Research reportEffects of nucleus accumbens amphetamine administration on performance in a delay discounting task
Introduction
Substance use disorders are associated with cognitive and neurobiological impairments that can persist long after cessation of substance use [1]. One facet of cognition that is severely impacted is intertemporal decision making. Substance users typically display an exaggerated preference for immediate rewards, such as substances themselves, over delayed, but more beneficial rewards, such as prolonged abstinence, health and employment. Such preference for smaller, sooner over larger, more delayed rewards, or “impulsive choice,” is commonly assessed with delay discounting procedures in which subjects choose between two options, one which yields a small immediate reward and the other which yields a large reward that is delivered after varying delays [2]. All subjects decrease their choice of large rewards as the delays to their delivery increase; however, chronic users of alcohol, cocaine, and opioids, among other substances, show a steeper decrease in preference for large, delayed rewards than nonusers (i.e., steeper delay discounting, or increased impulsive choice; [3], [4], [5]). Despite numerous demonstrations of this phenomenon, the mechanisms by which chronic substance, and particularly cocaine, use increases impulsive choice remain poorly elucidated.
Aside from cognitive deficits, another consequence of chronic cocaine, either passively or self-administered, is enhanced dopamine (DA) release in the nucleus accumbens (NAc) in response to rewards and reward-related stimuli [6], [7]. Studies in rodents have shown that this sensitized DA release is associated with increases in non-drug reward-directed behavior [8] as well as cocaine-dependent behaviors such as psychomotor sensitization [9]. Given the co-occurrence of increased impulsive choice and sensitized NAc DA release following chronic cocaine administration, changes in NAc DA release may be a mechanism by which cocaine could cause increased impulsive choice. Evidence for this hypothesis includes the fact that both sensitized NAc DA release and cocaine-induced increases in impulsive choice are long-lasting phenomena (they can persist for months if not longer) [7], [10]. Additionally, artificially augmented NAc DA release enhances other aspects of reward-directed behavior, such as Pavlovian-instrumental transfer [11], [12]. Berridge [13] proposed that enhancements in DA release in the NAc may augment the incentive salience attributed to smaller, more immediate rewards over larger, delayed rewards, thus biasing choice toward more immediate gratification. Indeed, human neuroimaging data show that greater activity in the NAc is associated with choice of smaller, more immediate over larger, delayed monetary rewards [14], possibly reflecting greater salience ascribed to the immediate rewards. Together, these lines of evidence suggest that enhanced DA activity in the NAc may play a causal role in increased impulsive choice caused by chronic cocaine, possibly by enhancing the salience of more immediate gratification.
To determine whether enhanced NAc DA release could account for increased impulsive choice observed following chronic cocaine administration, we microinjected the indirect DA agonist amphetamine acutely into the NAc of rats prior to testing in a delay discounting task. This manipulation has been shown to increase incentive salience attributed to reward cues [8] in a manner similar to that produced by chronic cocaine administration [15]. Further, acute (although not chronic) systemic amphetamine has been shown to alter impulsive choice in a rodent delay discounting task [16], [17], [18], [19], [20], [21], [22], [23]. However, the effects of amphetamine directly into the NAc on impulsive choice have yet to be tested. Based on previous work, we predicted that intra-NAc amphetamine would increase impulsive choice, and that this would be due to enhancement of the salience of the small, immediate reward.
Section snippets
Subjects
Male Long-Evans rats (n = 73; 70 days old upon arrival; Charles River Laboratories, Raleigh, NC) were individually housed in a temperature controlled vivarium and kept on a 12 h light/dark cycle. Rats received free access to food and water except as noted. During behavioral training, rats were maintained at 85% of their free-feeding weight, with target weights adjusted upward by 5 g/week to account for growth. All animal procedures were conducted in accordance with the University of Florida
Histology
Of the initial 48 rats in the ascending group, 13 were excluded due to illness or death during surgery and 20 were excluded due to cannula misplacements. In the descending group, 11 out of the initial 25 rats were excluded due to cannula misplacements. In this same group, three additional rats were excluded due to illness during the experiment. Locations of cannula placements for rats included in the study (ascending, n = 15; descending, n = 11) are depicted in Fig. 1.
