17 research outputs found
Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys
Although substantial research effort has focused on developing pharmacological treatments for
cocaine abuse, no effective medications have been developed. Recent studies show that enzymes
that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine
toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-
CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH
was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-
fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic
studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In
these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours
after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine
methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH
administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH
dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 ÎŒg/kg/
injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the
reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine
(0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of
cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine
abuse and toxicity is warranted.This research was supported in part by the Intramural Research Program of the NIH, National Institute on Drug
Abuse
Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist
Several recent studies suggest functional and molecular interactions between striatal adenosine A2A and cannabinoid CB1 receptors. Here, we demonstrate that A2A receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A2A receptor blockade on the reinforcing effects of deltaâ9âtetrahydrocannabinol (THC) and the endogenous CB1 receptor ligand anandamide under a fixedâratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A2A receptor antagonist MSXâ3 (1âmg/kg) caused downward shifts of THC and anandamide doseâresponse curves. In contrast, a higher dose of MSXâ3 (3âmg/kg) shifted THC and anandamide doseâresponse curves to the left. MSXâ3 did not modify cocaine or food pellet selfâadministration. Also, MSXâ3 neither promoted reinstatement of extinguished drugâseeking behavior nor altered reinstatement of drugâseeking behavior by nonâcontingent priming injections of THC. Finally, using in vivo microdialysis in freelyâmoving rats, a behaviorally active dose of MSXâ3 significantly counteracted THCâinduced, but not cocaineâinduced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSXâ3 suggest that adenosine A2A antagonists acting preferentially at presynaptic A2A receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSXâ3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A2A antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse
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Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuanaâs main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse
Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist
Several recent studies suggest functional and molecular interactions between striatal adenosine A2A and cannabinoid CB1 receptors. Here, we demonstrate that A2A receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A2A receptor blockade on the reinforcing effects of deltaâ9âtetrahydrocannabinol (THC) and the endogenous CB1 receptor ligand anandamide under a fixedâratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A2A receptor antagonist MSXâ3 (1âmg/kg) caused downward shifts of THC and anandamide doseâresponse curves. In contrast, a higher dose of MSXâ3 (3âmg/kg) shifted THC and anandamide doseâresponse curves to the left. MSXâ3 did not modify cocaine or food pellet selfâadministration. Also, MSXâ3 neither promoted reinstatement of extinguished drugâseeking behavior nor altered reinstatement of drugâseeking behavior by nonâcontingent priming injections of THC. Finally, using in vivo microdialysis in freelyâmoving rats, a behaviorally active dose of MSXâ3 significantly counteracted THCâinduced, but not cocaineâinduced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSXâ3 suggest that adenosine A2A antagonists acting preferentially at presynaptic A2A receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSXâ3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A2A antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse
Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates.
BACKGROUND:CB(1) cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors. However, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys. METHODS:We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Delta(9)-tetrahydrocannabinol (THC), anandamide, or cocaine and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay. RESULTS:URB597 (.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597, and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine, even though, as expected, it significantly potentiated anandamide self-administration. CONCLUSIONS:In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse
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Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.
Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement
Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors.
BackgroundRecent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.MethodsWe combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.ResultsThe PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).ConclusionsThese findings indicate that PPAR-α might provide a valuable new target for antismoking medications
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Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors.
BackgroundRecent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.MethodsWe combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.ResultsThe PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).ConclusionsThese findings indicate that PPAR-α might provide a valuable new target for antismoking medications
Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse
Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3â-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration doseâresponse functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB(1) receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shellâconsistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement