2016
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Foll, Bernard Le; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana
In: Neuropsychopharmacology, vol. 41, no. 9, pp. 2283–2293, 2016, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
@article{Schindler2016,
title = {Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.},
author = {Charles W Schindler and Godfrey H Redhi and Kiran Vemuri and Alexandros Makriyannis and Bernard Le Foll and Jack Bergman and Steven R Goldberg and Zuzana Justinova},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26888056},
doi = {10.1038/npp.2016.27},
issn = {1740-634X (Electronic); 0893-133X (Linking)},
year = {2016},
date = {2016-08-01},
journal = {Neuropsychopharmacology},
volume = {41},
number = {9},
pages = {2283--2293},
address = {Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.},
abstract = {Nicotine, the main psychoactive component of tobacco, and (-)-Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nicotine, the main psychoactive component of tobacco, and (-)-Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana
Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid. Journal Article
In: Neuropsychopharmacology, vol. 41, no. 9, pp. 2283–2293, 2016, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
@article{Schindler2016,
title = {Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.},
author = {Schindler, Charles W and Redhi, Godfrey H and Vemuri, Kiran and Makriyannis, Alexandros and Le Foll, Bernard and Bergman, Jack and Goldberg, Steven R and Justinova, Zuzana},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24121737},
doi = {10.1038/npp.2016.27},
issn = {1740-634X (Electronic); 0893-133X (Linking)},
year = {2016},
date = {2016-08-01},
journal = {Neuropsychopharmacology},
volume = {41},
number = {9},
pages = {2283--2293},
abstract = {Nicotine, the main psychoactive component of tobacco, and (-)-Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nicotine, the main psychoactive component of tobacco, and (-)-Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.
2015
Justinova, Zuzana; Panlilio, Leigh V; Secci, Maria E; Redhi, Godfrey H; Schindler, Charles W; Cross, Alan J; Mrzljak, Ladislav; Medd, Amy; Shaham, Yavin; Goldberg, Steven R
In: Biol Psychiatry, vol. 78, no. 7, pp. 452–462, 2015, ISSN: 1873-2402 (Electronic); 0006-3223 (Linking).
@article{Justinova2015,
title = {The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys.},
author = {Zuzana Justinova and Leigh V Panlilio and Maria E Secci and Godfrey H Redhi and Charles W Schindler and Alan J Cross and Ladislav Mrzljak and Amy Medd and Yavin Shaham and Steven R Goldberg},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25802079},
doi = {10.1016/j.biopsych.2015.01.014},
issn = {1873-2402 (Electronic); 0006-3223 (Linking)},
year = {2015},
date = {2015-10-01},
journal = {Biol Psychiatry},
volume = {78},
number = {7},
pages = {452--462},
address = {Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. Electronic address: zjustino@intra.nida.nih.gov.},
abstract = {BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.
Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R
Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse. Journal Article
In: Neuropsychopharmacology, vol. 40, no. 9, pp. 2185–2197, 2015, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
@article{Justinova2015,
title = {Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.},
author = {Zuzana Justinova and Leigh V Panlilio and Guillermo Moreno-Sanz and Godfrey H Redhi and Alessia Auber and Maria E Secci and Paola Mascia and Tiziano Bandiera and Andrea Armirotti and Rosalia Bertorelli and Svetlana I Chefer and Chanel Barnes and Sevil Yasar and Daniele Piomelli and Steven R Goldberg},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25754762},
doi = {10.1038/npp.2015.62},
issn = {1740-634X (Electronic); 0893-133X (Linking)},
year = {2015},
date = {2015-08-01},
journal = {Neuropsychopharmacology},
volume = {40},
number = {9},
pages = {2185--2197},
address = {Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.},
abstract = {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 alpha-type peroxisome proliferator-activated (PPAR-alpha) 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-alpha 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-alpha (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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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 alpha-type peroxisome proliferator-activated (PPAR-alpha) 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-alpha 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-alpha (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.
