What’s deficient in reward deficiency?
========================================

* Marco Leyton

It has been proposed that people with substance use disorders suffer from a reward deficiency syndrome. Sometimes this is framed as a pre-existing trait; sometimes it is framed as an acquired condition. Although the reward deficiency idea is often used as an explanation for excessive substance use, there is little consensus about the deficiency’s basis or how it might increase drug and alcohol use.

## Is there deficient reward in the absence of drug use?

At least 3 populations at elevated risk of addictions show evidence of having fewer rewarding experiences when abstaining from drugs and alcohol. First, individuals in depressive states typically have a reduced ability to experience pleasure (anhedonia) or a loss of interest in potential pleasures.1–3 Second, people with high sensation-seeking traits are often characterized as being easily bored and actively engaged by intense stimulation only.4,* Third, those who use drugs can have transient reductions in rewarding experiences in the immediate aftermath of a drug binge6,7 and, possibly, more enduring reductions following quite extensive substance use.6,8 In all 3 groups, it seems difficult to explain the initiation of reward seeking. Deficit states, in and of themselves, do not induce reward-seeking behaviours.9 Deficits can, however, produce a contrast effect, increasing the drawing power of rewards once the reward has been experienced.10 One can therefore imagine individuals who, after these initial experiences, are attracted to intensely rewarding substances and little else.

## Is there deficient drug-induced reward?

In a second version of the reward deficiency hypothesis it is the drug-induced responses that are reduced, and the only way for an affected individual to experience a reasonable amount of pleasure is to consume a greater amount of drug in a given length of time. One potential example is that elevated susceptibility to alcohol use disorders is associated with a lowered alcohol intoxication response.11 Of note, though, this low level of response predictor of alcohol use problems is based on reduced body sway. Thus, the diminished response might primarily reflect decreased sedative effects of alcohol rather than decreased positive affective experiences.† Contradicting the idea of a deficiency in the pleasure response is an equally compelling literature indicating that most individuals considered at risk for addictions report larger positive affective responses to drug challenges,14–16 raising the possibility that these affective features are either less relevant than has been suggested or instead reflect secondary features of other underlying processes.

## Is there deficient dopamine?

One prominent idea commonly embedded in the reward deficiency hypothesis is that drug use is the consequence of a low functioning midbrain dopamine (DA) system.17 For example, Blum and colleagues18 note that, despite the many incarnations of the hypothesis, it “continues to posit that hypodopaminergic function predisposes an individual to seek psychoactive substances and behaviours to release DA in reward circuits of the brain to overcome DA deficits.” This proposition is interesting and seems consistent with the proposal that some individuals at risk for addictions experience depressive mood states. However, the specific formulation also seems to reflect the now largely abandoned idea that increases in DA equal pleasure. Contemporary views are that elevated DA transmission enhances the ability of motivationally salient stimuli to draw and sustain approach, but these behavioural effects do not derive from increased pleasure.19–23,‡

What, then, is the empirical evidence for altered DA transmission in addictions in humans? In those with severe and sustained substance use disorders, reduced amphetamine-evoked DA responses have been seen with considerable consistency.24,25 Moreover, there is recent evidence that this muted response may be a pre-existing (or rapidly developing) vulnerability trait.26 The basis and meaning of these low DA responses, however, remain unclear. They could reflect neurotoxic effects in late-stage addictions,27 heritable endophenotypes, conditioned inhibitory effects induced by cues that signal the absence of reward,5,28 or some combination of these effects (e.g., initial predispositions aggravated by rapidly developing conditioned effects and later-stage neurotoxicity).

In support of the idea of conditioned inhibitory effects, low DA and other striatal responses have been observed in high-risk individuals when they are tested with cues associated with the absence of drugs.5,28 In comparison, augmented striatal responses have been seen when high-risk individuals are tested in the presence of drug-paired cues.5,13,28 Indeed, across stages of addiction, striatal DA release is induced by drug-paired cues alone.5,28,29 Thus, although the full clinical picture of addiction may well include periods of both increased and decreased DA transmission, the appearance of drug-related cues can provoke DA release, transforming a low DA state into a high one, fostering impulsive actions30 and drug-seeking behaviours.19,21,31–33

## Conclusion

The above observations suggest that 2 variants of a deficiency hypothesis might have some utility, though not as originally envisaged. First, there may be individuals for whom many reward effects are muted, with only quite potent events able to induce DA release and motivate approach and desire. This might be seen most typically during and immediately after an extended drug binge; in late-stage substance use disorders where the DA system may have suffered damage; or, possibly, in individuals with pre-existing traits, such as sensation seeking or aspects of depression. Second, there may be individuals for whom DA-related approach responses are augmented in the presence of cues previously paired with the addictive substance and inhibited by cues associated with their absence. Central to the current discussion, in each of these scenarios, individual bouts of drug seeking are precipitated by increases in DA transmission rather than decreases.

