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. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: J Psychiatr Res. 2018 Feb 13;101:80–103. doi: 10.1016/j.jpsychires.2018.02.002

Table 1.

Studies of Reward Processing in Animals.

Maternal Separation
Author,
year		 Species/
Strain		 Sex Timing of
Exposure		 Nature of
Exposure		 Methods/Group
Design		 Inferred Reward
Construct		 Method to
Assess
Reward		 Object PND
Test		 Main Findings Effect on Reward
Amiri et al., 2016 NMRI mice M PND 2-14 MS MS: separated from their mothers for 180 min/day. Reward responsiveness SPT 1% sucrose solution PND 50 Reduced consumption of sucrose compared to control rats. Decreased reward responsiveness.
Bai et al., 2014 Sprague Dawley rats M+F MS: PND 1-13
CUPS: 10 weeks		 MS,
CUPS, MS+CUPS		 MS: separated from their mothers for 6 hrs/day for 2 wks.
CUPS: exposed to one of various stressors once a day for 3 wks beginning at PND 70.
DUAL STRESS: MS + CUPS.
CONTROL: standard husbandry care.		 Reward responsiveness SPT 1% sucrose solution 13 wks Reduced consumption of sucrose in male MS and CUPS, but not MS + CUPS rats compared to controls.
Female MS+CUPS rats consumed less than control rats.		 Decreased reward responsiveness in males with only one exposure and in females with only dual exposure.
Bolton et al., 2017 Sprague Dawley rats M PND 2-9 Limited bedding Limited bedding: Pups and dam reduced nesting material PND 2-9.
Standard bedding on PND 10.

Controls: Normal bedding.		 Reward responsiveness, approach motivation SPT, social interaction 1.5% sucrose solution, social play with conspecific PND 56 Decreased sucrose preference and duration of social play in rats exposed to limited bedding. Decreased reward responsiveness.
Campbell et al., 2017 Wistar rats M PND 2-14 MS MS: separated from mother for 3 hrs/day.
Control: undisturbed.		 Approach motivation Sucrose self-administration (PR) 10% sucrose solution PND 70-75 MS rats similar self-administration on FR, decreased self-administration on PR. Decreased approach motivation.
Ferreira et al., 2013 Wistar rats M PND 1-10 MS MS: pups removed from home cages and placed in separate cages for 3 hrs/day.
NH: not handled until weaning.
H: pups were removed from home cages and placed in separate cages for 10 min/day.		 Reward responsiveness SPT 1% sucrose solution Not specified MS rats consumed more sucrose in the second hr of exposure. Increased reward responsiveness.
Hill et al., 2014 Wistar rats M+F PND 2-14 MS MS: pups separated from dam 3 hrs/day.
CONTROL: pups exposed to 10-15s of separation/day.
At 8 wks, all rats randomly assigned to receive 2 wks of cort or vehicle.		 Reward responsiveness SPT 1% sucrose solution Wk 14 No difference with MS in male or female. Decreased preference in MS females receiving cort. Decreased reward responsiveness with “two hit” of MS + cort in females but not males.
Hui et al., 2011 Sprague Dawley rats M+F PND 2-14 MS with or without EE post-weaning MS: litters separated from dams for 180 min/day.
Non-MS: stayed with dams.
Post weaning on PND 21, half the pups housed in standard conditions and half the pups housed in EE.		 Reward responsiveness SPT 1% sucrose solution PND 61-75 Reduced sucrose preference in MS rats.
EE rescued effect of MS sucrose preference.		 Decreased reward responsiveness.
Klug and Van de Bluse., 2012 Wistar rats M+F PND 2-14 MS MS: pups separated from dam 3 hrs/day.
CONTROL: exposed to 10-15s of separation.
At 8 wks, all rats received 2 wks of cannabinoid receptor agonist or vehicle.		 Reward responsiveness SPT 1% sucrose solution Wk 12 No difference with just MS in either sex. Decreased preference in MS males receiving cort. Decreased reward responsiveness with “two hit” of MS + cannabinoid in males but not females.
Kosten et al., 2006 Sprague Dawley rats F PND 2-9 MS MS: pups isolated individually for 1 hr/day.
