Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates
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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.
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.
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.
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.
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.
KeywordsSelf-administration Cocaine N-acetylcysteine Learning Cognitive flexibility Reinstatement Nonhuman Primates
The authors thank Roger Spealman for comments on a previous version of this manuscript.
This research was supported by grants K01-DA035974 (BDK) and R21-DA039301 (MJK) from the National Institute on Drug Abuse.
Compliance with ethical standards
The protocol for the present studies was approved by the Institutional Animal Care and Use Committee at McLean Hospital in a facility licensed by the US Department of Agriculture and in accordance with guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, Commission on Life Sciences (National Research Council 2011).
Conflict of interest
The authors declare that they have no conflicts of interest.
- Ben-Shahar OM, Szumlinski KK, Lominac KD, Cohen A, Gordon E, Ploense KL, DeMartini J, Bernstein N, Rudy NM, Nabhan AN, Sacramento A, Pagano K, Carosso GA, Woodward N (2012) Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex. Addict Biol 17:746–757CrossRefGoogle Scholar
- Hagos FT, Daood MJ, Ocque JA, Nolin TD, Bayir H, Poloyac SM, Kochanek PM, Clark RS, Empey PE (2017) Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine. Xenobiotica 47:346–353Google Scholar
- Hakami AY, Alshehri FS, Sari Y (2018) β-lactams modulate astroglial glutamate transporters and attenuate dependence to CP 55,940, a CB1 receptor agonist, in rat model. Behav Brain Res S0166-4328(18):30743–30745Google Scholar
- Hodebourg R, Murray JE, Fouyssac M, Puaud M, Everitt BJ, Belin D (2018) Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. Eur J Neurosci. https://doi.org/10.1111/ejn.13894
- Kelleher RT, Morse WH (1968) Determinants of the specificity of behavioral effects of drugs. Ergeb Physiol Biol Chem Exp Pharmakol 60:1–56Google Scholar
- Martinez D, Slifstein M, Nabulsi N, Grassetti A, Urban NB, Perez A, Liu F, Lin SF, Ropchan J, Mao X, Kegeles LS, Shungu DC, Carson RE, Huang Y (2014) Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [11C]ABP688 and magnetic resonance spectroscopy. Biol Psychiatry 75:165–171CrossRefGoogle Scholar
- National Institute on Drug Abuse (NIDA); National Institutes of Health; U.S. Department of Health and Human Services. Cocaine: Drug Facts, July 2018. www.drugabuse.gov/publications/drugfacts/cocaine; accessed 18 Nov 2018
- National Research Council (2011) Guide for the care and use of laboratory animals: eighth edition. National Academy Press, Washington DCGoogle Scholar
- Winhusen T, Lewis D, Adinoff B, Brigham G, Kropp F, Donovan DM, Seamans CL, Hodgkins CC, Dicenzo JC, Botero CL, Jones DR, Somoza E (2013a) Impulsivity is associated with treatment non-completion in cocaine- and methamphetamine-dependent patients but differs in nature as a function of stimulant-dependence diagnosis. J Subst Abus Treat 44:541–547CrossRefGoogle Scholar
- Woolverton WL, Schuster CR (1978) Behavioral tolerance to cocaine. NIDA Res Monogr 18:127–141Google Scholar