Narendran, Rajesh; Jedema, Hank P; Lopresti, Brian J; Mason, Neale Scott; Himes, Michael L; Bradberry, Charles W
In: Biol Psychiatry, vol. 77, no. 5, pp. 488–492, 2015, ISSN: 1873-2402 (Electronic); 0006-3223 (Linking).
@article{Narendran2015,
title = {Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates.},
author = {Rajesh Narendran and Hank P Jedema and Brian J Lopresti and Neale Scott Mason and Michael L Himes and Charles W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25062684},
doi = {10.1016/j.biopsych.2014.06.012},
issn = {1873-2402 (Electronic); 0006-3223 (Linking)},
year = {2015},
date = {2015-03-01},
journal = {Biol Psychiatry},
volume = {77},
number = {5},
pages = {488--492},
address = {Department of Radiology; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: narendranr@upmc.edu.},
abstract = {BACKGROUND: Consistent with postmortem data, in a recent positron emission tomography study, we demonstrated less [(11)C]-(+)-dihydrotetrabenazine ([(11)C]DTBZ) binding to striatal vesicular monoamine transporter type 2 (VMAT2) in cocaine abusers compared with control subjects. A major limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Furthermore, studies in rodents that evaluated VMAT2 binding before and after cocaine self-administration do not support a reduction in VMAT2. METHODS: To clarify these discrepant VMAT2 findings and attribute VMAT2 reduction to cocaine abuse, we imaged four rhesus monkeys with [(11)C]DTBZ positron emission tomography before and after 16 months of cocaine self-administration. [(11)C]DTBZ binding potential in the striatum was derived using the simplified reference tissue method with the occipital cortex time activity curve as an input function. RESULTS: Chronic cocaine self-administration led to a significant (25.8 +/- 7.8%) reduction in [(11)C]DTBZ binding potential. CONCLUSIONS: In contrast to the cocaine rodent investigations that do not support alterations in VMAT2, these results in nonhuman primates clearly demonstrated a reduction in VMAT2 binding following prolonged exposure to cocaine. Lower VMAT2 implies that fewer dopamine storage vesicles are available in the presynaptic terminals for release, a likely factor contributing to decreased dopamine transmission in cocaine dependence. Future studies should attempt to clarify the clinical significance of lower VMAT2 in cocaine abusers, for example, its relationship to relapse and vulnerability to mood disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Consistent with postmortem data, in a recent positron emission tomography study, we demonstrated less [(11)C]-(+)-dihydrotetrabenazine ([(11)C]DTBZ) binding to striatal vesicular monoamine transporter type 2 (VMAT2) in cocaine abusers compared with control subjects. A major limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Furthermore, studies in rodents that evaluated VMAT2 binding before and after cocaine self-administration do not support a reduction in VMAT2. METHODS: To clarify these discrepant VMAT2 findings and attribute VMAT2 reduction to cocaine abuse, we imaged four rhesus monkeys with [(11)C]DTBZ positron emission tomography before and after 16 months of cocaine self-administration. [(11)C]DTBZ binding potential in the striatum was derived using the simplified reference tissue method with the occipital cortex time activity curve as an input function. RESULTS: Chronic cocaine self-administration led to a significant (25.8 +/- 7.8%) reduction in [(11)C]DTBZ binding potential. CONCLUSIONS: In contrast to the cocaine rodent investigations that do not support alterations in VMAT2, these results in nonhuman primates clearly demonstrated a reduction in VMAT2 binding following prolonged exposure to cocaine. Lower VMAT2 implies that fewer dopamine storage vesicles are available in the presynaptic terminals for release, a likely factor contributing to decreased dopamine transmission in cocaine dependence. Future studies should attempt to clarify the clinical significance of lower VMAT2 in cocaine abusers, for example, its relationship to relapse and vulnerability to mood disorders.
2014
Jedema, Hank P; Narendran, Rajesh; Bradberry, Charles W
Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse. Journal Article
In: J Neurochem, vol. 130, no. 4, pp. 490–497, 2014, ISSN: 1471-4159 (Electronic); 0022-3042 (Linking).
