RÉSUMÉ
Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.
Sujet(s)
Neuroleptiques/pharmacologie , Dronabinol/pharmacologie , Réflexe de sursaut/effets des médicaments et des substances chimiques , Stimulation acoustique , Animaux , Dopamine/métabolisme , Halopéridol/pharmacologie , Inhibition psychologique , Mâle , Souris , Noyau accumbens/effets des médicaments et des substances chimiques , Noyau accumbens/métabolisme , Pipéridines/pharmacologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Pyrazoles/pharmacologie , Rimonabant , Rispéridone/pharmacologie , Test du rotarodRÉSUMÉ
The present study was undertaken to investigate the antagonistic effects of the methanolic extract of Polygala telephioides (PT) on morphine responses in mice. Single administration of PT tended to antagonize the morphine-induced analgesia in a hot-plate test. Moreover, PT (300 mg/kg, p.o.) improved the morphine-induced memory impairment in an elevated plus maze test. However, PT alone had no effect on behaviors in the open-field, hot-plate and elevated plus maze tests. We investigated the effects of PT on naloxone-induced jumping (as withdrawal sign) in morphine-dependent mice. To induce dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. Co-administrations of PT (10, 100 and 300 mg/kg, p.o.) during repeated morphine treatments significantly suppressed the naloxone (10 mg/kg, i.p.)-induced jumping. However, the naloxone-induced jumping was not affected by a single large administration of PT on the 5th day. The inhibitory effect of PT on the naloxone-induced jumping was due to the development of dependence rather than expression of withdrawal sign. Moreover, single administration of PT (30 mg/kg, p.o.) decreased the morphine levels in plasma. These results indicate that PT may be useful in facilitating narcotic detoxification.
Sujet(s)
Méthanol/pharmacologie , Morphine/pharmacologie , Antagonistes narcotiques/pharmacologie , Polygala , Temps de réaction/effets des médicaments et des substances chimiques , Animaux , Relation dose-effet des médicaments , Mâle , Souris , Souris de lignée C57BL , Antagonistes narcotiques/isolement et purification , Mesure de la douleur/effets des médicaments et des substances chimiques , Mesure de la douleur/méthodes , Extraits de plantes/isolement et purification , Extraits de plantes/pharmacologie , Temps de réaction/physiologieRÉSUMÉ
RATIONALE: Recently, Delta(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and synthetic cannabinoid receptor agonists reportedly reduced the head-twitches induced by the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI) in mice, which is mediated via the activation of 5-HT(2A) receptor. However, the effect of endogenous cannabinoid anandamide on the head-twitch response has not been studied. OBJECTIVES: In this study, we investigated the effect of anandamide on the DOI-induced head-twitch response in mice. METHODS: Five minutes after the injection of DOI (5 mg/kg IP), the number of head-twitches was counted for a 5-min period. THC or anandamide was injected IP 60 min or 10 min before the number of head-twitches was counted, respectively. RESULTS: THC and anandamide each reduced the DOI-induced head-twitch response. The inhibition of the DOI-induced head-twitch response by THC was reversed by SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), a CB(1) receptor antagonist, while the effect of anandamide was not blocked by SR141716A. Cyclooxygenase (COX) inhibitors such as aspirin and indomethacin reversed the inhibition of the DOI-induced head-twitch response by anandamide. On the other hand, COX inhibitors did not affect the inhibition of the DOI-induced head-twitch response by THC. CONCLUSIONS: Taken together, these findings suggest that the endocannabinoid anandamide may inhibit 5-HT(2A) receptor-mediated function via the arachidonic acid cascade, but not via a direct interaction with the CB(1) cannabinoid receptor, and that the mechanism of its action is clearly different from that of THC.