical" ones. By combining apomorphine- and physostigmine-induced yawning, it is possible to assess the anticholinergic component in the antagonism of this effect of apomorphine and this may be of value for the understanding of the mechanisms underlying the "atypical" character.

Chronic inhibition of enkephalinase induces changes in the antinociceptive and locomotor effects of the enkephalinase inhibitor acetorphan in rats.

The enkephalinase inhibitor thiorphan was infused intracerebroventricularly in rats during 14 days (25 micrograms/5 microliters/hr), inducing an average inhibition of cerebral enkephalinase of about 65%. Animals were tested during the infusion for their response to acetorphan, a parenterally active derivative of thiorphan. When administered intravenously on day 8 of the infusion, acetorphan (5 mg/kg) significantly increased locomotion in chronic saline-infused rats but not in animals receiving thiorphan. Furthermore, when injected at the same dose on day 10, acetorphan did not modify the latency to jump, in the hot plate test, in thiorphan-treated rats, whereas it elicited a significant analgesia in chronic saline-treated controls. These data show that the effects induced by the administration of an enkephalinase inhibitor were diminished after a period of chronic inhibition of the enzyme, suggesting the development of tolerance.