TABLE 5

Relapse after food choice–induced voluntary abstinence: summary of main findings

No.ReferenceGeneral Training ProceduresTestMajor Findings
1Caprioli et al. (2015a)Rat strain and sex
Sprague-Dawley males.
Food training
Five palatable food pellets per delivery for six sessions (9 h).
Drug training with choice probes
0.1 mg/kg/infusion methamphetamine (FR1) for 12 sessions (9 h, limited to 15 infusions per hour) with choice probes every 3 days.
Food choice–induced abstinence
Choice between five food pellets and methamphetamine (0.1 mg/kg/infusion) for 20 trials per session for 19 sessions.
Forced abstinence
Separate group of home-cage forced abstinence for 20 days.
Relapse tests
3-h pretreatment of AZD8529 (0, 20, 40 mg/kg, s.c.) on abstinence day 1 or day 21. Test for methamphetamine seeking for 30 min (n = 8–9 per AZD8529 dose after forced abstinence; n = 14–16 per AZD8529 dose after voluntary abstinence).
Incubation of methamphetamine craving is observed after food choice–induced voluntary abstinence. Systemic injections of the positive allosteric modulator of metabotropic glutamate receptor 2, AZD8529, decrease incubated methamphetamine seeking.
2Caprioli et al. (2017)Rat strain and sex
Sprague-Dawley males.
Fos-lacZ females.
Food training
Five palatable food pellets per delivery for six sessions (9 h).
Drug training with choice probes
0.1 mg/kg/infusion methamphetamine (FR1) for 12 sessions (9 h, limited to 15 infusions per hour) with choice probes every 3 days.
Food choice–induced abstinence
Choice between five food pellets and methamphetamine (0.1 mg/kg/infusion) for 20 trials per session for 14 or 19 sessions.
Forced abstinence
Separate group of home-cage forced abstinence for 20 days.
Daun02 induction
Short (15 min) methamphetamine or food seeking session followed by injections of vehicle or Daun02 75 min later on abstinence day 18.
Relapse tests
Test for methamphetamine seeking for 60- or 90-min sessions on abstinence day 1 or day 21 for Fos expression during relapse (n = 5 day 1; n = 5 day 21; n = 6 no test), or effect of injections into DMS of vehicle or Drd1 (SCH 39166) or Drd2 (raclopride) antagonists (1.0 µg/0.5 µl/side) 10 min before test sessions (n = 6–7 per dopamine receptor antagonist) or effect of Daun02 (4.0 µg/1.0 µl/side) manipulation (n = 13–14 female Fos-lacZ per Daun02 or vehicle).
Incubated methamphetamine seeking is associated with increased Fos expression in DMS Drd1 and Drd2 neurons. Injections of Drd1 or Drd2 antagonists and Daun02 inactivation in DMS decrease methamphetamine seeking.
3Venniro et al. (2017a)Rat strain and sex
Sprague-Dawley males.
Food training
Five palatable food pellets per delivery for six sessions (2 h).
Drug training with choice probes
0.1 mg/kg/infusion methamphetamine (FR1) for 21 sessions (2 h, limited to 15 infusions per hour).
Food choice–induced abstinence
Choice between five food pellets and methamphetamine (0.1 mg/kg/infusion) for 20 trials per session for 14 sessions.
Forced abstinence
Separate group of home-cage forced abstinence for 14 days.
Relapse tests
Test for methamphetamine seeking for 60- to 120-min sessions on abstinence day 15. Fos expression, n = 13–14 per dose with systemic SCH 39166 (0 or 20 µg/kg s.c.) injections, plus n = 8 per group no-test condition; RNAscope, n = 5–6 per condition; Fos + CTb labeling, n = 4; CeA or BLA SCH 39166 or raclopride (0, 0.5, or 1.0 µg/0.5 µl/side) injections, n = 7–9 per group; CeA CNO (0 or 1.0 mM/0.5 µl/side) injections, n = 15 group; AIV or OFC muscimol + baclofen i (0 or 50 + 50 ng/0.5 µl/side) injections, n = 8–12 per group.
Relapse to methamphetamine seeking is associated with increased Fos expression in CeA Drd1 neurons and projections from AIV to CeA in male rats. Injections of a Drd1 antagonist in CeA, muscimol + baclofen injections in AIV, and DREADD inhibition of projections from AIV to CeA decrease relapse.
4Venniro et al. (2017b)Rat strain and sex:
Sprague-Dawley males and females.