CONTROL: NH.		 Approach motivation Food self-administration (PR) Food pellets ~PND 90 (adult rats≥ 90) MS females demonstrated increased lever pressing for food on escalating PR schedule. Increased approach motivation/willingness to work.
Kundakovic et al. 2013 Balb/cJ (Balb/c) mice and C57BL/6J (B6) mice M+F PND 1-14 MS + Maternal Unpredictable stress MS: pups isolated together for 2 hours daily.
Maternal Stress: Dams exposed to either 20 min restraint stress or 2 min forced swim during separation.
Controls: left undisturbed.		 Reward responsiveness,
approach motivation		 SPT 1% sucrose PND 36-39 (SPT) -MS C57BL/6J males and females decreased sucrose preference vs controls.
-MS Balb/c males decreased sucrose preference vs controls.
-MS Balb/c females increased sucrose preference vs controls.		 Decreased reward responsiveness in C57BL/6J M+F and Balb/c M. Increased reward responsiveness in Balb/c females.
Lomanowska et al., 2006 Sprague Dawley rats M PND 5-17 Artificial Rearing Artificial Rearing: feeding though gastric cannulae.
Maternal Rearing: reared by foster dam.		 Reward responsiveness SPT Table sugar PND 42-63 Increased sucrose preference in artificially reared rats. Increased reward responsiveness.
Maniam &; Morris, 2010 Sprague Dawley rats M+F PND 2-14 MS NH: litters not handled
MS15: litters separated from dams for 15 min/day.
MS180: litters separated from dams for 180 min/day.		 Reward responsiveness SPT 2.5% sucrose solution PND 34 Male MS180 rats decreased sucrose preference compared to NH and MS15 rats. No differences in females. Decreased reward responsiveness in males only.
Matthews et al., 1996a Lister-hooded rats M+F PND 5-20 MS MS: removed from home cages for 6-hr periods on 10 random days.
CONTROL: litters removed from home cages and placed into identical wire baskets for 5 min/separation day.		 Approach motivation, learning (valuation) Conditioned locomotor activity to food, contrast effects on sucrose preference Food pellets, sucrose solutions 10 wks, 12 wks (experimentally naïve) or 28 wks MS females failed to develop conditioned locomotor response. No effect on sucrose preference.
Controls greater downward shift in lick frequency during negative contrast. Controls increased lick frequency more than MS during positive contrast.		 Decreased approach motivation and decreased learning.
Matthews et al., 1996b Lister- hooded rats M+F PND 5-20 MS MS: 6-hr separations on 10 random days.
CONTROL: separated for 2 min/separation day.		 Approach motivation Conditioned locomotor response to food, effects of amphetamine, sulpiride, SCH-23390, and clonidine Food pellets 10 wks MS rats attenuated and delayed conditioned locomotor response; blunted response to enhancing effect of amphetamine and enhanced sensitivity to depressant effects of D2 blockade. Decreased approach motivation. Pharmacological manipulations suggestive of decreased DA tone.
Matthews and Robbins, 2003 Lister-hooded rats F PND 5-20 MS MS: 6-hr separations performed on 10 random days.
CONTROL: separated for 2 min/separation day.		 Approach motivation, “hedonic capacity” Intracranial self-stimulation threshold Electrical current to lateral hypothalamus >20 wks No difference in baseline threshold for stimulation.
MS rats more sensitive to D2 antagonist.		 No baseline differences.
Michaels and Holtzman, 2006 Long-Evans hooded rats M PND 3-14 MS MS: 15 1-hr or 3-hr separations.
CONTROL: NH.		 Reward responsiveness SPT 10% sucrose solution vs deionized water ~ 3 months MS rats drank more fluid total, but no differences in sucrose preference. No differences.
Mrdalj et al., 2016 Wistar rats M PND 2-14 MS with or without CMS LMS: offspring separated from dams 180 min/day.
BMS: offspring separated from dams 10 min/day.
NH CONTROL: no separation.
At PND 90, half of each group was exposed to CMS for 4 wks.		 Reward responsiveness SPT 1% sucrose solution ~PND 90, 120 No effect of early life condition on sucrose preference. Decreased preference with CMS. Reduced reward responsiveness in rats with CMS.