Effects of intra-accumbens amphetamine on delay discounting task performance
Rats were trained in the delay
Discussion
Taken together, the data show that acute intra-NAc amphetamine administration affects delay discounting task performance, but that the direction of the effect depends upon the order in which the delays are presented. These findings are consistent with previous work demonstrating that the effects of systemic amphetamine may depend on several different factors, such as the parameters of the delay discounting task and baseline levels of impulsivity. For example, as with the current findings, Tanno
Acknowledgements
We thank the Drug Supply Program at NIDA for kindly providing D-amphetamine. Supported by a McKnight Brain Institute Fellowship and a Thomas H. Maren Fellowship (CAO), DA033074 (MRM), and DA024671 and DA036534 (BS).
References (54)
Delay discounting in currently using and currently abstinent cocaine-dependent outpatients and non-drug-using matched controls
Addict. Behav.
(2006)- et al.
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res. Rev.
(1993) - et al.
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res.
(1986) - et al.
Impulsive choice and environmental enrichment: effects of d-amphetamine and methylphenidate
Behav. Brain Res.
(2008) Critical involvement of dopaminergic neurotransmission in impulsive decision making
Biol. Psychiatry
(2006)- et al.
Nucleus accumbens core and shell inactivation differentially affects impulsive behaviours in rats
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2014) Mesolimbic dopamine dynamically tracks, and is causally linked to, discrete aspects of value-based decision making
Biol. Psychiatry
(2015)Neural substrates of cognitive inflexibility after chronic cocaine exposure
Neuropharmacology
(2009)- et al.
Impulsivity, risk taking, and timing
Behav. Process.
(2012) - et al.
Decision making, impulsivity and time perception
Trends Cogn. Sci.
(2008)
Comparative effects of nicotine and amphetamine on timing behavior in rats
Neuropharmacology
Systemic and intra-accumbens administration of amphetamine differentially affects cortical acetylcholine release
Neuroscience
Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum
Exp. Neurol.
Long-term opiate effects on amphetamine-induced dopamine release in the nucleus accumbens core and conditioned place preference
Pharmacol. Biochem. Behav.
Impulsivity as a determinant and consequence of drug use: a review of underlying processes
Addict. Biol.
Choice impulsivity: definitions, measurement issues, and clinical implications
Pers. Disord.
Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls
J. Exp. Psychol. Gen.
Hyperbolic temporal discounting in social drinkers and problem drinkers
Exp. Clin. Psychopharmacol.
Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies
Psychopharmacology (Berl.)
Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward wanting without enhanced liking or response reinforcement
J. Neurosci.
Cocaine and intertemporal decision making
Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered ‘wanting' for reward: entire core and medial shell mapped as substrates for PIT enhancement
Eur. J. Neurosci.
Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens
Psychopharmacology (Berl.)
The debate over dopamine's role in reward: the case for incentive salience
Psychopharmacology (Berl.)
Separate neural systems value immediate and delayed monetary rewards
Science
Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats
PLoS One
Effects of amphetamine and methylphenidate on delay discounting in rats: interactions with order of delay presentation
Psychopharmacology (Berl.)
Cited by (23)
Contrasting effects of d-amphetamine and atomoxetine on measures of impulsive action and choice
2021, Pharmacology Biochemistry and BehaviorCitation Excerpt :This design was motivated by the reports of Tanno et al. (2013) and Orsini et al. (2017), who reported that the effect of AMP on discounting was dependent on delay sequence. Despite the differences of injection route (systemic: Tanno et al., 2013; intra-accumbens: Orsini et al., 2017), in each case the effect of AMP was dependent on delay order, with a reduction in discounting under ascending delays, and an increased discounting under descending delays. The current study mirrored those findings.
Effects of a high-fat diet on impulsive choice in rats
2021, Physiology and BehaviorCitation Excerpt :After the last washout day, rats were shaped and tested in a progressive ratio schedule of reinforcement task for six days. Detailed shaping procedures for the delay discounting task have been previously described [31,32,48,49]. Briefly, rats underwent one session of magazine training, in which a single food pellet (45 mg) was delivered every 100 ± 40 s over a 64 min session.
Involvement of noradrenergic and serotonergic systems in risk-based decisions between options of equivalent expected value in rats
2020, Neurobiology of Learning and MemoryEffects of d-amphetamine and MK-801 on impulsive choice: Modulation by schedule of reinforcement and delay length
2019, Behavioural Brain ResearchContributions of medial prefrontal cortex to decision making involving risk of punishment
2018, Neuropharmacology