Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history
Highlights
► Cocaine use is associated with cognitive deficits that impact treatment success. ► Nicotinic acetylcholine receptor (nAChR) agonists are proven cognitive enhancers. ► nAChR agonists were tested on cognition in cocaine-exposed and naive rhesus monkeys. ► nAChR agonists improved working memory in both groups of monkeys. ► Cognitive enhancement via nAChR agonism may improve abstinence rates from cocaine.
Introduction
Chronic cocaine use continues to be a significant public health concern worldwide (SAMHSA, 2009). Cocaine binds to the dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters (DAT, SERT, and NET, respectively; Ritz et al., 1987) and induces numerous neurobiological changes throughout mesocorticolimbic regions that disrupt executive function (Volkow et al., 1993; Tomasi et al., 2009; Moeller et al., 2010). For example, compared to control groups, chronic cocaine users showed lower brain function measured via fMRI or positron emission tomography (PET) in regions mediating cognition and showed impaired performance on tasks measuring response inhibition, behavioral flexibility, impulsivity, and working memory (Volkow et al., 1991, 1992; Fillmore and Rush, 2002; Bolla et al., 2004; Hester and Garavan, 2004; Tomasi et al., 2007a, Tomasi et al., 2007b; Goldstein et al., 2007, 2010; Moeller et al., 2010).
Currently, there are no FDA-approved treatments for cocaine dependence (Karila et al., 2008). Behavioral treatment strategies have proven successful (see Vocci and Montoya, 2009 for review) and success rates have been shown to be directly correlated with neuropsychological measures upon treatment initiation (Teichner et al., 2001; Aharonovich et al., 2006; Turner et al., 2009; Schmitz et al., 2009; Moeller et al., 2010). Thus, cognitive enhancement may increase retention and success of behavioral treatments, resulting in improved overall abstinence from cocaine (e.g., Sofuoglu, 2010; Perry et al., 2011).
The acetylcholine (ACh) neurotransmitter system has been extensively studied as a mechanism to improve cognitive deficits associated with hypodopaminergic function such as depression and Parkinson's Disease (for reviews see Rezvani and Levin, 2001; Forgacs and Bodis-Wollner, 2004; Cincotta et al., 2008). Nicotine, a high-efficacy agonist that nonselectively binds at all nicotinic acetylcholine receptor (nAChR) subtypes indirectly stimulates dopamine release (e.g. Rollema et al., 2007, 2009) and has shown cognitive-enhancing effects on measures of attention and memory in rodent, monkey and human studies (see Rezvani and Levin, 2001 for review). However, the high abuse liability of nicotine may preclude its use clinically as a cognitive enhancer (e.g., Schorling et al., 1994; Roll et al., 1996).
The two primary nAChR subtypes distributed within the mammalian CNS are α7 and α4β2* receptors and subtype-selective agonists at each subtype have produced cognitive enhancing effects in animal models (e.g., Hahn et al., 2003; Bitner et al., 2007; Howe et al., 2010; Castner et al., 2011) and may have lower abuse liability than nicotine. Varenicline (Chantix©), an FDA-approved medication with success as a smoking cessation agent (Gonzalez et al., 2006; Jorenby et al., 2006), has high affinity and low-efficacy at α4β2* receptors and low affinity and high-efficacy at α7 receptors (Coe et al., 2005; Mihalak et al., 2006). Data from animal studies and limited clinical trials suggest that varenicline improves cognition across multiple domains (see Rollema et al., 2009 for review) and has limited abuse liability (Rollema et al., 2007; McColl et al., 2008; Gould et al., 2011).
Cognitive impairments have been described as one of the consequences of long-term cocaine use (e.g., Moeller et al., 2010; Hanlon et al., 2011). However, the direct effects of cocaine on nAChR distribution and function are not clear. Cocaine self-administration in animal models produces parallel neurobiological deficits including a hypodopaminergic state (e.g., Diana, 2011; Gould et al., 2012b) and cognitive deficits similar to those seen in human cocaine users (see Beveridge et al., 2008 for review) including impairments on attention, memory, impulsivity and behavioral flexibility in rodents (Dalley et al., 2005; George et al., 2008; Winstanley et al., 2007, 2009) and monkeys (Liu et al., 2008, 2009; Porter et al., 2011; Gould et al., 2012a). Thus, the first goal of this study was to extend the evaluation of cocaine-induced brain changes in rhesus monkeys with an extensive cocaine self-administration history from measures of glucose utilization (Gould et al., 2012a) to nAChR availability using [11C]-nicotine and PET imaging. A second goal was to examine the effects of subtype-selective nAChR agonists of various efficacies including nicotine, varenicline, and PNU-282987, a novel high-efficacy α7-selective nAChR agonist (Bodnar et al., 2005) on cognitive function in these same monkeys and age-matched drug-naive control monkeys. These compounds were tested on three distinct cognitive domains, associative learning, reversal learning and working memory – the latter two domains were shown to be impaired by cocaine self-administration in these monkeys (Gould et al., 2012a) and are mediated in part by distinct neurobiological substrates (e.g., Chudasama and Robbins, 2006; Mehta and Riedel, 2006).