Øines, Murison, Mrdalj, Grønli, &; Milde, 2012 Wistar rats M PND 2-14 MS with or without SIS LMS: offspring separated from dams for 180 min/day.
BMS: offspring separated from dams for 10 min/day.
NH CONTROL: dams and offspring left completely undisturbed.
From PND 72-75 until PND 85-88, rats from each group exposed to SIS or received standard animal care. SIS consisted of pairing each rat with a new rat daily for 14 days.		 Reward responsiveness SPT 1% sucrose solution PND 64-68, 86-90 No difference in preference for LMS offspring compared to NH and BMS offspring. No effect of SIS observed on sucrose preference, but overall liquid consumption less for LMS rats. No differences: LMS rats exhibited decreased liquid consumption overall.
Paul et al., 2000 Rhesus-Macaque monkeys M+F 3 days-7 months MS MS: separated from mothers at 3 days old to be hand/nursery reared. Pair housed at 7 months.
CONTROL: reared normally.		 Reward responsiveness Sucrose and quinine consumption Sucrose (2.74-175.0 mM) and quinine-HCl (0.1-5.0 mM) solutions 4-5 years MS monkeys consumed less sucrose containing solutions and more quinine containing solution. Unclear; authors speculate there may be reduced gustatory sensitivity overall.
Pryce et al., 2004 Marmoset monkeys M+F PND 2-28 MS MS: infant brought to remote isolation chamber for 30-120 min/day.
CONTROL: carrying parent restrained briefly and released.
Monkeys’ performance on VD/VR/VRR task was assessed.		 Reinforcement learning, approach motivation, reward responsiveness CANTAB (stimulus response with reversal learning, PR), free consumption Banana flavored milk 9 months MS monkeys made more errors during reversal learning, decreased responding on PR. Similar consumption of freely available reward. Decreased learning and approach motivation, similar reward responsiveness.
Rüedi-Bettschen et al., 2005 Wistar rats M PND 1-14 MS MS – pup isolated for 4 hrs/day.
MSxLightxWarm.
MSxLightxCold.
MSxDarkxWarm.
MSxDarkxCold.
NH:
NHxDark.
NHxLight.
Light (lights on 0700-1900) vs dark phase (lights off 0700-1900).
Cold (21° C) vs warm (32-33° C).		 Approach motivation, reward responsiveness PR responding, free consumption 7% sucrose solution 6 months MS during dark cycle (warm or cold) resulted in decreased responding and reinforcement on PR. No difference in free consumption. Decreased approach motivation and no change in reward responsiveness.
Sadeghi, Peeri, &; Hosseini, 2016 Albino Wistar rats M PND 2-14 MS CONTROL: no maternal separation.
MS: litters separated from mothers for 180 min/day.
MS + fluoxetine: 5 mL administered intraperitoneally from PND 28 to 60.
MS + voluntary wheel running: free access to running wheel 24 hrs/day from PND 28 to 60.
MS + mandatory treadmill: rats treated to exercise for increasing interval of time over 4 wk period.		 Reward responsiveness SPT 1% sucrose solution PND 60 Reduced sucrose consumption in MS rats compared to control rats. Decreased reward responsiveness.
Sasagawa et al., 2017 C57BL/6N mice M+F PND 1-14 MS+SI MS+SI: Each pup separated from dam and placed in separate container for 3 hours daily.
Control: Left undisturbed until weaning.

All mice rehoused at weaning in groups of 3-4.		 Reward responsiveness, approach motivation Free consumption
+
CPP		 Milk Chocolate 3-4 Months Similar free consumption of chocolate in MS+SI mice. Reduced CPP for chocolate in MS+SI females. Decreased approach motivation in females but not males.
Shalev and Kafkafi., 2002 Long-Evans rats M PND 3-14 MS EH: pups separated from dams for 15 min/day at room temperature.
MS: pups handled similarly to EH pups, but separated from dams for 180 min/day.
NH: pups were undisturbed.		 Reward responsiveness, reinforcement learning, approach motivation SPT,
concentration response test,
progressive reinforcement test		 1%, 3% and 0.5% sucrose solutions 10 wks, 3 months, 11 wks No differences for SPT, concentration response test or progressive reinforcement test. MS rats increased locomotor response compared to NH rats. No changes.
