1,721,003 research outputs found
Elevation of kynurenic acid levels suppresses Delta9-tetrahydrocannabinol-induced excitation of mesolimbic dopamine and prefrontal cortex pyramidal neurons.
No full textPeroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: preclinical evidence.
No full textThis review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together these preclinical data indicate that PPAR agonists are promising new medications for drug addiction treatment
The endocannabinoid system: a new molecular target for the treatment of tobacco addiction
No full textTobacco addiction is one of the leading preventable causes of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Several lines of evidence suggest that the rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors reduces or eliminates many behavioral and neurochemical effects of nicotine that are related to its addictive potential.
This review will focus on the recently published literature about the role of the endocannabinoid system in nicotine addiction and on the endocannabinoid system as a novel molecular target for the discovery of medications for tobacco dependence
Nicotinic α7 receptors as a new target for treatment of cannabis abuse
No full textIncreasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha(7) nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective alpha 7 nicotinic acetylcholine receptor antagonist methyllycaconitine ( MLA), but not the selective heteromeric non-alpha(7) nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, ( 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol ( THC), the main active ingredient in cannabis, ( 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [( R)-( +)-[ 2,3-dihydro-5-methyl-3[( 4-morpholinyl)methyl] pyrrolo[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone, mesylate salt], and ( 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of alpha(7) nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to alpha(7) nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans
Nicotinic facilitation of delta-9-tetrahydrocannabinol discrimination involves endogenous anandamide
No full textIncreasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha(7) nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective alpha 7 nicotinic acetylcholine receptor antagonist methyllycaconitine ( MLA), but not the selective heteromeric non-alpha(7) nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, ( 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol ( THC), the main active ingredient in cannabis, ( 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [( R)-( +)-[ 2,3-dihydro-5-methyl-3[( 4-morpholinyl)methyl] pyrrolo[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone, mesylate salt], and ( 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of alpha(7) nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to alpha(7) nicotinic antagonists as potentially useful agents in the treatment o
Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.
No full textNicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain and provide a potential new target for the treatment of nicotine addictio
Cannabinoid facilitation of behavioral and biochemical hedonic taste responses
No full textCannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation)
Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys
No full textRationale: N-(4-hydroxyphenyl)-arachidonamide (AM404) is an anandamide transport inhibitor shown to reduce rewarding and relapse-inducing effects of nicotine in several animal models of tobacco dependence. However, the reinforcing/rewarding effects of AM404 are not clear. Objectives: We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys. Methods and results: In monkeys with a history of anandamide or cocaine self-administration, we substituted injections of AM404 (1–100 μg/kg/injection). Using a 10-response, fixed-ratio schedule, self-administration behavior was maintained by AM404. Dose–response curves had inverted U shapes, with peak response rates occurring at a dose of 10 μg/kg/injection. In anandamide-experienced monkeys, we also demonstrated self-administration of another anandamide transport inhibitor VDM11. In addition to supporting self-administration, priming injections of AM404 (0.03–0.3 mg/kg) reinstated drug-seeking behavior previously reinforced by cannabinoids (∆9-tetrahydrocannabinol (THC) or anandamide) or cocaine. Both AM404 self-administration behavior and reinstatement of drug seeking by AM404 were reduced by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.3 mg/kg). Moreover, the reinforcing effects of AM404 were potentiated by the treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg) suggesting a major role of anandamide in these effects. Finally, AM404 (0.3 mg/kg) potentiated the reinforcing effects of anandamide but not those of cocaine. Conclusions: In non-human primates, AM404 effectively reinforced self-administration behavior and induced reinstatement of drug-seeking behavior in abstinent monkeys. These effects appeared to be mediated by cannabinoid CB1 receptors. Therefore, compounds that promote actions of endocannabinoids throughout the brain by inhibiting their membrane transport may have a potential for abus
Delta9-tetrahydrocannabinol enhances cortical and hippocampal acetylcholine release in vivo: a microdialysis study
No full textThe intravenous administration of synthetic cannabinoid agonists was recently shown to dose dependently increase acetylcholine release from the rat prefrontal cortex and hippocampus (Eur. J. Pharmacol. 401 (2000) 179]. We report here that the active ingredient of cannabis preparations, Delta (9)-tetrahydrocannabinol, administered at 10, 37.5, 75 and 150 mug/kg, dose dependently stimulated acetylcholine release from rat prefrontal cortex and hippocampus estimated by means of in vivo brain microdialysis with vertical concentric probes. At these doses, Delta (9)-tetrahydrocannabinol induced behavioural stimulation. The administration of the CB1 receptor antagonist, ((N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidie)HCl) SR 141716A (200 mug/kg i.p.) significantly reduced the effect of Delta (9)-tetrahydrocannabinol (75 mug/kg i.v.) on acetylcholine release from rat prefrontal cortex and hippocampu
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