1,721,265 research outputs found
Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats
No full textCannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CBI cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit. Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade
Endocannabinoids and 3,4-methylenedioxymethamphetamine (MDMA) interaction
No full textCannabis and MDMA are two of the most widely used recreational drugs. This review considered their neuropsychological
effects, when taken singly or in combination,
in humans or animals. In humans, prolonged use of MDMA and cannabis together is associated with a variety of psychological problems, including elevated impulsiveness,
anxiety, somatic complaints, obsessive–compulsive patterns,and psychotic behavior. It is not clear to what extent the combination of MDMA and cannabis contributes to fatal motor vehicles accidents though an additive adverse effect on visual perception in MDMA/D9-THC users has been reported. Neurocognitive deficits (memory, learning, word fluency, speed of processing, and manual dexterity) in several brain areas (hippocampus, frontal lobe) have been
reported in those taking both drugs. Endocrine abnormalities in MDMA users have been closely related to their use of
cannabis too. A recent study investigated whether coadministered cannabinoids and MDMA in rats affected the long-term neurotoxic properties of MDMA through a hypothermic action, an antioxidant action, or both. Very
few studies have set out to clarify the consequences of chronic exposure to concomitant cannabinoids and MDMA
for their abuse liability in animals. MDMA showed some cross-discriminative stimulus effects with cannabinoids (delta9-THC), and it has been demonstrated in rats that the
endocannabinoid system is involved in MDMA selfadministration.However, these findings have not been confirmed by microdialysis studies in mesolimbic structures
which might further clarify this interaction.
These findings may help explain the use of marijuana and MDMA together by polydrug users in order to overcome the unpleasant effect which often arise as the
initial euphoria dissipates. It has recently been confirmed,using a CPP task, that the endocannabinoid system is involved when the reinforcing properties of MDMA, given
centrally, were blocked by pretreatment with SR 141716
Eptastigmine : ten years of pharmacology, toxicology, pharmacokinetic, and clinical studies
No full textEptastigmine (heptyl-physostigmine tartrate) is a carbamate derivative of physostigmine in which the carbamoylmethyl group in position 5 of the side chain has been substituted with a carbamoylheptyl group. In vitro and ex vivo results suggest that eptastigmine has a long-lasting reversible brain cholinesterase (i.e., acetylcholinesterase and butyryl-cholinesterase) inhibitory effect. When administered in vivo to rodents by various routes, eptastigmine inhibits cerebral acetylcholinesterases (AChE) and increases acetylcholine (Ach) brain levels by 2500-3000%, depending on the dose. This effect leads to an improvement in the cerebral blood flow in the ischemic brain, excitatory and inhibitory effects on the gastrointestinal tract and to a protection from acute soman and diisopropylfluorophosphate intoxication. Eptastigmine, by either acute or chronic administration, has been found to have memory enhancing effects in different species of normal, aged and lesioned animals. It also restored to normal the age-related increase of EEG power without affecting spontaneous motor activity. Clinical investigations on more than 1500 patients with Alzheimer's disease demonstrated that eptastigmine significantly improved cognitive performance (as assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale) as compared with placebo. This improvement was most evident in patients with more severe cognitive impairment at the baseline. The relationship between patient performance and average steady-state AChE inhibition was described by an inverted U-shaped dose-response curve. Pharmacokinetic studies have revealed that after oral administration eptastigmine is rapidly distributed to the tissues and readily enters the CNS, where it can be expected to inhibit AChE for a prolonged period. Eptastigmine is generally well tolerated and the majority of adverse events (cholinergic) were mild to moderate in intensity. However, the adverse hematologic (granulocytopenia) effects reported in two studies have resulted in the suspension of further clinical trials
Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors
No full textRationale: The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied. Objectives: Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated. Methods: Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1–20 mg/kg), PMA (0.0005–2 mg/kg), or MDMA (0.5–160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025–2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated. Results: MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor. Conclusion: Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens
Eptastigmine restores the aged rat's normal cortical spectral power pattern
No full textWe studied the ability of eptastigmine, a second-generation acetylcholinesterase inhibitor (AChEI), to reverse the age-related increase of electroencephalogram (EEG) mean cortical spectral power in slow-wave delta activity and decrease in fast-wave alpha and beta activity. The relative basal spectral power profile evaluated for 50 min of the old (27-30 months) in comparison to young (4-6 months) awake rats was consistently different, showing a significant increase in delta (0.2-4.0 Hz) frequency and a significant decrease of alpha (8.2-13.0 Hz) and beta (13.2-25.0) bands. When 0.5, 1, 2, 4 mg kg(-1) of eptastigmine were administered orally as single increasing doses for old and young rats 2 h prior to the EEG recordings, lasting 2 h, the relative mean spectral power difference (Delta%) showed a linear log dose-related decrease in 6 activity and a progressive increase in a and beta activity in old rats. Compared to vehicle, in young rats, the eptastigmine dose of 0.5 mg kg(-1) produced a significant decrease in 6 activity and an increase in beta activity. The spontaneous motor activity, evaluated through cumulative horizontal and vertical counts for 30 min in old rats was significantly decreased when compared to young rats. Single oral treatment with eptastigmine (0.5 mg kg(-1) for young and 2 mg kg(-1) for old rats) given 2 h before the test did not significantly change motor activity in comparison to vehicle group of the same age. These results suggest a possible strategy to alleviate the severe slowing of neocortical EEG accompanying the cognitive decline