Shu et al., 2015 Sprague Dawley rats M PND 2-14 MS with or without CMS MS: litters separated 3 hrs/day from mothers.
CONTROL: no separation.
After reaching adulthood, half of pups in control group and half of pups in MS group randomly assigned to CMS from PND 91 to 112.		 Reward responsiveness SPT 1% sucrose solution PND 91, 112 Decreased sucrose consumption in rats with MS compared to control rats without MS. Sucrose consumption of rats with CMS alone was lower than sucrose consumption of rats with MS. Decreased reward responsiveness.
Uchida et al., 2010 Sprague Dawley rats M+F PND 2-14 MS with or without repeated restrained stress AFR: animals handled twice a wk during regular cage changes.
MS15: pups separated from dams 15 min/day.
MS180: pups separated from dams 180 min/day.
At 8 wks old, adult rats subjected to 2 hrs/day of restraint stress for 14 days (held in wire mesh restrainers with head and feet secured).		 Reward responsiveness SPT 1% sucrose solution 10 wks No effect of MS alone on sucrose preference. MS180 rats given repeated restraint stress had decreased sucrose preference compared with non-restrained controls and MS 180 rats. Decreased reward responsiveness with combination of MS and restraint.
Vazquez et al., 2005 Long-Evans rats M PND1-14 MS MS: pups separated from dam for 3 hrs/day.
CONTROL: no handling other than cage cleaning.		 Approach motivation, reward responsiveness SPT, morphine CPP, morphine consumption 0.025% sucrose solution, 2mg/kg morphine for CPP, 25mg/L morphine solution for consumption 2.5-3 months Slightly increased sucrose preference in MS rats. Increased CPP and morphine consumption for morphine in MS rats. Increased approach motivation and reward responsiveness for morphine; increased reward responsiveness for sucrose.
Zhang et al., 2005 Sprague Dawley rats M PND 2-9 MS MS: pups isolated individually for 1 hr/day.
CONTROL: NH.
Responding for food under FR15 and PR5 and PR escalation schedules was tested.		 Approach motivation Food self-administration (FR, PR) Food pellets ~PND 70-90 Lower responding rates at FR15 for food for MS rats than NH rats, but similar performance at PR for food. Decreased approach motivation.
Social Isolation
Author, year Strain Sex Timing of Exposure Nature of Exposure Methods/Group Design Inferred Construct Method to Assess Reward Object PND Test Main Findings Effect on Reward
Amitai et al., 2014 Long- Evans rats M PND 24 SI SI: single-housed
Socials: housed in groups of 3.		 Reward learning Reversal learning Strawberry milkshake 18 and 52 wks post-weaning SI rats required more sessions in order to reach criterion performance when reward contingencies were reversed. Decreased reward learning.
Brenes &; Fornaguera, 2008 Sprague Dawley rats M PND 30- 114 SI SI: housed individually under standard conditions.
GH: housed under standard conditions in groups of 3.
EE: housed in special cages with plastic objects, PVC tubes, food dispensers and water bottles.		 Reward responsiveness SPT 32% sucrose solution PND 65-66, 93-94, 108-109 SI rats showed greater preference for sucrose at PND 66 and consumed significantly more sucrose at PND 94 than GH and EE groups. Increased reward responsiveness.
Brenes &; Fornaguera, 2009 Sprague Dawley rats M PND 28- 94 SI SI: housed singly in cages.
GH: housed in groups of 3.		 Reward responsiveness SPT 32% sucrose solution PND 90-91, 94-95 SI rats had significantly increased sucrose consumption at PND 91 compared with GH rats. Increase reward responsiveness.
Colonnello, Iacobucci, Anderson, &; Panksepp, 2011 Octodon Degus M+F PND 25 SI SI: housed in isolation for 4 wks; handled daily to be moved to treatment cages alone 1 hr/day.
Partial SI: housed in isolation for 4 wks; allowed 1 hour of socialization with 2 same-sex sibs/day.
Social Housing Group: housed with sex- matched sib; allowed 1 hour of socialization with sex-matched partial SI sib/day.		 Reward responsiveness SPT 2% sucrose solution PND 25, 39 and 53-56 Greater preference for sucrose at wk 4 in SI group than the partial SI and social groups. Increased reward responsiveness.