Food training
Five palatable food pellets per delivery (FR1) for six sessions (6 h, limited to 15 deliveries per hour).
Drug training with choice probes
0.1 mg/kg/infusion methamphetamine or heroin (FR1) for 12 sessions (6 h, limited to 15 infusions per hour) with choice probes every 3 days.
Food choice–induced abstinence
Choice between five food pellets and methamphetamine or heroin (0.1 mg/kg/infusion) for 20 trials per session for 20 sessions.
Forced abstinence
Separate group of home-cage forced abstinence for 14 days.
Relapse tests
Test for methamphetamine or heroin seeking for 30 min on abstinence day 1 and 120 min on abstinence day 21 (n = 10 males and n = 10–11 females per abstinence condition for methamphetamine; n = 11–15 males and n = 15–16 females per abstinence condition for heroin).
Incubation of methamphetamine craving after food choice–induced abstinence generalizes to female rats. Rats with a history of heroin self-administration do not show incubation of heroin craving after food choice–induced voluntary abstinence. No sex differences were observed in any of the behavioral measures, except for a small decrease in food choice in female rats trained to self-administer methamphetamine compared with male rats.
5Reiner et al. (2020)Rat strain and sex
Sprague-Dawley males and females.
Food training
Five pellets per delivery (FR1) for six sessions (6 h, limited to 12 total deliveries per hour).
Drug training with choice probes
2.5 µg/kg/infusion fentanyl (FR1) for 12 sessions (6 h, limited to 12 infusions per hour) with choice probes every 3 days.
Food choice–induced abstinence
Choice between five food pellets and 2.5 µg/kg/infusion fentanyl for 20 trials per session for 10–14 sessions.
Relapse tests
Test for fentanyl seeking for 30 min on abstinence day 1 and 60 min on abstinence day 14 (n = 22 males; n = 20 females) or 3-h test on abstinence day 15 for Fos expression associated with fentanyl relapse (n = 7 per test condition), vehicle, or muscimol + baclofen (50 + 50 ng/0.5 µl/side) injections in OFC (n = 10–17 per dose), AIC (n = 13 per dose), and Pir (n = 14–15 per dose), or OFC-Pir disconnection test (n = 5–11 per dose).
Rats with a history of fentanyl self-administration do not show incubation of fentanyl craving after food choice–induced abstinence. Relapse to fentanyl seeking is associated with increased Fos expression in OFC, AIC, Pir, and projections from Pir to OFC. Injections of muscimol + baclofen in these regions and asymmetric anatomic disconnection between Pir and OFC decrease relapse. No sex differences were observed for any of the behavioral measures except for voluntary abstinence in one experiment in which females had a lower food preference. However, when data from all experiments are combined, this sex difference is not observed.
6Rossi et al. (2020)Rat strain and sex
Sprague-Dawley males.
Food training
0.4 ml delivery of 1% sucrose + 1% maltodextrin solution (FR1) for six sessions (6 h, limited to 120 deliveries per session).
Drug training with choice probes
0.1 mg/kg/infusion methamphetamine (FR1) for 12 sessions (6 h, limited to 120 infusions per session) with choice probes every 3 days.
Food choice–induced abstinence
Choice between 1% sucrose + 1% maltodextrin solution and 0.1 mg/kg/infusion methamphetamine for 20 trials per session for 14 sessions.
Relapse tests
Test for methamphetamine seeking for 60 min on abstinence day 1 or 15 for Fos expression associated with incubated methamphetamine seeking (n = 3–5 per test condition); muscimol + baclofen (50 + 50 ng/0.5 µl/side) injections in NAc core or shell (n = 6–8 per dose); Drd1-Drd2 antagonist (flupentixol, 10 µg/0.5 µl/side, n = 7 per dose) injections in NAc core; Drd1 antagonist (SCH 39166, 1.0 µg/0.5 µl/ side, n = 6–8 per dose) and Drd2 antagonist (raclopride, 1.0 µg/0.5 µl/side, n = 6–8 per dose) in NAc core.
Incubated methamphetamine seeking is associated with increased Fos expression in NAc core (but not shell) Drd1 and Drd2 neurons. Injections of muscimol + baclofen, a Drd-Drd2 antagonist (flupentixol), or selective Drd1 (SCH 39166) and Drd2 (raclopride) antagonists in NAc core decrease relapse.
  • AIC, AI cortex; CNO, Clozapine-N-oxide; FR, fixed ratio.