TABLE 3

Relapse after punishment-induced voluntary abstinence: summary of main findings

No.ReferenceGeneral Training ProceduresTestMajor Findings
1Panlilio et al. (2003)Rat strain and sex
Long-Evans males.
Drug training
Completion of 100 infusions for 4 µg/kg/infusion remifentanil (FR1) for 3 or 27 sessions.
Punishment
Responses for remifentanil paired with a 0.5-s, 1.5-mA foot shock for three sessions.
Reinstatement
Five priming intravenous infusions of remifentanil at the start of the session with additional priming injections at 1, 2, and 3 h if responding did not commence. Sessions lasted for 5 h or when 100 remifentanil trials were completed (n = 4 to 5 per priming condition).
Priming infusions of remifentanil increase reacquisition of remifentanil self-administration after punishment.
2Panlilio et al. (2005)Rat strain and sex
Sprague-Dawley males.
Drug training
Completion of 100 infusions for 4 µg/kg/infusion remifentanil (FI5 for three sessions followed by VR4 for two sessions) within 5 h.
Punishment
Responses for remifentanil paired with foot shock (increasing in duration by 0.01 s per trial within session), which increased in intensity over training sessions (0.25 mA to 0.51 mA).
Extinction
After drug self-administration training and 5 additional days of FI5 training, a separate group of rats were placed on extinction training in which drug was no longer available for 16 sessions.
Reinstatement
After 1 h without responding (foot shock set to 1 mA for 0.5 s), test injection of vehicle or lorazepam was administered (0.08, 0.16, 0.31, 0.62, 1.25, 2.5, 5, and 10 mg/kg, i.p.). After injection, the remainder of test sessions continued with foot shock off but remifentanil available. Sessions lasted for 4 h after injection or when 100 remifentanil trials were completed (n = 4).
Reinstatement (with extinction training)
Same as above, but remifentanil was not available. Additional double injections of lorazepam and heroin (0.075, 0.25, 0.75 mg/kg, s.c.) were also tested (n = 4 punishment; n = 7 extinction).
Priming injections of heroin or lorazepam induce relapse to remifentanil seeking after punishment.
3Economidou et al. (2009)Rat strain and sex
Outbred Lister hooded males.
Impulsivity assessment
Rats were assigned to high- or low-impulsivity groups based on training on a five-choice serial reaction-time task.
Drug training
0.25 mg/infusion of cocaine under a FR1-RI120 second-order reinforcement schedule for 10–15 sessions. Sessions ended when 11 cocaine infusions were earned.
Punishment
50% of seeking responses now punished by 0.5-s foot shock. Sessions lasted 2 h and rats were trained for eight sessions.
Extended access
FR1 for cocaine for 12 sessions. Sessions lasted for 6 h or when 150 infusions were earned.
Retraining for drug and punishment reassessment
Retraining on FR1-RI120 schedule for cocaine for four sessions (as described in drug training section) followed by retraining on punishment for eight sessions (as described in punishment section).
Forced abstinence
Rats returned to home cage for 7 days.
Relapse
Test for relapse under the FR1-RI20s schedule for 1 h (n = 9 high impulsive; n = 12 low impulsive).
Relapse with atomoxetine
7 days after punishment, rats were given pretreatment of atomoxetine (3.0 mg/kg, i.p.) 20 min prior to relapse test (n = 10 high impulsive; n = 10 low impulsive).
Extended-access cocaine self-administration increases relapse after punishment plus 7 days of forced abstinence in the high-impulsivity group; this effect is decreased by atomoxetine.
4Pelloux et al., (2013)Rat strain and sex
Outbred Lister hooded males.
Drug training
0.25 mg/infusion of cocaine under an FR1 schedule for five to seven sessions. Sessions lasted for 2 h or when 30 cocaine reinforcers were earned. Followed by training on FR1-RI120-s schedule for nine sessions. Sessions ended when 11 cocaine infusions were earned.
Motivational assessments
Training under progressive ratio for two sessions followed by probe of seeking under extinction for one session and finally baseline second-order retraining for four sessions.
Punishment
50% of seeking responses now punished by 0.5-s foot shock. Sessions lasted 2 h for eight sessions.
Forced abstinence
Rats returned to home cage for 7 days.
Reinstatement
Lever presses under the second-order schedule without cocaine or punishment (n = 10–16 per brain region).
Dorsal mPFC lesions decrease relapse to cocaine seeking, whereas AI lesions increase relapse after punishment plus 7 days of forced abstinence.