Cuenya et al., 2015 Wistar rats M PND 21-36 SI SI: housed alone. CONTROL: housed in groups of 5-6.
From PND 36-60, isolated subjects were regrouped.		 Reinforcement learning, Approach motivation Sucrose consumption following shifts in concentration 32% and 4% sucrose solution PND 90 SI enhanced consumption compared to controls following increase positive contrast (4%-32%). Increased approach motivation.
Hall et al., 1997 Lister-hooded rats M PND 21 onward SI SI: housed individually.
CONTROL: housed 4 rats/cage .		 Reward responsiveness, approach motivation SPT in fed and deprived states, positive and negative contrast 0.7%, 2.1%, 7.0%, 21.0%, 34.0% sucrose solutions under non-deprived conditions, 0.7%, 7.0% and 34.0% sucrose solutions under deprived conditions and for tests of positive and negative contrast 8 wks No difference between groups in consumption of sucrose in fed or deprived conditions.
SI rats consumed more sucrose under conditions of positive and negative contrast and were more sensitive to positive contrast/less sensitive to negative contrast.		 Increased approach motivation due to isolation.
Hall et al., 1998a Fawn- hooded and Wistar rats M PND 21 SI SI: housed singly for 8 wks.
CONTROL: housed 2 animals per cage for 8 wks.		 Reward responsiveness Voluntary consumption of sucrose and saccharine 0.7%, 2.1%, 7.0%, 21.0% and 34% sucrose solutions, 0.01%, 0.04%, 0.16%, and 0.64% saccharin solutions ~PND 77 SI rats had increased sucrose consumption at all concentrations.
Isolated rats increased saccharin consumption at high concentrations.		 Increased reward responsiveness.
Hong et al., 2012 Sprague Dawley rats M+F PND 30-49 SI SI: housed one per cage.
CONTROL: housed in groups of 2-3.
Forced swim test at P49-50. All rats group-housed P50-P70. 2nd FST P70-P71. Rats isolated around ~P90 for habituation to sucrose.		 Reward responsiveness SPT following 30 min of restraint 1% sucrose solution ~PND 100 Females but not males increased sucrose intake during SPT. Increased reward responsiveness in female rats isolated in adolescence.
Jones, Marsden, &; Robbins, 1990 Lister- hooded rats F PND 21 SI SI: housed individually for the duration of the experiment.
GH: housed 6 rats/cage for the duration of the experiment.		 Approach motivation Exp 1: Locomotor activity conditioned to food presentation
Exp 2: Operant responding to a conditioned reinforcer (stimulus previously associated with sucrose)		 Standard rat chow, 10% sucrose solution ~14 wks SI resulted in increased conditioned locomotor activity and increased responding for conditioned reinforcer. Increased approach motivation.
Li et al., 2007 Sprague Dawley rats M PND 21 SI SI: housed individually.
Control: housed 3 per cage.		 Reward learning Reversal learning in alternating T-maze Food pellets 8 wks post-weaning No differences in initial acquisition of task. SI rats required more trials to acquire reversal learning. Decreased reward learning.
McCool and Chappell, 2009 Long-Evans rats M Starting between PND 28-32 SI SI: housed individually.
GH: housed 4 animals/cage.
Wks 1, 2 &; 4: self-administration of either 10% ethanol or 3% sucrose.
Wks 3&; 5: extinction trials.		 Reward responsiveness, approach motivation Sucrose self-administration (FR) 3% sucrose solution ~PND 70 No difference in response rate for sucrose between SI and GH animals. No differences.
Morgan and Einon, 1975 Lister-hooded rats F PND 25-120 SI SI: housed in plastic mesh cages.
CONTROL: housed in groups of 4.		 Reinforcement learning, Approach motivation Two-lever DRL in which rat must alternate levers for food reward, waiting 30s in between responding 45 mg Noyes sucrose pellet PND 120 SI rats show both increased perseverative (pressing same lever before 30s interval is up) and anticipatory (pressing alternate lever before 30s interval is up) responses compared to controls. Increased approach motivation.
Pisu et al., 2011 Sprague Dawley CD rats M ~ PND 25 SI SI: housed individually in smaller cages for 30 days.
