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Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

Rationale Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotrans... Full description

Journal Title: Psychopharmacology 2019, Vol.236 (7), p.2143-2153
Main Author: Kangas, Brian D
Other Authors: Doyle, Rachel J , Kohut, Stephen J , Bergman, Jack , Kaufman, Marc J
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0033-3158
Link: https://www.ncbi.nlm.nih.gov/pubmed/30877326
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6626691
title: Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates
format: Article
creator:
  • Kangas, Brian D
  • Doyle, Rachel J
  • Kohut, Stephen J
  • Bergman, Jack
  • Kaufman, Marc J
subjects:
  • Abnormalities
  • Acetylcysteine
  • Acetylcysteine - administration & dosage
  • Analysis
  • Animal behavior
  • Animals
  • Attentional bias
  • Bergman, Jack
  • Biomedical and Life Sciences
  • Biomedicine
  • Chronic exposure
  • Cocaine
  • Cocaine - administration & dosage
  • Cocaine-Related Disorders - drug therapy
  • Cocaine-Related Disorders - psychology
  • Cognition
  • Cognition - drug effects
  • Cognition - physiology
  • Cognitive ability
  • Cognitive Flexibility
  • Cognitive tasks
  • Conditioning, Operant - drug effects
  • Conditioning, Operant - physiology
  • Discrimination
  • Discrimination Learning - drug effects
  • Discrimination Learning - physiology
  • Dopamine Uptake Inhibitors - administration & dosage
  • Dose-Response Relationship, Drug
  • Drug abuse
  • Drug addiction
  • Drug self-administration
  • Drug therapy
  • Drug-Seeking Behavior - drug effects
  • Drug-Seeking Behavior - physiology
  • Exposure
  • Extinction behavior
  • Extinction, Psychological - drug effects
  • Extinction, Psychological - physiology
  • Flexibility
  • Free Radical Scavengers - administration & dosage
  • Glutamate
  • Glutamatergic transmission
  • Homeostasis
  • Learning
  • Male
  • Monkeys
  • N-acetylcysteine
  • Neuromodulation
  • Neurosciences
  • Neurotransmission
  • Nonhuman Primates
  • Original Investigation
  • Pharmacology/Toxicology
  • Photic Stimulation - methods
  • Primates
  • Psychiatry
  • Reinforcement, Psychology
  • Reinstatement
  • Rodents
  • Saimiri
  • Self Administration
  • Touch screens
ispartof: Psychopharmacology, 2019, Vol.236 (7), p.2143-2153
description: Rationale Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N -acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13–3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.
language: eng
source:
identifier: ISSN: 0033-3158
fulltext: no_fulltext
issn:
  • 0033-3158
  • 1432-2072
url: Link


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titleEffects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates
creatorKangas, Brian D ; Doyle, Rachel J ; Kohut, Stephen J ; Bergman, Jack ; Kaufman, Marc J
creatorcontribKangas, Brian D ; Doyle, Rachel J ; Kohut, Stephen J ; Bergman, Jack ; Kaufman, Marc J
descriptionRationale Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N -acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13–3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.
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subjectAbnormalities ; Acetylcysteine ; Acetylcysteine - administration & dosage ; Analysis ; Animal behavior ; Animals ; Attentional bias ; Bergman, Jack ; Biomedical and Life Sciences ; Biomedicine ; Chronic exposure ; Cocaine ; Cocaine - administration & dosage ; Cocaine-Related Disorders - drug therapy ; Cocaine-Related Disorders - psychology ; Cognition ; Cognition - drug effects ; Cognition - physiology ; Cognitive ability ; Cognitive Flexibility ; Cognitive tasks ; Conditioning, Operant - drug effects ; Conditioning, Operant - physiology ; Discrimination ; Discrimination Learning - drug effects ; Discrimination Learning - physiology ; Dopamine Uptake Inhibitors - administration & dosage ; Dose-Response Relationship, Drug ; Drug abuse ; Drug addiction ; Drug self-administration ; Drug therapy ; Drug-Seeking Behavior - drug effects ; Drug-Seeking Behavior - physiology ; Exposure ; Extinction behavior ; Extinction, Psychological - drug effects ; Extinction, Psychological - physiology ; Flexibility ; Free Radical Scavengers - administration & dosage ; Glutamate ; Glutamatergic transmission ; Homeostasis ; Learning ; Male ; Monkeys ; N-acetylcysteine ; Neuromodulation ; Neurosciences ; Neurotransmission ; Nonhuman Primates ; Original Investigation ; Pharmacology/Toxicology ; Photic Stimulation - methods ; Primates ; Psychiatry ; Reinforcement, Psychology ; Reinstatement ; Rodents ; Saimiri ; Self Administration ; Touch screens
ispartofPsychopharmacology, 2019, Vol.236 (7), p.2143-2153
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descriptionRationale Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N -acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13–3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.
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1Acetylcysteine
2Acetylcysteine - administration & dosage
3Analysis
4Animal behavior
5Animals
6Attentional bias
7Bergman, Jack
8Biomedical and Life Sciences
9Biomedicine
10Chronic exposure
11Cocaine
12Cocaine - administration & dosage
13Cocaine-Related Disorders - drug therapy
14Cocaine-Related Disorders - psychology
15Cognition
16Cognition - drug effects
17Cognition - physiology
18Cognitive ability
19Cognitive Flexibility
20Cognitive tasks
21Conditioning, Operant - drug effects
22Conditioning, Operant - physiology
23Discrimination
24Discrimination Learning - drug effects
25Discrimination Learning - physiology
26Dopamine Uptake Inhibitors - administration & dosage
27Dose-Response Relationship, Drug
28Drug abuse
29Drug addiction
30Drug self-administration
31Drug therapy
32Drug-Seeking Behavior - drug effects
33Drug-Seeking Behavior - physiology
34Exposure
35Extinction behavior
36Extinction, Psychological - drug effects
37Extinction, Psychological - physiology
38Flexibility
39Free Radical Scavengers - administration & dosage
40Glutamate
41Glutamatergic transmission
42Homeostasis
43Learning
44Male
45Monkeys
46N-acetylcysteine
47Neuromodulation
48Neurosciences
49Neurotransmission
50Nonhuman Primates
51Original Investigation
52Pharmacology/Toxicology
53Photic Stimulation - methods
54Primates
55Psychiatry
56Reinforcement, Psychology
57Reinstatement
58Rodents
59Saimiri
60Self Administration
61Touch screens
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titleEffects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates
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1Acetylcysteine
2Acetylcysteine - administration & dosage
3Analysis
4Animal behavior
5Animals
6Attentional bias
7Bergman, Jack
8Biomedical and Life Sciences
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13Cocaine-Related Disorders - drug therapy
14Cocaine-Related Disorders - psychology
15Cognition
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17Cognition - physiology
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19Cognitive Flexibility
20Cognitive tasks
21Conditioning, Operant - drug effects
22Conditioning, Operant - physiology
23Discrimination
24Discrimination Learning - drug effects
25Discrimination Learning - physiology
26Dopamine Uptake Inhibitors - administration & dosage
27Dose-Response Relationship, Drug
28Drug abuse
29Drug addiction
30Drug self-administration
31Drug therapy
32Drug-Seeking Behavior - drug effects
33Drug-Seeking Behavior - physiology
34Exposure
35Extinction behavior
36Extinction, Psychological - drug effects
37Extinction, Psychological - physiology
38Flexibility
39Free Radical Scavengers - administration & dosage
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41Glutamatergic transmission
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46N-acetylcysteine
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abstractRationale Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N -acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13–3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.
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