Review: brain neurobiology of gambling disorder based on rodent models

Figures & data

Figure 1 Flow diagram of publication selection process. The diagram presents the plan used for publications choice, starting from initial Pub Med database search, up to the final articles incorporated in the publication.

Table 1 Summary of main studies included in the review – Neurotransmitters

Author & year	Silveira et al, 2015^Citation19	Yates et al, 2015^Citation20	Yates et al, 2015^Citation20	Gueye et al, 2016^Citation21	Di Ciano et al, 2015^Citation30	Pes et al, 2017^Citation43
Messenger & receptor	Acetylcholine – muscarinic	Glutamate –NMDA	Glutamate –NMDA	Cannabinoids – CB1/CB2 receptors	Dopamine –D4 receptor	Dopamine –D2/D3 receptor
Brain area	na	na	na	na	na	na
Drug name, effect, route	Scopolamine, antagonist, sc	MK-801, antagonist, sc	Ketamine, antagonist, ip	WIN 55, 212–2, agonist, ip	PD 168077, agonist, ip, L-745,870, antagonist, ip	Pramipexole, agonist, sc
Mental process and/or conduct analyzed	Decision making	Decreased sensitivity to delayed and uncertain reinforcement	Decreased sensitivity to reinforcer amount without altering delay/probability discounting	Improved choice strategy and increased choice latency (SO group); but increased perseverations punished (O group)	- D4 agonist small decrease latencies - D4 antagonist small increase latencies	Increase unfavorable decisions, impaired the discounting of probabilistic losses, and augment risk-taking behaviors
Behavioral test	Rodent gambling task	Delayed/probabilistic reinforcement, sensitivity to reinforcer amount	Delayed/probabilistic reinforcement, sensitivity to reinforcer amount	Rodent gambling task	Rodent gambling task	Probability discounting task
Species	Rats	Rats	Rats	Rats	Rats	Rats
Relevance of study	Receptor affect decision making under conditions of risk and uncertainty	- NMDA differ mediating Impulsivity - MK-801 increased risky decision - MK-801 may be ineffective for GD	- NMDA differ mediating impulsivity	Agonism of CB1/CB2 affect gambling choice differentially in healthy and dysfunctional subjects	Modest effect on latency in decision making	- Pramipexole distorted representation of rewards and impaired ability to discern contingencies (unfavorable and favorable) - Pramipexole conduct effects dissociates from changes in mesolimbic dopamine

Abbreviations: CB₁, cannabinoid receptor 1; CB₂, cannabinoid receptor 2; D₂, dopamine 2 receptor; D₃, dopamine 3 receptor; D₄, dopamine 4 receptor; GD, gambling disorder; ip, intraperitoneal administration; NMDA, N-methyl-D-aspartate; na, not applicable (because non-specific brain area was studied); O group, optimal group; sc, subcutaneous administration; SO group, suboptimal group.