5Marchant et al. (2013a)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Two-bottle choice for 20% v/v alcohol versus water every other day (12 × 24-h sessions).
Drug training
Context A: 0.1 ml 20% alcohol (FR1 to FR5) for seven sessions (2 h, no limit noted) followed by VI30 for four sessions (2 h, no limit noted).
Punishment group
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (starting at 0.45 mA to 1.09 mA) for three to seven sessions.
Extinction group
Context B: Responses on active lever that met the VI30 requirement led to presentation of light-tone cue but not alcohol or foot shock for 13 sessions (2 h).
Relapse test
Test of relapse in context A and context B (counterbalanced) for 30 min (n = 15 punished; n = 11 unpunished; n = 8 noncontingent).
Re-exposure to self-administration context (context A) induces relapse to alcohol seeking after punishment or extinction in context B. The study introduces the new model.
6Krasnova et al. (2014)Rat strain and sex
Sprague-Dawley males.
Drug or food training
FR1 for 0.1 mg/kg/infusion methamphetamine for 14 sessions (9 h, limited to 35 infusions/3 h) or FR1 for five pellets for 14 sessions (9 h).
Punishment
50% of responses for methamphetamine or food paired with 0.5-s foot shock (0.12 mA, increased to 0.6 or 0.66 mA) for 9–10 sessions (9 h).
Forced abstinence
Rats returned to home cage until relapse test.
Relapse tests
Test for methamphetamine or food seeking for 1 h on abstinence day 2 and 21 (n = 26 punished methamphetamine; n = 20 unpunished methamphetamine; n = 24 punished food; n = 22 unpunished food).
Incubation of methamphetamine and food craving is observed after punishment plus 21 days of home-cage forced abstinence.
7Marchant et al. (2014)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Two-bottle choice for 20% v/v alcohol versus water every other day (12 × 24-h sessions).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for six sessions (2 h, no limit noted) followed by VI30 for six sessions (2 h, no limit noted).
Punishment
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (starting at 0.3 mA to 0.7 mA) for three to seven sessions (2 h).
Relapse test
Test of relapse in context A and/or context B for 90 min for Fos (n = 8 punishment context B; n = 8 alcohol training context A; n = 5 home cage) and Fos + CTb labeling (n = 8 punishment context B; n = 8 alcohol training context A; n = 6 no test) or for 30 min with infusions of muscimol + baclofen (0.06 + 0.6 mM or 3.6 + 64.1 ng/0.5 µl/side) nto LH (n = 8 vehicle; n = 10 muscimol + baclofen in LH; n = 7 muscimol + baclofen in dorsal to LH).
Context-induced relapse of alcohol seeking after punishment in male rats is associated with increased Fos expression in LH and selective activation of NAc shell neurons projecting to LH. Inactivation of LH using muscimol + baclofen decreases context-induced relapse in alcohol-preferring P rats.
8Marchant and Kaganovsky (2015)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Two-bottle choice for 20% v/v alcohol vs. water every other day (12 × 24-h sessions).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for six sessions (2 h, no limit noted) followed by VI30 for six sessions (2 h, no limit noted).
Punishment
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (starting at 0.1 mA to 0.7 mA) for 7–11 sessions.
Relapse test
Test of relapse in context A and/or context B for 90 min with systemic (n = 7, 5 µg/kg; n = 9, 10 µg/kg SCH 23390; n = 9, vehicle) or microinfusions of Drd1 receptor antagonist SCH 23390 (n = 9, 0.6 μg/side SCH 23390 and n = 15, vehicle in shell; n = 8, 0.6 μg/side SCH 23390, and n = 12 vehicle in core).
Systemic and NAc shell and core injections of the Drd1 receptor antagonist SCH 23390 decreases context-induced relapse to alcohol seeking after punishment in alcohol-preferring P rats.
9Marchant et al. (2016)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Two-bottle choice for 20% v/v alcohol vs. water every other day (12 × 24-h sessions).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for six sessions (2 h, no limit noted) followed by VI30 for six sessions (2 h, no limit noted).
Punishment
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (starting at 0.1 mA to 0.7 mA) for six to seven sessions.
Relapse test
Test of relapse in context A and/or context B for 30 or 90 min with infusions of muscimol + baclofen (0.06 + 0.6 mM or 3.6 + 64.1 ng/0.5 µl/side) into vSub (n = 7 per test group in muscimol + baclofen).
Context-induced relapse is associated to alcohol seeking is associated with selective activation of vSub→NAc shell projection. Inactivation of vSub using muscimol + baclofen and DREADD inhibition of vSub→NAc projection decreases relapse.
