Effects of disulfiram on choice behavior in a rodent gambling task: association with catecholamine levels
Gambling disorder is a growing societal concern, as recognized by its recent classification as an addictive disorder in the DSM-5. Case reports have shown that disulfiram reduces gambling-related behavior in humans.
The purpose of the present study was to determine whether disulfiram affects performance on a rat gambling task, a rodent version of the Iowa gambling task in humans, and whether any changes were associated with alterations in dopamine and/or norepinephrine levels.
Rats were administered disulfiram prior to testing on the rat gambling task or prior to analysis of dopamine or norepinephrine levels in brain homogenates. Rats in the behavioral task were divided into two subgroups (optimal vs suboptimal) based on their baseline levels of performance in the rat gambling task. Rats in the optimal group chose the advantageous strategy more, and rats in the suboptimal group (a parallel to problem gambling) chose the disadvantageous strategy more. Rats were not divided into optimal or suboptimal groups prior to neurochemical analysis.
Disulfiram administered 2 h, but not 30 min, before the task dose-dependently improved choice behavior in the rats with an initial disadvantageous “gambling-like” strategy, while having no effect on the rats employing an advantageous strategy. The behavioral effects of disulfiram were associated with increased striatal dopamine and decreased striatal norepinephrine.
These findings suggest that combined actions on dopamine and norepinephrine may be a useful treatment for gambling disorders.
KeywordsNorepinephrine Dopamine Gambling Antabuse
We thank Doug Bernhard for his technical assistance with the HPLC system.
The current study was funded through a mid-level grant provided by the Ontario Problem Gambling Research Council to PDC and BLF and by the National Institute of Drug Abuse (DA038453 to DW) and the National Institute of Neurological Disorders and Stroke (NS088528 to EJH).
Compliance with ethical standards
This study was carried out in strict accordance with the recommendations by the Canadian Council on Animal Care. The protocol was approved by the Centre for Addiction and Mental Health Animal Care Committee.
Conflict of interest
The authors declare that they have no conflicts of interest.
- American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, fifth edition, DSM-5. In: American Psychiatric Association (5th ed.)Google Scholar
- Barnum CJ, Bhide N, Lindenbach D, Surrena MA, Goldenberg AA, Tignor S, Klioueva A, Walters H, Bishop C (2012) Effects of noradrenergic denervation on L-DOPA-induced dyskinesia and its treatment by alpha- and beta-adrenergic receptor antagonists in hemiparkinsonian rats. Pharmacol Biochem Behav 100:607–615CrossRefPubMedGoogle Scholar
- Boileau I, Payer D, Chugani B, Lobo D, Behzadi A, Rusjan PM, Houle S, Wilson AA, Warsh J, Kish SJ, Zack M (2013) The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [(11) C]-(+)-propyl-hexahydro-naphtho-oxazin and [(11) C]raclopride. Addiction 108:953–963CrossRefPubMedGoogle Scholar
- Clark L, Stokes PR, Wu K, Michalczuk R, Benecke A, Watson BJ, Egerton A, Piccini P, Nutt DJ, Bowden-Jones H, Lingford-Hughes AR (2012) Striatal dopamine D(2)/D(3) receptor binding in pathological gambling is correlated with mood-related impulsivity. NeuroImage 63:40–46CrossRefPubMedPubMedCentralGoogle Scholar
- Cocker P, Rogers R, Le Foll B, Winstanley C (2011) Dopamine D4 receptors influence “near-miss”-like errors on a rodent slot machine task. American College of Neuropsychopharmacology 50th Annual Conference, Kona, HawaiiGoogle Scholar
- Cocker PJ, Le Foll B, Rogers RD, Winstanley CA (2013) A selective role for dopamine D receptors in modulating reward expectancy in a rodent slot machine task. Biol PsychiatryGoogle Scholar
- de Visser L, Homberg JR, Mitsogiannis M, Zeeb FD, Rivalan M, Fitoussi A, Galhardo V, van den Bos R, Winstanley CA, Dellu-Hagedorn F (2011) Rodent versions of the Iowa gambling task: opportunities and challenges for the understanding of decision-making. Front Neurosci 5:109PubMedPubMedCentralGoogle Scholar
- Faiman MD, Kaul S, Latif SA, Williams TD, Lunte CE (2013) S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: a microdialysis study. Neuropharmacology 75:95–105CrossRefPubMedPubMedCentralGoogle Scholar
- Gobert A, Billiras R, Cistarelli L, Millan MJ (2004) Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors. J Neurosci Methods 140:141–152CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, AustraliaGoogle Scholar
- Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine beta-hydroxylase. Neuropsychopharmacology 35:2440–2449CrossRefPubMedPubMedCentralGoogle Scholar
- Stephan RA, Alhassoon OM, Allen KE, Wollman SC, Hall M, Thomas WJ, Gamboa JM, Kimmel C, Stern M, Sari C, Dalenberg CJ, Sorg SF, Grant I (2017) Meta-analyses of clinical neuropsychological tests of executive dysfunction and impulsivity in alcohol use disorder. Am J Drug Alcohol Abuse 43:24–43CrossRefPubMedGoogle Scholar
- Winefield RD, Heemskerk AA, Kaul S, Williams TD, Caspers MJ, Prisinzano TE, McCance-Katz EF, Lunte CE, Faiman MD (2015) N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration. J Pharm Biomed Anal 107:518–525CrossRefPubMedPubMedCentralGoogle Scholar