Table 2 Summary of main studies included in the review – Brain structures

Author & year	Fitoussi et al, 2015^Citation44	Tremblay et al, 2014^Citation45	Zeeb & Winstanley, 2013^Citation46		Cocker et al, 2016^Citation48	Cocker et al, 2016^Citation48	Pittaras et al, 2016^Citation50
Brain area	Amygdala	Basolateral amygdala	Orbitofrontal cortex – basolateral amygdala pathway		Anterior cingulate cortex	Cingulate cortex (anterior)	Hippocampus
Messenger & receptor	Serotonin, Serotonergic receptor	—	—		GABA, GABAA and GABAB	Dopamine, D4	Dopamine, serotonin and noradrenalin
Drug name, effect, route	—	—	—		Muscimol, agonist, infusion and baclofen, agonist, infusion	PD168077, agonist, infusion	—
Behavioral test	Rat gambling task	Loss – chasing task, the betting task	Rat gambling task		Rodent slot machine task	Rodent slot machine task	Mice gambling task
Other technique/treatment used	—	Lesion of basolateral amygdala	Disconnection of pathway		—	—	—
Mental process and/or conduct analyzed	Decision making	Risk seeking	—		—	—	—
Species	Rat	Rat	Rat		Rat	Rat	Mice
Relevance of study	Amygdala: low serotonergic metabolism and constant action related to poor decision	- Amygdala plays a role in choice biases related to losses. - Basolateral amygdala lesions reduced loss aversion. - Communication is vital for adequate assessment of reward value to influence choice.	- Disconnection retarded acquisition of the task. - Disconnection prevented changes in the value of a specific reward from contributing appropriately to cost-benefit decision making		Impaired differentiation of wins and loses outcomes in the task. Anterior cingulate cortex is involved in analyzing the best response when competing stimulus and outcome associations are activated	Qualitatively equal effect (compared to left column – GABA), but augment reward expectancy was only evident on archetypal “near-miss” trials	High levels of dopamine, serotonin, and noradrenalin predicted the emergence of more exploratory and risky behaviors in healthy inbred mice
Author & year	Koot et al, 2013^Citation51	Mizoguchi et al, 2015^Citation52	Ishii et al, 2012^Citation53		Ishii et al, 2015^Citation54	Ishii et al, 2015^Citation54	Pushparaj et al, 2015^Citation55
Brain area	Insular cortex	Insular cortex	Anterior insular cortex		Anterior insular cortex	Anterior insular cortex	Caudal agranular Insular cortex
Messenger & receptor	Corticosteroid hormones	GABA, GABAA, and GABAB	GABA, GABAA, and GABAB		Dopamine, D2	Serotonin, 5-HT1A	GABA, GABAA and GABAB
Drug name, effect, route	Corticosteroid hormones, Agonist, sc	Muscimol, agonist, infusion and Baclofen, agonist, infusion	Muscimol, agonist, infusion and Baclofen, agonist, infusion		Eticlopride hydrochloride, antagonist, infusion	WAY100635, antagonist, infusion	Muscimol, agonist, infusion and baclofen, agonist, infusion
Behavioral test	Rodent gambling task	Radial arm maze (gambling adapted)	The amount gambling task, and the delay gambling task		Rodent gambling task (modified)	Rodent gambling task (modified)	Rodent gambling task
Other technique/treatment used	c-fos immuno - histochemistry	—	—		—	—	Lesion by infusion of ibotenic acid
Mental process and/or conduct analyzed	Decision making	Risk taking behaviors	Risk preference		Risk preference	Risk preference	Decision making: does not favor options linked to high reward frequency and low punishment
Species	Rat	Rat	Rat		Rat	Rat	Rat
Relevance of study	Stress (corticosteroid rapid action) disrupts decision making (reward-based)	Insular cortex inactivation induces risk-taking behaviors linked to altered decision-making during tests	Anterior insular cortex inactivation decreased risk preference		Anterior insular cortex blockade increased risk preference, after winning in a previous risky choice	Anterior insular cortex blockade increased risk preference, after losing in a previous risky choice	Caudal agranular Insular cortex is not involved in decision-making behavior under risk
Author & year	Pushparaj et al, 2015^Citation55	Peak et al, 2015^Citation56	Fitoussi et al, 2015^Citation44		Koot et al, 2013^Citation51	Zeeb et al, 2015^Citation49	Zeeb et al, 2015^Citation49
Brain area	Rostral agranular insular cortex	Lateral ventricle	Infralimbic area		Infralimbic area	Infralimbic area	Infralimbic area
Messenger & receptor	GABA, GABAA, and GABAB	—	Serotonin		Corticosteroid hormones	GABA, GABAA, and GABAB	Dopamine, D2
Drug name, effect, route	Muscimol, agonist, infusion and baclofen, agonist, infusion	—	—		Corticosteroid hormones, agonist, sc	Muscimol, agonist, infusion and baclofen, agonist, infusion	Eticlopride hydrochloride, antagonist, infusion
Behavioral test	Rodent gambling task	Rodent gambling task	Rodent gambling task		Rodent gambling task	Rodent gambling task	Rodent gambling task
Other technique/treatment used	Lesion by means of ibotenic acid infusion	Maternal vitamin D depletion (before and during pregnancy)	c-fos immuno-histochemistry		c-fos immuno-histochemistry	—	—
Mental process and/or conduct analyzed	Decision making: favor options with high reward frequency and low punishment	Decision making	Decision making		Decision making	Decision making (disrupted by inactivation)	Choice preference (not altered)
Species	Rat	Rat	Rat		Rat	Rat	Rat
Relevance of study	Rostral agranular insular cortex is involved in decision-making behavior under risk	Lateral ventricles enlargement did not alter decision making of the offspring	Infralimbic higher serotonergic metabolism relates to poor decision making		Stress (corticosteroid rapid action) disrupts decision making (reward-based)	Inactivation of infralimbic area has effects on option choice: increase for bad and decrease for good choices	Infralimbic disruption does not alter choice preference nor optimal performance