10Torres et al. (2017)Rat strain and sex
Sprague-Dawley males.
Drug training
0.1 mg/kg/infusion methamphetamine or saline control (FR1) for 22 sessions (9 h, limited to 35 infusions/3 h).
Punishment
50% of responses for methamphetamine paired with 0.5-s foot shock (0.18 mA, increased 0.06 mA each session until 0.42 mA) over 13 sessions (9 h). Saline rats had yoked foot-shock delivery.
Forced abstinence
After voluntary abstinence rats were returned to home cage for 21 days of forced abstinence.
Relapse tests
Test for methamphetamine seeking for 1 h on abstinence day 2 and 21 (n = 9 shock sensitive; n = 7 shock; n = 5 saline control).
Incubation of methamphetamine craving after punishment and forced abstinence is greater in punishment-resistant rats.
11Krasnova et al. (2017)Rat strain and sex
Sprague-Dawley males.
Drug training
0.1 mg/kg/infusion methamphetamine or saline control (FR1) for 20 sessions (9 h, limited to 50 infusions/3 h).
Punishment
50% of responses for methamphetamine paired with 0.5-s foot shock (0.18, increased 0.06 mA each session until 0.30 mA) over five sessions (9 h). Saline rats had yoked foot-shock delivery.
Forced abstinence
After voluntary abstinence, rats were returned to home cage for 30 days of forced abstinence.
Relapse tests
Test for methamphetamine seeking for 1 h on abstinence day 2 and 30 (n = 8 shock sensitive; n = 9 shock resistant; n = 8 saline).
Incubation of methamphetamine craving after punishment plus forced abstinence in male rats is associated with upregulation of several genes in striatum (e.g., oxytocin in NAc and CARTpt in dorsal striatum) in punishment-resistant rats.
12Pelloux et al. (2018a)Rat strain and sex
Sprague-Dawley males.
Drug training
Context A: 0.75 mg/kg/infusion cocaine (FR1) for six sessions (6 h, no limit noted) followed by VI30 for six sessions (6 h, no limit noted).
Punishment
Context B: 50% of responses for cocaine paired with 0.5-s foot shock (0 mA, increased by 0.1 mA each session until 0.5 or 0.7 mA) for eight sessions (6 h, VI30). Rats divided into two groups: paired (foot shock paired with drug delivery) and unpaired (yoked foot-shock delivery).
Relapse tests
Test for cocaine seeking in contexts A and B for 60 min (n = 8 paired; n = 6 unpaired) or 90 min in context A, context B, or home cage for Fos expression (n = 5–7 per context).
Context-induced relapse of cocaine seeking after punishment is associated with selective activation of dorsal and ventral mPFC, AI, dorsal striatum, BLA, PVT, LHb, SN, vSub, and DR, but not NAc, CeA, LH, VTA, and other brain regions.
13Pelloux et al. (2018b)Rat strain and sex
Sprague-Dawley males.
Drug training
Context A: 0.75 mg/kg/infusion cocaine (FR1) for six sessions (6 h, no limit noted) followed by (VI30) for six sessions (6 h, no limit noted).
Punishment
Context B: 50% of responses for cocaine paired with 0.5-s foot shock (0 mA, increased by 0.1 mA each session until 0.5 or 0.7 mA) for eight sessions (6 h, VI30).
Extinction
Context B: Responses on active lever led to presentation of light-tone cue but not cocaine or foot shock.
Relapse tests
Test for cocaine seeking for 1 h in context A or B with injections of muscimol + baclofen (50 + 50 ng/0.5 µl/side) into BLA (n = 11 punishment; n = 12 extinction) or CeA (n = 14 punishment; n = 16 extinction).
BLA inactivation with muscimol + baclofen increases context-induced relapse of cocaine seeking after punishment but not after extinction in context B. BLA or CeA inactivation with muscimol + baclofen induces relapse in context B after punishment in this context.
14Campbell et al. (2018)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Intermittent two-bottle access of 20% v/v alcohol and water (three to four times per week) for eight sessions (24 h).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for seven sessions (20 min, no limit noted), followed by (VI30) for six sessions (20 min, no limit noted).
Voluntary abstinence
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (0.2 mA, increased by 0.2 mA each session until 0.6 or 0.7 mA) for six sessions (20 min, VI30).
Relapse tests
Test for alcohol seeking in context A or context B for 20 min for effect of paternal alcohol exposure (n = 6 control-sired offspring; n = 24 alcohol-sired offspring).
