Unpredictable saccharin reinforcement enhances locomotor responding to amphetamine

doi:10.1016/j.bbr.2011.09.003

Behavioural Brain Research

Volume 226, Issue 1, 1 January 2012, Pages 340-344

https://doi.org/10.1016/j.bbr.2011.09.003 Get rights and content

Abstract

Drug-naïve, non-deprived rats were trained to lever press for saccharin under fixed-ratio (FR) or variable-ratio (VR) schedules of reinforcement. Rats trained on the VR schedule in which saccharin reinforcement was not predicted by a fixed number of lever presses subsequently showed an enhanced locomotor response to a threshold amphetamine challenge injection (0.5 mg/kg IP) administered 2 weeks following the last saccharin session. This finding suggests that chronic exposure to gambling-like conditions of uncertain reinforcement can induce neuroadaptations in brain reward systems that are similar to those produced by repeated psychostimulant exposure and may lead to the development of addictive behaviors.

Highlights

► Drug-naïve rats were trained to self-administer saccharin. ► Saccharin reinforcement was either predictable or unpredictable. ► Unpredictable saccharin reinforcement produced cross-sensitization to amphetamine.

Section snippets

Report

Repeated exposure to psychostimulants such as amphetamine leads to an enhancement of their behavioral and biochemical effects, known as sensitization. Neuroadaptations associated with sensitization occur in specific brain regions and may underlie the transition from casual drug use to craving and abuse [1], [2]. In animal models of drug abuse, sensitization has been manifested by enhanced locomotor activation and nucleus accumbens (NAcc) dopamine (DA) overflow in response to the drug, as well

Acknowledgements

Research reported in the article was funded by US National Institutes of Health (NIH) grants R01 DA09397 (PV), T32 DA07255 (BFS), and F31 DA030021-01A1 (BFS). Work by B.F. Singer was partially funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust.

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Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex
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Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation.
To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings.
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While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.
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Reward uncertainty can sensitize reward pathways, promoting increased reward-seeking and -taking behaviours. This is relevant to human conditions such as pathological gambling, eating disorders and drug addiction. In the context of addiction, preclinical self-administration procedures have been developed to model the intermittency of human drug use. These intermittent-access (IntA) procedures involve intermittent but predictable access to drug during self-administration sessions. However, human drug use typically involves intermittent and unpredictable drug access. We introduce a new procedure modeling unpredictable, intermittent access (UIntA) to a reinforcer, and we compare it to procedures that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Female rats self-administered water or liquid sucrose in daily hour-long sessions. IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had predictable 5-min reinforcer ON and 25-min reinforcer OFF periods. ContA rats had 60 min of reinforcer access during each session. For UIntA rats, variation in the length of ON and OFF periods (1, 5 or 9 min/period), response requirement (variable ratio 3 schedule of reinforcement), reinforcer probability (50%) and quantity (0, 0.1 or 0.2 ml) introduced reward uncertainty. Following 14 daily self-administration sessions, UIntA rats showed the highest levels of responding for water or sucrose under progressive ratio conditions, responding under extinction conditions, and cue-induced reinstatement of sucrose seeking. Thus, unpredictable, intermittent reward access promotes increased reward pursuit. This has implications for modeling addiction and other disorders of increased reward seeking.
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Influential learning-based accounts of substance addictions posit the attribution of incentive salience to drug-associated cues, and its escalation by the direct dopaminergic effects of drugs. In translating this account to disordered gambling, we have noted how the intermittent nature of monetary rewards in gambling (i.e. the variable ratio) may allow for analogous learning processes, via effects on dopaminergic signalling. The aim of the present article is to consider how multiple sources of reward variability operate within modern gambling products, and how similar sources of variability, as well as some novel sources of variability, also apply to other digital products implicated in behavioural addictions, including gaming, shopping, social media and online pornography. Online access to these activities facilitates not only unparalleled accessibility but also introduces novel forms of reward variability, as seen in the effects of infinite scrolls and personalized recommendations. We use the term uncertainty to refer to the subjective experience of reward variability. We further highlight two psychological factors that appear to moderate the effects of uncertainty: 1) the timecourse of uncertainty, especially with regard to its resolution, 2) the frequency of exposure, allowing temporal compression. Collectively, the evidence illustrates how qualitative and quantitative variability of reward can confer addictive potential to non-drug reinforcers by exploiting the psychological and neural processes that rely on predictability to guide reward seeking behaviour.
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Drug self-administration has been regarded as a gold-standard preclinical model of addiction and substance-use disorder (SUD). However, investigators are becoming increasingly aware, that certain aspects of addiction or SUDs experienced by humans are not accurately captured in our preclinical self-administration models. The current review will focus on two such aspects of current preclinical drug self-administration models: 1) Predictable vs. unpredictable drug access in terms of the time and effort put into obtaining drugs (i.e., response requirement) and drug quality (i.e., amount) and 2) rich vs. lean access to drugs. Some behavioral and neurobiological mechanisms that could contribute to excessive allocation of behavior toward drug-seeking and drug-taking at the expense of engaging in nondrug-related activities are discussed, and some directions for future research are identified. Based on the experiments reviewed, lean and unpredictable drug access could worsen drug-seeking and drug-taking behavior in individuals with SUDs. Once more fully explored, this area of research will help determine whether and how unpredictable and lean cost requirements affect drug self-administration in preclinical laboratory studies with nonhuman subjects and will help determine whether incorporating these conditions in current self-administration models will increase their predictive validity.

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Short communicationUnpredictable saccharin reinforcement enhances locomotor responding to amphetamine

Abstract

Highlights

Section snippets

Report

Acknowledgements

Neurosci Biobehav Rev

Brain Res Brain Res Rev

Prog Neuropsychopharmacol Biol Psychiatry

Neurosciences

Pharmacol Biochem Behav

Brain Res

Neuron

Neurosci Biobehav Rev

Alcohol

Neurosciences

Mol Brain Res

Mol Brain Res

Brain Res

Neurosci Lett

Physiol Behav

Eur J Psychiatry

Neuron

Brain Res Mol Brain Res

Neuropharmacology

Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine

J Neurosci

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies

Psychopharmacology (Berl)

Relationship between pathological gambling, alcoholism and drug addiction

Ann Ig

Gambling in mild-moderate alcohol-dependent outpatients

Subst Use Misuse

Cocaine abuse and pathological gambling

Am J Addiction

Pathological gambling among cocaine-dependent outpatients

Am J Psychiatry

Parallel roles for dopamine in pathological gambling and psychostimulant addiction

Curr Drug Abuse Rev

Amphetamine primes motivation to gamble and gambling-related semantic networks in problem gamblers

Neuropsychopharmacology

Predictability modulates human brain response to reward

J Neurosci

BOLD responses reflecting dopaminergic signals in the human ventral tegmental area

Science

Dopamine release in ventral striatum during Iowa Gambling Task performance is associated with increased excitement levels in pathological gambling

Addiction

Short communication
Unpredictable saccharin reinforcement enhances locomotor responding to amphetamine