GH:6-8 rats/cage for 30 days.		 Reward responsiveness SPT 32% sucrose solution PND 55-60 SI rats exhibited reduced intake and preference for sucrose compared to group-housed animals. Decreased reward responsiveness.
Schrijver and Würbel, 2001 Lister-hooded rats M PND 21 SI SI: housed individually.
Control: housed 3 per cage.		 Reward learning Reversal Learning and Set Shifting Spatial and Non-Spatial Radial Arm Maze Food pellets PND 80 No difference on acquisition or reversal learning within Spatial or Non-Spatial task. SI rats required more trials to acquire shift between spatial and non-spatial cues. Decreased reward learning.
Van den Berg et al., 1999 Wistar rats M PND 22-35 SI SI: individually housed at 4 wks.
GH: pair housed in cages.		 Approach motivation CPP for social interaction, anticipation Social interaction, 5% sucrose solution ~Wks 8-11 Isolation resulted in decreased CPP for social interaction and decreased anticipatory locomotion for sucrose. Decreased approach motivation for social and food rewards.
Van den Berg, Van Ree, &; Spruijt, 2000 Wistar rats M PND 21 SI SI: housed in isolation with no social contact.
PARTIAL SI: housed in isolation with 30 min of social contact/day.
GH: housed 5 rats per cage.		 Reward responsiveness Sucrose consumption 5% sucrose solution PND 22-35 Increased sucrose consumption in SI rats compared to partial SI and GH. Partial SI rats had increased consumption compared to non-isolated rats. Increased reward responsiveness.
Other ELS Paradigms
Author, year Strain Sex Timing of Exposure Nature of Exposure Methods/Group Design Inferred Construct Method to Assess Reward Object PND Test Main Findings Effect on Reward
Bourke and Neigh., 2011 Wistar rats M+F PND 37-49 Combination SD and restraint Stress group: 6 total exposures to social defeat, 6 total exposures to 60-min restraint over 12 days.
Adolescent CONTROL: pair-housed rats of each sex.
Adult CONTROL: individually housed.		 Reward responsiveness Sucrose consumption 0.8% sucrose solution Adoles-cent: PND 48-55 Adult: PND 96-103 Adolescent stress resulted in decreased sucrose consumption in adolescence and adulthood in female but not male rats. Decreased reward responsiveness in females but not males.
Novick et al., 2013 Sprague Dawley rats M PND 35-40 SD SD: put in cage of larger, aggressive adult rat 1x/day for 5 days.
CONTROL: adolescent rats removed from home cages and put into novel cages for duration of SD task each day.		 Approach motivation Sweetened condensed milk (SCM) consumption &; CPP SCM ~PND 60 No difference in CPP or total consumption. No difference.
Pohl et al., 2007 Long-Evans rats M+F PND 23-51 CMS,
SSS		 CMS: exposed to variable stressors everyday for 4 weeks.
SSS: exposed to 45 min restraint during water immersion or 5 min of 3x0.6 shocks, at random intervals twice a wk throughout the stress period.
CONTROL: handled twice per wk.		 Reward responsiveness Sucrose consumption 0%, 7%, and 10% sucrose solutions 45 wks Females but not males in SSS and CMS stress groups consumed significantly less 10% sucrose solution. Decreased reward responsiveness in females following stress.
Toth et al., 2008 Sprague Dawley rats M PND 30 CMS CMS: exposed to variable stressors. everyday for 4 weeks
CONTROL: ordinary care.		 Reward responsiveness SPT 0.2% sucrose solution ~PND 60 (directly after CMS) No difference in sucrose preference between CMS and control animals. No difference.

Abbreviations: AFR, animal facility rearing; BMS, brief maternal separation; CMS, chronic mild stress; cort, corticosterone; CPP, conditioned place preference; CUPS, chronic unpredictable stress; EE, enriched environment; EH, early handling; FR, Fixed Ratio; GH, group housed; H, neonatal handling; LMS, long maternal separation; MS, maternal separation; NH, non-handled; ; PND, post-natal day; PR, Progressive Ratio; SD, social defeat; SI, Social Isolation; SIS, Social Instability Stress; SPT, sucrose preference test; SSS, severe sporadic stress