TABLE 7

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

No.ReferenceGeneral Training ProceduresTestMajor Findings
1Venniro et al. (2018)Strain and sex
Sprague-Dawley males and females.
Social self-administration training
60 s access to social partner (FR1) for six sessions (20 or 60 trials; 40 or 120 min).
Drug training
Methamphetamine or heroin (0.05–0.1 mg/kg/infusion) training (FR1) for 3–50 sessions (6 h, limited to 15 infusions per hour).
Methamphetamine self-administration under extended access (6 h/day, 9 days, FR1) and intermittent schedules (9 days of 12 daily sessions of 5 min ON, 25 min OFF) of drug reinforcement.
Food training
Five pellets per delivery (FR1) for six sessions (6 h).
Social choice–induced abstinence
Choice between 60 s access to social partner or five food pellets and 0.1 mg/kg/infusion methamphetamine for 15 trials per session for 14 sessions.
Forced abstinence
Separate group of home-cage forced abstinence.
Relapse tests
Test for methamphetamine seeking during 30-, 60-, or 90-min sessions on abstinence days 1, 15, 30, and 45 (n = 42 after three-criteria–based training; n = 27 after escalation and intermittent training; n = 10–12 males after choice-induced abstinence incubation; n = 6 males per group and n = 6 females per group for incubation after forced versus social choice–induced abstinence comparison; neurobiological assessments (immunohistochemistry: no test, n = 15 males; day 1, n = 16 males; day 15 forced and social abstinence, n = 7 males per group. RNAscope: no test, day 15 forced and social abstinence, n = 7 males per group).
Rats trained in established addiction models—escalation (both males and females), three-criteria DSM-IV–based, and intermittent access—voluntarily abstain when given mutually exclusive choices between methamphetamine or heroin versus social interaction. Social choice–induced abstinence prevents incubation of methamphetamine craving. This protective effect is associated with activation (assessed by the activity marker Fos) of inhibitory CeA PKCδ-expressing neurons and decreased neuronal activity in AIC.
2Venniro et al. (2019)Strain and sex
Sprague-Dawley males and females.
Social self-administration training
60 s access to social partner (FR1) for six sessions (20 or 60 trials; 40 or 120 min).
Drug training
0.1 mg/kg/infusion heroin training (FR1) for 12 sessions (6 h, limited to 15 infusions per hour).
Social choice–induced abstinence
Choice between 60 s access to social partner or five food pellets and 0.1 mg/kg/infusion heroin for 15 trials per session for 10 sessions.
Forced abstinence
Separate group of home-cage forced abstinence.
Relapse tests
Test for heroin seeking during 30-min session on abstinence day 1 or 15 (n = 16 males and females for forced abstinence; n = 18 males and females for voluntary). Test for heroin seeking during 30-min session on abstinence day 1 or 15 with semiautomatic and fully automatic procedure (n = 4 males and 3 females for semiautomatic; n = 7 males and 8 females for fully automatic).
Social choice–induced abstinence decreases incubation of heroin craving. There are no differences in social self-administration, social choice–induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the newer fully automatic procedure. No sex differences were observed in any behavioral measure.
3Venniro et al. (2020b)Strain and sex
Sprague-Dawley males.
Social self-administration training
60 s access to social partner (FR1) for six sessions (20 trials, 40 min).
Drug training
0.1 mg/kg/infusion methamphetamine (FR1) for 12 sessions (6 h, limited to 15 infusions per hour).
Social choice–induced abstinence
Choice between 60 s access to social partner and 0.1 mg/kg/infusion methamphetamine for 15 trials per session for 10 sessions.
Forced abstinence
Separate group of home-cage forced abstinence for 14 days.
Relapse tests
Test for methamphetamine seeking for 30 min (abstinence day 1) or 90 min (abstinence day 15). Effect of CeL PKCδ knockdown on methamphetamine incubation after social choice–induced abstinence (n = 11–12 per virus condition). Effect of CeL SOM knockdown on incubation of methamphetamine craving after forced abstinence (n = 13 per virus condition).
The protective effect of social reward on incubation of methamphetamine craving is mediated by activation of CeL PKCδ, leading to inhibition of CeM output neurons. The study introduces novel AAV shRNAs to selectively knockdown PKCδ or SOM in wild-type rodents.
  • AAV, adeno-associated virus; AIC, AI cortex; FR, fixed ratio; shRNA, short hairpin RNA.