Section snippets
Subjects
Nine singly housed adult male rhesus macaques (Macaca mulatta) of Indian origin served as subjects. Four monkeys (13–14 years old) had an extensive cocaine self-administration history (∼6 yrs; mean 1463 mg/kg cumulative cocaine intake) at the initiation of this study (Czoty et al., 2007; Blaylock et al., 2011; Gould et al., 2012a). Intakes for the monkeys prior to Exp. 1 were: R-1374 (1995 mg/kg), R-1375 (976 mg/kg), R-1377 (1647 mg/kg) and R-1381 (1234 mg/kg). Five additional monkeys,
Experiment 1: effects of cocaine self-administration on nAChR availability
PET imaging of [11C]-nicotine demonstrated a rapid uptake in rhesus monkey brain with peaks in the time–activity curves within 6 min, and rapid washout that became linear around 30 min. The highest uptake was seen in cortical and subcortical regions, with lesser binding in the cerebellum and least binding in white matter, as has been reported in rhesus monkeys (Sihver et al., 1999). For both groups of monkeys, the between-subject variability was low in most regions, rarely exceeding 10% (Table 1
Discussion
The present study examined nicotinic acetylcholine receptor availability and the influence of nAChR stimulation on cognition in rhesus monkeys with a chronic cocaine self-administration history compared to cocaine-naive monkeys. Monkeys with a cocaine self-administration history showed higher [11C]-nicotine uptake in the hippocampus compared to cocaine-naive monkeys measured via PET imaging, supporting the examination of nicotinic receptor agonists on cognition in both groups of monkeys. When
Acknowledgments
The authors wish to acknowledge Dr. Robert Kraft and Dr. James Daunais for assistance with MR acquisition, Dr. Donald Gage for assistance with PET data analysis and the technical assistance of Dr. Rachid Nazhi, Kimberly Black, Holly Smith, Tonya Calhoun, Susan Martelle, and Susan Nader. This work was funded by National Institute on Drug Abuse grants DA010584 and DA006634 and the authors declare no conflict of interest.
References (95)
- et al.
Cognitive deficits predict low treatment retention in cocaine dependent patients
Drug Alcohol Depend.
(2006) - et al.
Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance
Trends Pharmacol. Sci.
(2005) - et al.
Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors
Biol. Psychiatry
(2011) - et al.
Frontal cortical α7 and α4β2 nicotinic acetylcholine receptors in working and reference memory
Neuropharmacology
(2007) - et al.
Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans
Biol. Psych.
(2006) - et al.
Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model
Brain Res.
(2009) - et al.
Impaired inhibitory control of behavior in chronic cocaine users
Drug Alcohol Depend.
(2002) - et al.
Role of anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction
Neuroscience
(2007) - et al.
Attentional effects of nicotinic agonists in rats
Neuropharmacology
(2003) - et al.
(S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET
Int. J. Rad Appl. Instrum. B
(1992)
Effects of psychoactive drugs on short-term memory in rats and rhesus monkeys
Jpn. J. Pharmacol.
Impairment of reversal learning and response perseveration after repeated intermittent cocaine administration to monkeys
Neuropsychopharmacology
A touch screen based stop signal response task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration
J. Neurosci. Methods
Nicotinic acetylcholine receptors and the ascending dopamine pathways
Biochem. Pharmacol.
Working memory fMRI activation in cocaine-dependent subjects: association with treatment response
Psychiatry Res.
Prefrontal cortex and drug abuse vulnerability: translation to prevention and treatment interventions
Brain Res. Rev.
Alpha7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioral changes in a modified Y-maze task in mice
Eur. J. Pharmacol.
Cognitive effects of nicotine
Biol. Psychiatry
A comparison of cocaine-dependent cigarette smokers and non-smokers on demographics, drug use and other characteristics
Drug Alcohol Depend.
Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid
Neuropharmacology
Preclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition
Biochem. Pharmacol.
In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-) [11C]nicotine in rhesus monkeys
Nucl. Med. Biol.
Thalamo-cortical dysfunction in cocaine abusers: implications in attention and perception
Psychiatry Res.
Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence
Brain Res.
Measures of cognitive functioning as predictors of treatment outcome for cocaine dependence
J. Subst. Abuse Treat.
Behavioral effects of PNU-282987, an alpha7 nicotinic receptor agonist, in mice
Behav. Brain Res.
Altered cholinergic receptor systems in cocaine-addicted subjects
Neuropsychopharmacology
Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain
J. Neurochem.
Review: parallel studies of cocaine related neural and cognitive impairment in humans and monkeys
Philos. Trans. R. Soc. London B Biol. Sci.
Broad-spectrum efficacy across cognitive domains by α7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways
J. Neurosci.
Influence of cocaine history on the behavioral effects of Dopamine D(3) receptor-selective compounds in monkeys
Neuropsychopharmacology
Discovery and structure-activity relationship of quinuclidine benzamides as agonists of α7 nicotinic acetylcholine receptors
J. Med. Chem.
Prefrontal cortical dysfunction in abstinent cocaine abusers
J. Neuropsychiatry Clin. Neurosci.
Effect of smoking history on [3H]nicotine binding in human postmortem brain
J. Pharmacol. Exp. Ther.
Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction
Curr. Opin. Investig. Drugs
Varenicline: an α4β2 nicotinic acetylcholine receptor partial agonist for smoking cessation
J. Med. Chem.
Inverted-U-shaped dopamine actions on human working memory and cognitive control
Biol. Psych.
Long-term cocaine self-administration under fixed-ratio and second-order schedules in monkeys
Psychopharmacology
Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin
Psychopharmacology
Effects of nicotinic therapies on attention and executive functions in chronic low-dose MTPT-treated monkeys
Eur. J. Neurosci.
The dopamine hypothesis of drug addiction and its potential therapeutic value
Front. Psych.
Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse
Am. J. Psychiatry
Nicotinic receptors and cognition in Parkinson's Disease: the importance of neuronal synchrony
J. Neural Transm.
Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments
Neuropsychopharmacology
Using cerebral white matter for estimation of nondisplaceable binding of 5-HT1A receptors in temporal lobe epilepsy
J. Nucl. Med.
Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task
Proc. Nat. Acad. Sci. U. S. A.
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial
JAMA
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Present address: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.