Author & year	Zeeb et al, 2015^Citation49	Peak et al, 2015^Citation56	Roitman & Loriaux, 2014^57	Lobo et al, 2015^Citation58		Ishii et al, 2012^Citation53	Ishii, et al 2015^Citation54
Brain area	Prelimbic cortex	Neocortex	Nucleus accumbens	Olfactory Tubercle (Islands of Calleja, and islands of Calleja Major)		Orbitofrontal cortex	Orbitofrontal cortex
Messenger & receptor	GABA, GABAA, and GABAB	—	—	D3		GABA, GABAA and GABAB	Serotonin, 5-HT1A
Drug name, effect, route	Muscimol, agonist, infusion and baclofen, agonist, infusion	—	—	—		Muscimol, agonist, infusion and baclofen, agonist, infusion	WAY100635, antagonist, infusion
Behavioral test	Rodent gambling task	Rodent gambling task	Go - no/go task	Rodent gambling task		The amount of gambling task. The delay gambling task	Rodent gambling task (modified)
Other technique/treatment used	—	Maternal vitamin D depletion (before and during pregnancy)	Electrophysiological recordings of neurons	In situ hybridization (messenger ribonucleic acid levels of D3)		—	—
Mental process and/or conduct analyzed	Choice selection was unaffected by inactivation	Decision making	Impulsivity/Restrain (Nucleus accumbens cue responses correlated with action, regardless of cue type or accuracy)	—		Risk preference	Risk preference
Species	Rat	Rat	Rat	Rat		Rat	Rat
Relevance of study	Prelimbic inactivation: does not alter choice preference	Thinner neocortex did not alter decision making of the offspring	Individual cue-responsive neurons showed either increases or decreases in activity at cue onset	messenger ribonucleic acid levels of D3 in Islands of Calleja (r =−0.91), and Islands of Calleja Major (r =0.62) are correlated with performance in task		Orbitofrontal cortex inactivation increase risk preference	Orbitofrontal cortex antagonism decreased risk preference
Author & year	Ishii et al, 2015^Citation54	Ishii et al, 2015^Citation54	Zeeb et al, 2015^Citation49	Paine et al, 2013^Citation60		Paine et al, 2015^Citation61	Baarendse et al, 2013^Citation62
Brain area	Orbitofrontal cortex	Orbitofrontal cortex	Orbitofrontal cortex	Medial prefrontal cortex		Medial prefrontal cortex	Medial prefrontal cortex
Messenger & receptor	Dopamine, D1 and D2	Serotonin and 5-HT2A	GABA, GABAA, and GABAB	—		GABA and GABAA	—
Drug name, effect, route	SCH 23390 hydrochloride, antagonist, infusion Eticlopride, hydrochloride, antagonist, infusion	M100907, antagonist and infusion	Muscimol, agonist, infusion and baclofen, agonist, infusion	—		Bicuculline methiodide, antagonist and infusion	—
Behavioral test	Rodent gambling task (modified)	Rodent gambling task (modified)	Rodent gambling task	Rodent gambling task		Rodent gambling task	Rodent gambling task
Other technique/treatment used	—	—	—	- Excitotoxic lesion by ibotenic acid - But, SCH 23390 hydrochloride lessened the lesion induced deficit		—	- Social Isolation: P21 - P42 - Cellular Electrophysiology - Five-Choice Serial Reaction Time task
Mental process and/or conduct analyzed	Risk preference	Risk preference	Decision making	Decision making impaired: fewer good choices, and chose the best choice less frequently		Decision making disrupted	Impulsivity/restrain and decision making
Species	Rats	Rats	Rats	Rats		Rats	Rats
Relevance of study	Orbitofrontal cortex antagonism did not alter risk preference	Orbitofrontal cortex antagonism did not alter risk preference	Orbitofrontal cortex inactivation did not affect decision making	Medial prefrontal cortex lesion impaired decision making		Disruptions in GABA dynamics contribute to decision-making deficits	- Isolation: impaired impulsive and decision processes under novel or demanding context. - Isolation induced lasting changes in pyramida neurons and synapses of the medial prefrontal cortex
Author & year	Fitoussi et al, 2015^Citation44	Cocker et al, 2012^Citation63	Gadziola and Wesson, 2016^Citation64	Phillips et al, 2016^Citation65		Aleksandrova et al, 2013^Citation66
Brain area	Prefrontal – subcortical network	Striatum	Ventral striatum, olfactory tubercle	Ventral striatum		Subthalamic nucleus
Messenger & receptor	Dopamine and serotonin	Dopamine, D2 and D3	—	—		—
Drug name, effect, route	—	—	—	—		—
Behavioral test	Rodent gambling task	Novel task for decision making	Novel water - motivated instrumental task	Stereotypic behavior paradigm		Rodent gambling task
Other technique/treatment used	- Histology and chromatographic analyses of post-mortem sample, - c-fos immuno - histochemistry	Micro – positron emission tomography, and autoradiography using^11C raclopride	In vivo electrophysiological recording	Immunohistochemical staining of FosB and ΔFosB technique		- Deep brain stimulation - Histology
Mental process and/or conduct analyzed	Decision making	Bet sensitivity	- Organization of goal directed behavior. - Process of reward information	Stereotypic behavior		Impulsivity/restrain
Species	Rats	Rats	Mice	Mice		Rats
Relevance of study	- Good decision: wider network, a disengagement of key prefrontal areas (insular and infralimbic areas) and the amygdala. - Poor decision: making: low network action and sustained amygdala activity	Low striatal D2 and D3 density correlates to high wager sensitivity	Encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward	- Elevated activity of the ventral striatum relates to stereotypic behavior- Related to the compulsivity seen in ludopathy		Sustained deep brain stimulation in the subthalamic nucleus, induced increase of premature responding in the task, and this persisted after finishing deep brain stimulation