@article{Jedema2016,
title = {Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse.},
author = {Hank P Jedema and Rajesh Narendran and Charles W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24749782},
doi = {10.1111/jnc.12743},
issn = {1471-4159 (Electronic); 0022-3042 (Linking)},
year = {2014},
date = {2014-08-01},
journal = {J Neurochem},
volume = {130},
number = {4},
pages = {490--497},
address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.},
abstract = {The psychostimulant amphetamine (AMPH) is frequently used to increase catecholamine levels in attention disorders and positron emission tomography imaging studies. Despite the fact that most radiotracers for positron emission tomography studies are characterized in non-human primates (NHPs), data on regional differences of the effect of AMPH in NHPs are very limited. This study examined the impact of AMPH on extracellular dopamine (DA) levels in the medial prefrontal cortex and the caudate of NHPs using microdialysis. In addition to differences in magnitude, we observed striking differences in the temporal profile of extracellular DA levels between these regions that can likely be attributed to differences in the regulation of dopamine uptake and biosynthesis. The present data suggest that cortical DA levels may remain elevated longer than in the caudate which may contribute to the clinical profile of the actions of AMPH. Using microdialysis probes implanted in the cortex and caudate region of non-human primate brains, we observed in vivo differences in the magnitude and temporal profile of extracellular dopamine levels in response to intravenous amphetamine administration.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The psychostimulant amphetamine (AMPH) is frequently used to increase catecholamine levels in attention disorders and positron emission tomography imaging studies. Despite the fact that most radiotracers for positron emission tomography studies are characterized in non-human primates (NHPs), data on regional differences of the effect of AMPH in NHPs are very limited. This study examined the impact of AMPH on extracellular dopamine (DA) levels in the medial prefrontal cortex and the caudate of NHPs using microdialysis. In addition to differences in magnitude, we observed striking differences in the temporal profile of extracellular DA levels between these regions that can likely be attributed to differences in the regulation of dopamine uptake and biosynthesis. The present data suggest that cortical DA levels may remain elevated longer than in the caudate which may contribute to the clinical profile of the actions of AMPH. Using microdialysis probes implanted in the cortex and caudate region of non-human primate brains, we observed in vivo differences in the magnitude and temporal profile of extracellular dopamine levels in response to intravenous amphetamine administration.
Narendran, R; Jedema, H P; Lopresti, B J; Mason, N S; Gurnsey, K; Ruszkiewicz, J; Chen, C-M; Deuitch, L; Frankle, W G; Bradberry, C W
Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study. Journal Article
In: Mol Psychiatry, vol. 19, no. 3, pp. 302–310, 2014, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).
@article{Narendran2014,
title = {Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study.},
author = {R Narendran and H P Jedema and B J Lopresti and N S Mason and K Gurnsey and J Ruszkiewicz and C-M Chen and L Deuitch and W G Frankle and C W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23439486},
doi = {10.1038/mp.2013.9},
issn = {1476-5578 (Electronic); 1359-4184 (Linking)},
year = {2014},
date = {2014-03-01},
journal = {Mol Psychiatry},
volume = {19},
number = {3},
pages = {302--310},
address = {1$]$ Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA $[$2$]$ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.},
abstract = {In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose-dependent increase in dialysate (0.3 mg kg(-1): 999+/-287%; 0.5 mg kg(-1): 1320+/-432%; 1.0 mg kg(-1): 2355+/-1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6+/-6%; 0.5 mg kg(-1): -16+/-4%; 1.0 mg kg(-1): -24+/-2%) as measured with PET. The relationship between amphetamine-induced peak DeltaDA and Delta[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose-dependent increase in dialysate (0.3 mg kg(-1): 999+/-287%; 0.5 mg kg(-1): 1320+/-432%; 1.0 mg kg(-1): 2355+/-1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6+/-6%; 0.5 mg kg(-1): -16+/-4%; 1.0 mg kg(-1): -24+/-2%) as measured with PET. The relationship between amphetamine-induced peak DeltaDA and Delta[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction.