## Acknowledgements

The author thanks Jane Stewart, John Salamone and Chawki Benkelfat for their feedback on an earlier version of this editorial.

## Footnotes

*   * Compared with most other people, sensation seekers appear to have reduced appetitive responses to low salience stimuli. Their response to motivationally salient stimuli, though, might be greater than average in absolute magnitude, greater in proportion to their response to low salience stimuli, or neither. Behavioural and neuro-imaging studies suggest that the latter possibility is the least likely.5

*   † Disentangling sedative from stimulant effects of ethanol has been difficult. In a self-report measure of the low alcohol response, the items considered most sensitive are Alcohol Effect, Clumsy, Confused, Dizzy, Drunk, High and Trouble Concentrating.12 Of note, this low intoxication response is reported to be associated with large, rather than blunted, striatal dopamine responses when individuals drink alcohol.13

*   ‡ As summarized by John Salamone, “We don’t seek DA; DA makes us seek” (personal communication, 2014).

## References

1.  Leventhal AM, Brightman M, Ameringer KJ, et al.Anhedonia associated with stimulant use and dependence in a population-based sample of American adults.Exp Clin Psychopharmacol 2010;18:562–9.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1037/a0021964&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=21186931&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

2.  Kushner MG, Wall MW, Krueger RF, et al.Alcohol dependence is related to overall internalizing psychopathology load rather than to particular internalizing disorders: evidence from a national sample.Alcohol Clin Exp Res 2012;36:325–31.
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=21895708&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

3.  Conway KP, Compton W, Stinson FS, et al.Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiological Survey on Alcohol and Related Disorders.J Clin Psychiatry 2006;67:247–57.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.4088/JCP.v67n0211&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=16566620&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000235931000011&link_type=ISI) 

4.  Stautz K, Cooper A.Impulsivity-related personality traits and adolescent alcohol use: a meta-analytic review.Clin Psychol Rev 2013;33:574–92.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.cpr.2013.03.003&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=23563081&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

5.  Leyton M, Vezina P.Dopamine ups and downs in vulnerability to addictions: a neurodevelopmental model.Trends Pharmacol Sci 2014;35:268–76.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.tips.2014.04.002&link_type=DOI) 

6.  Gawin FH, Kleber HD.Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations.Arch Gen Psychiatry 1986;43:107–13.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1001/archpsyc.1986.01800020013003&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=3947206&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1986AYS4000001&link_type=ISI) 

7.  Koob GF.Addiction is a reward deficit and stress surfeit disorder.Front Psychiatry 2013;4:72
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.3389/fpsyt.2013.00072&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=23914176&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

8.  Leventhal AM, Kahler CW, Ray LA, et al.Anhedonia and amotivation in psychiatric outpatients with fully remitted stimulant use disorder.Am J Addict 2008;17:218–23.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1080/10550490802019774&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=18463999&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000256355600009&link_type=ISI) 

9.  1.  Bindra D, 
    2.  Stewart J
    
    , eds (1966) Motivation (Penguin).
    
    

10. Toates F (1986) Motivational Systems (Cambridge University Press, Cambridge (UK)).
    
    

11. Schuckit MA.Subjective responses to alcohol in sons of alcoholics and control subjects.Arch Gen Psychiatry 1984;41:879–84.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1001/archpsyc.1984.01790200061008&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=6466047&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1984TH27100007&link_type=ISI) 

12. Schuckit MA, Smith TL, Kalmijn J, et al.Response to alcohol in daughters of alcoholics: a pilot study and a comparison with sons of alcoholics.Alcohol Alcohol 2000;35:242–8.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1093/alcalc/35.3.242&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=10869242&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000088496900004&link_type=ISI) 

13. Setiawan E, Pihl RO, Dagher A, et al.Differential striatal dopamine responses following oral alcohol in individuals at varying risk for dependence.Alcohol Clin Exp Res 2014;38:126–34.
    