Paternal alcohol exposure decreases context-induced relapse after punishment in F1 offspring.
15Farrell et al. (2019)Rat strain and sex
Long-Evans males and females.
Drug training
Context A: 0.58 mg/kg/infusion (male rats) or 0.66 mg/kg/infusion cocaine (female rats) (FR1) for five sessions (2 h, no limit noted) followed by three sessions VI5 (no limit noted), three sessions VI10 (no limit noted), and three to six sessions VI15 .
Voluntary abstinence
Context B: 50% of responses for cocaine paired with 0.5-s foot shock (0.3 mA) for three to four sessions (2 h, VI30), followed by increasing shock 0.15 mA every two sessions, up to 0.75 mA.
Relapse tests
Test for cocaine seeking for 2 h in context A (no cue, cue, no cue + 10 mg/kg cocaine priming) or B (cue) with DREADD inhibition of VP (n = 10 males and n = 10 females in control; n = 26 males and n = 20 females in Gi-DREADD).
Chemogenetic inhibition of VP decreases cocaine priming and context-induced relapse to cocaine seeking after punishment. No sex differences were observed in cocaine self-administration, voluntary abstinence, or reinstatement, but female rats show greater cocaine-induced locomotion.
16Campbell et al. (2019a)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Intermittent two-bottle access of 20% v/v alcohol and water (three to four times per week) for 8–12 sessions (24 h).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for seven sessions (20 min, no limit noted), followed by (VI30) for six sessions (20 min, no limit noted).
Punishment
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (0.2 mA, increased by 0.2 mA each session until 0.6 or 0.7 mA) for six sessions (20 min, VI30).
Forced abstinence
After voluntary abstinence rats were returned to home cage for 28 days of forced abstinence.
Relapse tests
Test for alcohol seeking in context A or context B for 20 min on abstinence day 1 (n = 12 per context) and 30 (n = 21–23 per context) with Fos expression associated with incubation of alcohol craving (n = 6–8 per context) and muscimol + baclofen (50 + 50 ng/0.5 µl/side) inactivation in AI (n = 8–10 per condition, testing only in context B on abstinence day 30).
Incubation of alcohol craving after punishment plus forced abstinence selectively occurs in context B but not context A; AI inactivation with muscimol + baclofen decreases incubation in context B.
17Campbell et al. (2019b)Rat strain and sex
Alcohol-preferring males.
Home-cage alcohol intake
Intermittent two-bottle access of 20% v/v alcohol and water (three to four times per week) for 10 sessions (24 h).
Drug training
Context A: 0.1 ml 20% alcohol (FR1) for seven sessions (20 min, no limit noted), followed by (VI30) for six sessions (20 min, no limit noted).
Punishment
Context B: 50% of responses for alcohol paired with 0.5-s foot shock (0.2–0.7 mA) for six sessions (20 min, VI30).
Forced abstinence
After voluntary abstinence, rats were returned to home cage for 30 days of forced abstinence.
Relapse (extinction) tests
Test for alcohol seeking in context A or context B for 20 min on abstinence days 1 and 32 for effect of environmental enrichment (n = 8–10 per context and enrichment group).
Enriched environment for 30 days in home cage decreases context A–induced relapse to alcohol seeking after punishment.
18Hu et al. (2019)Rat strain and sex
Sprague-Dawley males.
Drug training
0.1 mg/kg/infusion methamphetamine or saline control (FR1) for 20 sessions (9 h, no limit noted).
Voluntary abstinence
50% of responses for methamphetamine or saline control paired with 0.5-s foot shock (0.18, 0.24, 0.3, 0.3, and 0.3 mA) over five sessions (9 h).
Forced abstinence
After voluntary abstinence, rats were returned to home cage for 30 days of forced abstinence.
Relapse tests
Test for methamphetamine seeking for 30 min on abstinence days 3 and 30 (n = 11 shock sensitive; n = 7 shock resistant; n = 11 saline control).
fMRI signaling increases in OFC-DMS circuitry and decreases in dorsal mPFC-NAc circuitry after abstinence in rats that are more resistant to punishment. No differences in incubation of methamphetamine craving after punishment plus forced abstinence between punishment-resistant versus punishment-sensitive rats.
  • CARTpt, the gene encoding cocaine- and amphetamine-regulated transcript protein; DR, dorsal raphe; FI, fixed interval; FR, fixed ratio; LHb, lateral habenula; RI, random interval; SN, subtantia nigra; VI, variable interval; VR, variable ratio.