Abbreviations: ^[11C] carbon 11; D₁, dopamine 1 receptor; D₂, dopamine 2 receptor; D₃, dopamine 3 receptor; D₄, dopamine 4 receptor; GABA, gamma-aminobutyric acid; GABA_A, gamma-aminobutyric acid receptor A; GABA_B, gamma-aminobutyric acid receptor B; P₂₁, post-natal day 21; P₄₂, post-natal day 42; 5-HT_1A, serotonin 1A receptor; 5-HT_2A, serotonin 2A receptor; sc, subcutaneous administration.

Silveira MM, Malcolm E, Shoaib M, Winstanley CA. Scopolamine and amphetamine produce similar decision-making deficits on a rat gambling task via independent pathways. Behav Brain Res. 2015;281:86–95. doi:10.1016/j.bbr.2014.12.02925529186

 PubMed Web of Science ®Google Scholar

Yates JR, Batten SR, Bardo MT, Beckmann JS. Role of ionotropic glutamate receptors in delay and probability discounting in the rat. Psychopharmacology. 2015;232(7):1187–1196. doi:10.1007/s00213-014-3747-325270726

 PubMed Web of Science ®Google Scholar

Gueye AB, Trigo JM, Vemuri KV, Makriyannis A, Le Foll B. Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling. Behav Pharmacol. 2016;27(2–3Spec Issue):258–269. doi:10.1097/FBP.000000000000022226905189

 PubMed Web of Science ®Google Scholar

Di Ciano P, Pushparaj A, Kim A, et al. The impact of selective dopamine D2, D3 and D4 ligands on the rat gambling task. PLoS One. 2015;10(9):e0136267. doi:10.1371/journal.pone.013626726352802

 PubMed Web of Science ®Google Scholar

Pes R, Godar SC, Fox AT, et al. Pramipexole enhances disadvantageous decision-making: lack of relation to changes in phasic dopamine release. Neuropharmacology. 2017;114:77–87. doi:10.1016/j.neuropharm.2016.11.01427889491

 PubMed Web of Science ®Google Scholar

Fitoussi A, Le Moine C, De Deurwaerdere P, et al. Prefronto-subcortical imbalance characterizes poor decision-making: neurochemical and neural functional evidences in rats. Brain Struct Funct. 2015;220(6):3485–3496. doi:10.1007/s00429-014-0868-825134683

 PubMed Web of Science ®Google Scholar

Tremblay M, Cocker PJ, Hosking JG, Zeeb FD, Rogers RD, Winstanley CA. Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized. Cogn Affect Behav Neurosci. 2014;14(4):1184–1195. doi:10.3758/s13415-014-0271-124668615

 PubMed Web of Science ®Google Scholar

Zeeb FD, Winstanley CA. Functional disconnection of the orbitofrontal cortex and basolateral amygdala impairs acquisition of a rat gambling task and disrupts animals’ ability to alter decision-making behavior after reinforcer devaluation. J Neurosci. 2013;33(15):6434–6443. doi:10.1523/JNEUROSCI.3971-12.201323575841

 PubMed Web of Science ®Google Scholar

Cocker PJ, Hosking JG, Murch WS, Clark L, Winstanley CA. Activation of dopamine D4 receptors within the anterior cingulate cortex enhances the erroneous expectation of reward on a rat slot machine task. Neuropharmacology. 2016;105:186–195. doi:10.1016/j.neuropharm.2016.01.01926775821

 PubMed Web of Science ®Google Scholar

Pittaras E, Callebert J, Chennaoui M, Rabat A, Granon S. Individual behavioral and neurochemical markers of unadapted decision-making processes in healthy inbred mice. Brain Struct Funct. 2016;221(9):4615–4629. doi:10.1007/s00429-016-1192-226860089