2011
Porter, Jessica N; Olsen, Adam S; Gurnsey, Kate; Dugan, Brian P; Jedema, Hank P; Bradberry, Charles W
Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory. Journal Article
In: J Neurosci, vol. 31, no. 13, pp. 4926–4934, 2011, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Porter2011,
title = {Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory.},
author = {Jessica N Porter and Adam S Olsen and Kate Gurnsey and Brian P Dugan and Hank P Jedema and Charles W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21451031},
doi = {10.1523/JNEUROSCI.5426-10.2011},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2011},
date = {2011-03-30},
journal = {J Neurosci},
volume = {31},
number = {13},
pages = {4926--4934},
address = {Center for Neuroscience at the University of Pittsburgh, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.},
abstract = {Cocaine users display a wide range of cognitive impairments. Because treatment outcome is dependent on baseline cognitive ability, it is clinically important to understand the underlying neurobiology of these deficits. Therefore, it is crucial to determine whether cocaine exposure by itself is an etiological factor and, if so, to determine the overall nature of cognitive deficits associated with cocaine use. This will help to guide therapeutic approaches that address cognitive components of cocaine use to improve treatment outcome. We used rhesus monkeys in a longitudinal study in which 14 animals were characterized before assignment to matched control (n = 6) and cocaine self-administration (n = 8) groups. Self-administration took place on 4 consecutive days/week over 9 months, with a maximum (and typical) daily cumulative intake of 3.0 mg/kg. Weekly cognitive assessments (total of 36) were conducted after a 72 h drug-free period. We used a stimulus discrimination task with reversal to evaluate associative learning and the cognitive control/flexibility needed to adapt to changes in reward contingencies. After extended self-administration, initial accuracy on the stimulus discrimination indicated intact associative learning. However, animals were impaired at maintaining high levels of accuracy needed to reach criterion and initiate the reversal. Increasing the reward contrast between stimuli permitted evaluation of reversal performance and revealed striking deficits in the cocaine group. Impairments in visual working memory were also observed using a delayed match-to-sample task. These results suggest a combination of generalized, possibly attentional, impairments, along with a more specific cognitive control impairment implicating orbitofrontal cortex dysfunction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cocaine users display a wide range of cognitive impairments. Because treatment outcome is dependent on baseline cognitive ability, it is clinically important to understand the underlying neurobiology of these deficits. Therefore, it is crucial to determine whether cocaine exposure by itself is an etiological factor and, if so, to determine the overall nature of cognitive deficits associated with cocaine use. This will help to guide therapeutic approaches that address cognitive components of cocaine use to improve treatment outcome. We used rhesus monkeys in a longitudinal study in which 14 animals were characterized before assignment to matched control (n = 6) and cocaine self-administration (n = 8) groups. Self-administration took place on 4 consecutive days/week over 9 months, with a maximum (and typical) daily cumulative intake of 3.0 mg/kg. Weekly cognitive assessments (total of 36) were conducted after a 72 h drug-free period. We used a stimulus discrimination task with reversal to evaluate associative learning and the cognitive control/flexibility needed to adapt to changes in reward contingencies. After extended self-administration, initial accuracy on the stimulus discrimination indicated intact associative learning. However, animals were impaired at maintaining high levels of accuracy needed to reach criterion and initiate the reversal. Increasing the reward contrast between stimuli permitted evaluation of reversal performance and revealed striking deficits in the cocaine group. Impairments in visual working memory were also observed using a delayed match-to-sample task. These results suggest a combination of generalized, possibly attentional, impairments, along with a more specific cognitive control impairment implicating orbitofrontal cortex dysfunction.
2010
Jedema, H P; Gianaros, P J; Greer, P J; Kerr, D D; Liu, S; Higley, J D; Suomi, S J; Olsen, A S; Porter, J N; Lopresti, B J; Hariri, A R; Bradberry, C W
In: Mol Psychiatry, vol. 15, no. 5, pp. 512–522, 2010, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).
@article{Jedema2010,
title = {Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.},
author = {H P Jedema and P J Gianaros and P J Greer and D D Kerr and S Liu and J D Higley and S J Suomi and A S Olsen and J N Porter and B J Lopresti and A R Hariri and C W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19721434},
doi = {10.1038/mp.2009.90},
issn = {1476-5578 (Electronic); 1359-4184 (Linking)},
year = {2010},
date = {2010-05-01},
journal = {Mol Psychiatry},
volume = {15},
number = {5},
pages = {512--522},
address = {Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15261, USA.},
abstract = {A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.