    

14. Tremblay LK, Naranjo CA, Cardenas L, et al.Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine.Arch Gen Psychiatry 2002;59:409–16.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1001/archpsyc.59.5.409&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=11982444&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000175409800001&link_type=ISI) 

15. Quinn PD, Fromme K.Subjective response to alcohol challenge: a quantitative review.Alcohol Clin Exp Res 2011;35:1759–70.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1111/j.1530-0277.2011.01521.x&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=21777258&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

16. de Wit H, Phillips TJ.Do initial responses to drugs predict future use or abuse?.Neurosci Biobehav Rev 2012;36:1565–76.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.neubiorev.2012.04.005&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=22542906&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

17. Blum K, Braverman ER, Holder JM, et al.Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.J Psychoactive Drugs 2000;32Suppl i–iv1–112.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1080/02791072.2000.10400206&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=11280926&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000086655300001&link_type=ISI) 

18. Blum K, Gardner E, Oscar-Berman M, et al.“Liking” and “wanting” linked to reward deficiency syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry”.Curr Pharm Des 2012;18:113–8.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.2174/138161212798919110&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=22236117&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

19. Berridge KC, Robinson TE.Parsing reward.Trends Neurosci 2003;26:507–13.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/S0166-2236(03)00233-9&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=12948663&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000185311500014&link_type=ISI) 

20. Salamone JD.Functions of mesolimbic dopamine: changing concepts and shifting paradigms.Psychopharmacology (Berl) 2007;191:389
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1007/s00213-006-0623-9&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17334798&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

21. Venugopalan VV, Casey KF, O’Hara C, et al.Acute phenylalanine/tyrosine depletion reduces motivation to smoke across stages of addiction.Neuropsychopharmacology 2011;36:2469–76.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1038/npp.2011.135&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=21775977&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000296070900011&link_type=ISI) 

22. Liggins J, Pihl RO, Benkelfat C, et al.The dopamine augmenter L-DOPA does not affect positive mood in healthy human volunteers.PLoS ONE 2012;7:e28370
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1371/journal.pone.0028370&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=22238577&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

23. Wise RA.Dopamine, learning and motivation.Nat Rev Neurosci 2004;5:483–94.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1038/nrn1406&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=15152198&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000221785900015&link_type=ISI) 

24. Volkow ND, Wang G-J, Fowler JS, et al.Addiction circuitry in the human brain.Annu Rev Pharmacol Toxicol 2012;52:321–36.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1146/annurev-pharmtox-010611-134625&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=21961707&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

25. Trifilieff P, Martinez D.Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity.Neuropharmacology 2014;76Pt B498–509.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.neuropharm.2013.06.031&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=23851257&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000330083600029&link_type=ISI) 

26. Casey KF, Benkelfat C, Cherkasova MV, et al.Reduced dopamine response to amphetamine in subjects at ultra high risk for addiction.Biol Psychiatry 2014;76:23–30.
    
    

27. Little KY, Krolewski DM, Zhang L, et al.Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users.Am J Psychiatry 2003;160:47–55.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1176/appi.ajp.160.1.47&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=12505801&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000180195400010&link_type=ISI) 

28. Leyton M, Vezina P.Striatal ups and downs: their roles in vulnerability to addictions in humans.Neurosci Biobehav Rev 2013;379 Pt A1999–2014.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.neubiorev.2013.01.018&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=23333263&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

29. Oberlin BG, Dzemidzic M, Tran SM, et al.Beer flavor provokes striatal dopamine release in male drinkers: mediation by family history of alcoholism.Neuropsychopharmacology 2013;38:1617–24.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1038/npp.2013.91&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=23588036&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=000321823400003&link_type=ISI) 

30. Leyton M.Conditioned and sensitized responses to stimulant drugs in humans.Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1601–13.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1016/j.pnpbp.2007.08.027&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17888557&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

31. Stewart J.Psychological and neural mechanisms of relapse.Philos Trans R Soc Lond B Biol Sci 2008;363:3147–58.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1098/rstb.2008.0084&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=18640921&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 

32. Stewart J, de Wit H, Eikelboom R.The role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants.Psychol Rev 1984;91:251–68.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1037/0033-295X.91.2.251&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=6571424&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom) 
    
    [Web of Science](http://jpn.ca/lookup/external-ref?access_num=A1984SL56400005&link_type=ISI) 

33. Salamone JD, Correa M, Farrar A, et al.Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits.Psychopharmacology (Berl) 2007;191:461–82.
    
    [CrossRef](http://jpn.ca/lookup/external-ref?access_num=10.1007/s00213-006-0668-9&link_type=DOI) 
    
    [PubMed](http://jpn.ca/lookup/external-ref?access_num=17225164&link_type=MED&atom=%2Fjpn%2F39%2F5%2F291.atom)