Background and purpose: Drugs targeting brain k-opioid receptors produce profound alterations in mood. In the present study we investigated the possible anxiolytic-and antidepressant-like effects of the k-opioid receptor agonist salvinorin A, the main active ingredient of Salvia divinorum, in rats and mice. Experimental approach: Experiments were performed on male Sprague-Dawley rats or male Albino Swiss mice. The anxiolytic-like effects were tested by using the elevated plus maze, in rats. The antidepressant-like effect was estimated through the forced swim (rats) and the tail suspension (mice) test. k-Opioid receptor involvement was investigated pretreating animals with the k-opioid receptor antagonist, nor-binaltorphimine (1 or 10 mg·kg ). Salvinorin A reduced fatty acid amide hydrolase activity in amygdala but had very weak affinity for cannabinoid CB1 receptors.
Conclusions and implications:The anxiolytic-and antidepressant-like effects of Salvinorin A are mediated by both k-opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.
Taken together, these results indicate that salvinorin A, as is sometimes reported in humans, exhibits rewarding effects, independently from its motor activity, suggesting the usefulness of the zebrafish model to study addictive behavior. These effects appear mediated by activation of both kappa-opioid and cannabinoid CB(1) receptors.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal form of epilepsy characterized by seizures occurring during non-REM sleep. We have developed and characterized the first mouse model for ADNFLE type III carrying the V287L mutation of the beta2 subunit of neuronal nicotinic receptor. Mice expressing mutant receptors show a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant beta2 subunit is driven by a neuronal-specific tetracycline-controlled promoter, which allows planned silencing of transgene expression in a reversible fashion and tracking the involvement of mutant receptor in crucial phases of epileptogenesis. We found that restricted silencing during development is sufficient to prevent the occurrence of epileptic seizures in adulthood. Our data indicate that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.
1 Recently, a potential neuroprotective effect of rimonabant, independent of the CB 1 receptor interaction, has been proposed. In the present study, the role of transient receptor potential channel vanilloid subfamily member 1, named VR 1 , on neuroprotective effect of rimonabant, on global cerebral ischemia in gerbils, was investigated. 2 Rimonabant (0.05-3 mg kg À1 ), given i.p. 5 min after recirculation, dose dependently antagonized the ischemia-induced decrease in electroencephalographic (EEG) total spectral power and restored relative frequency band distribution 7 days after ischemia. 3 Rimonabant (0.125-0.5 mg kg À1 ) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. 4 At 7 days after ischemia, the survival of pyramidal cells, in the CA 1 subfield, was respectively 91 and 96%, in the animals given rimonabant 0.25 and 0.5 mg kg À1 , compared to the vehicle group. Higher doses were not protective. 5 The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg À1 . 6 Capsazepine (0.01 mg kg À1 ), a selective VR 1 vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA 1 hippocampal neuronal loss. 7 These findings suggest that VR 1 vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.
Background and purpose: It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB 1 ) agonist, D 9 -tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil. Experimental approach: The effects of AM 404 (0.015-2 mg kg À1 ) and THC (0.05-2 mg kg À1 ), given 5 min after ischaemia, were measured from 1 h to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA 1 neuronal count. Key results: Over the dose range tested, AM 404 (2 mg kg À1 ) and THC (1 mg kg À1 ) completely reversed the ischaemiainduced behavioural, EEG and histological damage. Only THC (1 and 2 mg kg À1 ) induced a decrease of body temperature. Pretreatment with the selective CB 1 receptor antagonist, AM 251 (1 mg kg À1 ) and the opioid antagonist, naloxone (2 mg kg À1 ) reversed the protective effect induced by both AM 404 and THC while the TRPV 1 vanilloid antagonist, capsazepine (0.01 mg kg À1 ), was ineffective. Conclusions and implications: Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB 1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies.
Abstract. We examined the toxicity of cocatropine (cocaine / atropine mixture) and the therapeutic potential of diazepam on some behavioral and physiological parameters in rats. Atropine (20 and 60 mg / kg) or cocaine (40 mg / kg) alone did not induce any seizure or death, but the combination significantly increased both, after both acute and binge treatment. There was a significant increase of EEG mean total spectral power in cocatropine-in comparison with cocaine-treated animals. Hyperlocomotion was observed in non-seizuring rats treated with cocaine or cocatropine. Cocaine, atropine 60, and cocatropine (40 + 20 and 40 + 60) all induced hyperthermic effects in non-seizuring rats, while cocatropine (40 + 60)-seizuring animals had hypothermia. An initial hypertensive and tachycardiac effect within 15 min was followed by a secondary fall in the cocatropine (40 + 60) group. Cocatropine toxicity was partially or fully reversed by diazepam (5 mg / kg), given intraperitoneally after the first seizure. The present findings provide, for the first time, details of a synergistic toxic effect of the cocaine / atropine mixture and of the potential of diazepam for treating cocatropine-related hospital emergencies.
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