2009
Baeg, Eun Ha; Jackson, Mark E; Jedema, Hank P; Bradberry, Charles W
Orbitofrontal and anterior cingulate cortex neurons selectively process cocaine-associated environmental cues in the rhesus monkey. Journal Article
In: J Neurosci, vol. 29, no. 37, pp. 11619–11627, 2009, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Baeg2009,
title = {Orbitofrontal and anterior cingulate cortex neurons selectively process cocaine-associated environmental cues in the rhesus monkey.},
author = {Eun Ha Baeg and Mark E Jackson and Hank P Jedema and Charles W Bradberry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/19759309},
doi = {10.1523/JNEUROSCI.3206-09.2009},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2009},
date = {2009-09-16},
journal = {J Neurosci},
volume = {29},
number = {37},
pages = {11619--11627},
address = {Department of Psychiatry, University of Pittsburgh, Veterans Affairs Pittsburgh Health Services, Pittsburgh, Pennsylvania 15261, USA.},
abstract = {Encounters with stimuli associated with drug use are believed to contribute to relapse. To probe the neurobiology of environmentally triggered drug use, we have conducted single-unit recordings in rhesus monkeys during presentation of two distinct types of drug paired cues that differentially support drug-seeking. The animals were highly conditioned to these cues via exposure during self-administration procedures conducted over a 4 year period. The cues studied were a discriminative cue that signaled response-contingent availability of cocaine, and a discrete cue that was temporally paired with the cocaine infusion (0.1 or 0.5 mg/kg). Two cortical regions consistently activated by cocaine-associated cues in human imaging studies are the orbitofrontal (OFC) and anterior cingulate cortex (ACC), though little is known about cortical neuronal activity responses to drug cues. We simultaneously recorded single-unit activity in OFC and ACC as well as in dorsal striatum in rhesus monkeys during cocaine self-administration. Dorsal striatal neurons were less engaged by drug cues than cortical regions. Between OFC and ACC, distinct functionality was apparent in neuronal responses. OFC neurons preferentially responded to the discriminative cue, consistent with a role in cue-induced drug-seeking. In contrast, the ACC did not respond more to the discriminative cue than to the discrete cue. Also distinct from the OFC, ACC showed sustained firing throughout the 18 s duration of the discrete cue. This pattern of sustained activation in ACC is consistent with a role in reward expectation and/or in mediating behavioral effects of discrete cues paired with drug infusions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Encounters with stimuli associated with drug use are believed to contribute to relapse. To probe the neurobiology of environmentally triggered drug use, we have conducted single-unit recordings in rhesus monkeys during presentation of two distinct types of drug paired cues that differentially support drug-seeking. The animals were highly conditioned to these cues via exposure during self-administration procedures conducted over a 4 year period. The cues studied were a discriminative cue that signaled response-contingent availability of cocaine, and a discrete cue that was temporally paired with the cocaine infusion (0.1 or 0.5 mg/kg). Two cortical regions consistently activated by cocaine-associated cues in human imaging studies are the orbitofrontal (OFC) and anterior cingulate cortex (ACC), though little is known about cortical neuronal activity responses to drug cues. We simultaneously recorded single-unit activity in OFC and ACC as well as in dorsal striatum in rhesus monkeys during cocaine self-administration. Dorsal striatal neurons were less engaged by drug cues than cortical regions. Between OFC and ACC, distinct functionality was apparent in neuronal responses. OFC neurons preferentially responded to the discriminative cue, consistent with a role in cue-induced drug-seeking. In contrast, the ACC did not respond more to the discriminative cue than to the discrete cue. Also distinct from the OFC, ACC showed sustained firing throughout the 18 s duration of the discrete cue. This pattern of sustained activation in ACC is consistent with a role in reward expectation and/or in mediating behavioral effects of discrete cues paired with drug infusions.