 PubMed Web of Science ®Google Scholar

Koot S, Baars A, Hesseling P, van Den Bos R, Joels M. Time-dependent effects of corticosterone on reward-based decision-making in a rodent model of the Iowa gambling task. Neuropharmacology. 2013;70:306–315. doi:10.1016/j.neuropharm.2013.02.00823474014

 PubMed Web of Science ®Google Scholar

Mizoguchi H, Katahira K, Inutsuka A, et al. Insular neural system controls decision-making in healthy and methamphetamine-treated rats. Proc Natl Acad Sci U S A. 2015;112(29):E3930–E3939. doi:10.1073/pnas.141801411226150496

 PubMed Web of Science ®Google Scholar

Ishii H, Ohara S, Tobler PN, Tsutsui K, Iijima T. Inactivating anterior insular cortex reduces risk taking. J Neurosci. 2012;32(45):16031–16039. doi:10.1523/JNEUROSCI.2278-12.201223136439

 PubMed Web of Science ®Google Scholar

Ishii H, Ohara S, Tobler PN, Tsutsui K, Iijima T. Dopaminergic and serotonergic modulation of anterior insular and orbitofrontal cortex function in risky decision making. Neurosci Res. 2015;92:53–61. doi:10.1016/j.neures.2014.11.00925481848

 PubMed Web of Science ®Google Scholar

Pushparaj A, Kim AS, Musiol M, et al. Differential involvement of the agranular vs granular insular cortex in the acquisition and performance of choice behavior in a rodent gambling task. Neuropsychopharmacol. 2015;40(12):2832–2842. doi:10.1038/npp.2015.133

 Web of Science ®Google Scholar

Peak JN, Turner KM, Burne TH. The effect of developmental vitamin D deficiency in male and female Sprague-Dawley rats on decision-making using a rodent gambling task. Physiol Behav. 2015;138:319–324. doi:10.1016/j.physbeh.2014.09.00725447469

 PubMed Web of Science ®Google Scholar

Zeeb FD, Baarendse PJ, Vanderschuren LJ, Winstanley CA. Inactivation of the prelimbic or infralimbic cortex impairs decision-making in the rat gambling task. Psychopharmacology. 2015;232(24):4481–4491. doi:10.1007/s00213-015-4075-y26387517

 PubMed Web of Science ®Google Scholar

Lobo DS, Aleksandrova L, Knight J, et al. Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models. Mol Psychiatry. 2015;20(8):1002–1010. doi:10.1038/mp.2014.11325266122

 PubMed Web of Science ®Google Scholar

Paine TA, Asinof SK, Diehl GW, Frackman A, Leffler J. Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: reversal by D1 receptor antagonist administration. Behav Brain Res. 2013;243:247–254. doi:10.1016/j.bbr.2013.01.01823354057

 PubMed Web of Science ®Google Scholar

Paine TA, O’Hara A, Plaut B, Lowes DC. Effects of disrupting medial prefrontal cortex GABA transmission on decision-making in a rodent gambling task. Psychopharmacology. 2015;232(10):1755–1765. doi:10.1007/s00213-014-3816-725420610

 PubMed Web of Science ®Google Scholar

Baarendse PJ, Counotte DS, O’Donnell P, Vanderschuren LJ. Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function. Neuropsychopharmacol. 2013;38(8):1485–1494. doi:10.1038/npp.2013.47

 Web of Science ®Google Scholar

Cocker PJ, Dinelle K, Kornelson R, Sossi V, Winstanley CA. Irrational choice under uncertainty correlates with lower striatal D(2/3) receptor binding in rats. J Neurosci. 2012;32(44):15450–15457. doi:10.1523/JNEUROSCI.0626-12.201223115182

 PubMed Web of Science ®Google Scholar

Gadziola MA, Wesson DW. The neural representation of goal-directed actions and outcomes in the Ventral Striatum’s olfactory tubercle. J Neurosci. 2016;36(2):548–560. doi:10.1523/JNEUROSCI.3328-15.2016

 Google Scholar

Phillips D, Choleris E, Ervin KS, et al. Cage-induced stereotypic behaviour in laboratory mice covaries with nucleus accumbens FosB/DeltaFosB expression. J Neurosci. 2016;301:238–242.

 Google Scholar

Aleksandrova LR, Creed MC, Fletcher PJ, Lobo DS, Hamani C, Nobrega JN. Deep brain stimulation of the subthalamic nucleus increases premature responding in a rat gambling task. Behav Brain Res. 2013;245:76–82. doi:10.1016/j.bbr.2013.02.01123434606

 PubMed Web of Science ®Google Scholar