Eptastigmine improves eight-arm radial maze performance in aged rats
No full textEptastigmine, a potent and long-lasting cholinesterase inhibitor on age-related memory deficits, was studied. Four groups of 3-, 18-, 23- and 27-month-old Wistar rats were first submitted to spontaneous motor activity evaluation and then trained in an eight-arm radial maze until they reached the criterion. The effect of introducing a 2-h delay between the fourth and fifth choices was then evaluated under the influence of acute oral dose of eptastigmine (0.5mgkg−1 ) 120 min before the test. Eptastigmine reversed the impairment observed in vehicle-treated rats at all the tested ages. Two naive groups of 3- and 18-month-old rats were treated twice a day for 30 days with eptastigmine ( 0.25 mgkg−1p.o.) or vehicle and trained daily in the maze. Subchronic administration did not affect the performance in young rats, while in 18-month-old rats, the mean number of days needed to reach the criterion decreased and the percentage of animals reaching the criterion increased when compared to the vehicle group. The 18-month-old rats (ex-eptastigmine and ex-vehicle) were then allowed to age in their home cage without any further treatment for an additional 5 and 9 months, until they reached 23 and 27 months. The ex-eptastigmine rats tested at 23 months, without any treatment, showed better performance than that observed in ex-vehicle rats. When the same rats were tested again at 27 months of age, no difference was seen in comparison with ex-vehicle rats. Eptastigmine might, therefore, be helpful for correcting age-related memory impairment attributed to cholinergic hypofunction
Role of the endocannabinoid system in MDMA intracerebral self-administration in rats
No full textI.c.v. self-administration of MDMA (0.01-2 μg per infusion), alone and in combination with CP 55,940 (0.4 μg infusion -1), was studied on an operant responding procedure. On the basis of individual preference for one of two levers, developed during training, rats were allowed to self-administer vehicle from the preferred lever and MDMA from the other. Pressings on the MDMA associated-lever, except for the maximal unit dose, progressively increased. The combination of CP 55,940 with MDMA (1 μg infusion -1) reduced the number of drug-associated lever pressings compared to the single drugs. Pre-treatment with SR 141716A (0.5 mg kg -1 i.p.), 15 min before each daily session, significantly increased MDMA self-administration. These findings suggest that MDMA self-administration is under endogenous tonic control by the endocannabinoid system
Naltrexone, naltrindole, and ctop block cocaine-induced sensitization to seizures and death
No full textICV injection for 9 days of either naltexone (NTX) (5, 10, 20, 40 mu g/rat) or a selective mu peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 mu g/rat) or delta (naltrindole) (NLT) (5, 10, 20 mu g/rat) subtype opioid receptor antagonist affected sensitization to cocaine (COG) (50 mg/kg, IP) administered 10 min after. NTX (5 and 40 mu g/rat), NLT (10 and 20 mu g/rat), and the peptide CTOP (0.25-0.5 mu g/rat) attenuated seizure parameters (percent of animals showing seizures, mean score and latency) in a day-related manner. The DD50 (days to reach 50% of death) value for COC was 2.69, whereas it was 9.67 and 7.27 for NTX 5 and 40 mu g/rat, 8.59 for NLT (10 mu g/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 mu g/rat respectively). These findings suggest a concurrent involvement of mu- and delta-opioid receptor subtype in COC-induced sensitization to toxic effects
Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system
No full textCannabinoids appear atypical as drugs of abuse since controversial data exist concerning the ability to lower the thresholds for electrical self-stimulation (Stark and Dews, 1980; Gardner et al., 1988; Gardner, 1992) and to support self-administration (Martellotta et al., 1998; Tanda et al., 2000) or conditioned place preference in animals (Lepore et al., 1995; Parker and Gillies, 1995; McGregor et al., 1996; Sañudo-Peña et al., 1997; Chaperon et al., 1998; Hutcheson et al., 1998; Mallet and Beninger, 1998; Cheer et al., 2000; Valjent and Maldonado, 2000). Opioids and cannabinoids share some pharmacological properties (Manzanares et al., 1999). The most interactions were found in antinociception (Welch and Stevens, 1992; Smith et al., 1994) and, to a lesser extent, in drug reinforcement (Chen et al., 1990; Vela et al., 1995; Tanda et al., 1997). In the present study we asked whether: (1) a potent synthetic cannabinoid receptor agonist, [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptil)-phenyl]-trans-4-(3-hydroxy propyl) cyclohexanol] (CP 55,940) (from 10 to 40 microg/kg), which binds to the brain cannabinoid receptors with high affinity (Herkenham et al., 1991), would induce conditioned place preference, in comparison with heroin (from 0.1 to 5 mg/kg); (2) what type of receptor was involved; (3) what kind of interaction there was between the two drugs, when given in combination, on reward. CP 55,940 elicited a conditioned place preference only at a dose of 20 microg/kg similar in intensity to that of heroin (2 mg/kg). The reinforcing properties of the cannabinoid agonist were fully antagonised by pretreatment with the brain cannabinoid receptor-1 (CB(1)) antagonist, [N-piperidino-5-(4-chlorophenyl) 1-(2,4-dichloro-phenyl)-4-methyl pyrazole-3-carboxamide hydrochloride] (SR 141716A) and naloxone. The combination of CP 55,940 and heroin, at the reinforcing doses, led to a reward which did not show any additive effect. Taken together these findings are important for understanding how the cannabinoids produce reward and the interconnection of the opioid and cannabinoid system in the motivation
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