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Volitional social interaction prevents drug addiction in rat models

Abstract

Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCδ-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.

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Fig. 1: Preference for drug vs. social reward: effects of drug dose, delay of social reward, punishment of social-reward choice, or forced abstinence.
Fig. 2: Preference for methamphetamine vs. social reward in addicted and nonaddicted rats.
Fig. 3: High addiction score does not predict lower social preference.
Fig. 4: Effect of social-choice voluntary abstinence on incubation of methamphetamine craving.
Fig. 5: Effect of social-choice voluntary abstinence on Fos expression, and Fos + PKCδ or Fos + SOM in CeL and CeM: immunohistochemistry.

Data availability

Materials, datasets, and protocols are available upon reasonable request to M.V. or Y.S. See the Nature Research Reporting Summary for details.

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Acknowledgements

We thank M. Jin, A. Minier Toribio, and O. Lofaro for their help during the experiments. The research was supported by the Intramural Research Program of NIDA, a fellowship from the NIH Center on Compulsive Behaviors (M.V.), and NARSAD Distinguished Investigator Grant Award (Y.S.).

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Contributions

M.V., D,C., and Y.S designed the experiments; M.V., M.Z., and D.C. built the custom-made social self-administration chambers, M.V., M.Z., D.C., J.K.H., S.A.G. and C.H. collected the behavioral data; M.V., M.Z., J.K.H., and M.M. performed and quantified the biochemical assays; M.V., M.Z., D.H.E., and Y.S. analyzed the data; M.V., M.M., D.H.E., and Y.S. wrote the paper with feedback from the other authors.

Corresponding authors

Correspondence to Marco Venniro or Yavin Shaham.

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The authors declare no competing interests.

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Integrated supplementary information

Supplementary Figure 1 Custom-made social-choice self-administration apparatus.

(Top) Five steps to build the apparatus, starting with a Standard Modular Operant Test Chamber with Modified Top for Rat (ENV—008CT, Med Associates). (Bottom) Picture of the apparatus in the configuration we used, plus a list of all the Med Associates components. Related to Fig. 1J.

Supplementary Figure 2 Addiction score-based methamphetamine self-administration.

(A) Methamphetamine self-administration training. Number of methamphetamine infusions during the training phase of the Low, Medium, and High addiction-score groups (Low n = 25; Medium n = 9; High n = 8). Related to Fig. 2 (Exp. 2). (B) Methamphetamine self-administration training. Number of methamphetamine infusions during the training phase of the Low, Medium, and High addiction-score groups (Low n = 13; Medium n = 8; High n = 6). Related to Fig. 3 (Exp. 3). Statistical details are included in Supplementary Table 1.

Supplementary Figure 3 Discrete-choice sessions during training, devaluation, or progressive-ratio tests.

(A) Discrete choice sessions during training (rewards: social, palatable pellets or drug infusion). Number of food or social rewards and methamphetamine infusions earned during the 3 choice sessions performed during self-administration training. (B) Devaluation/satiety tests. Number of food or social rewards and methamphetamine infusions earned during the 6 choice sessions performed after extended exposure to palatable food or social partner in the homecage, respectively. (C) Progressive ratio. Number of food or social rewards and methamphetamine infusions earned during progressive-ratio tests. Data are mean±SEM. Food-choice-induced versus Social-choice-induced abstinence n = 10 and 12, respectively; Related to Fig. 4 (Exp. 4A). Statistical details are included in Supplementary Table 1.

Supplementary Figure 4 Effect of social-choice voluntary abstinence on c-Fos expression, and c-Fos + PKCδ or c-Fos + SOM in CeL and CeM: RNAscope.

(A) Timeline of the experiment. (B) Self-administration training (rewards: social or drug infusion). Number of social rewards (2 h) or methamphetamine infusions (6 h). (C) Voluntary abstinence. Number of social rewards or methamphetamine infusions earned during the 10 discrete-choice sessions. (D) Relapse test day 15 (RNAscope®). Lever presses on the active or inactive levers during the 90-min test session on day 15 (No-test, Day 15 Forced and Social-induced-abstinence, n = 7 per group). (E) RNAscope. Representative photomicrographs of PKCδ or SOM in CeL and CeM, Scale bar: 100 µm. (F) Representative CeL and CeM photomicrographs of Fos expression in PKCδ or SOM positive cells in the No-test group (left panels, n = 7), Social-choice Day 15 group (middle panels, n = 7), and Forced abstinence Day 15 group (right panels, n = 7). Arrows indicate representative cells and double arrows indicate double-labeled cells (Fos, white; PKCδ, green; SOM, red), Scale bar: 20 µm. (G) Fos neurons quantification. Number of Fos-IR nuclei per mm2 in the CeL and CeM. (H) Double-labeled cells quantification. Number of Fos-IR double-labeled with PKCδ or SOM per mm2 in the CeL and CeM. (I) PKCδ and SOM quantification. Number of PKCδ-IR or SOM-IR in CeL and CeM. * Different from other groups, p<0.05; # Different from the No-test group, p<0.05. Data are mean±SEM. Related to Fig. 5. Statistical details are included in Supplementary Table 1.

Supplementary Figure 5 Quantification of c-Fos expression in other brain regions.

(A) Immunohistochemistry. Quantification of Fos-IR positive cells in (B) anterior insular cortex ventral and dorsal (AIV, AID), (C) anterior cingulate cortex (ACC), (D) dorsal and (E) ventral medial PFC (dmPFC and vmPFC), (F) medial and lateral OFC (mOFC and lOFC), and (G) basolateral amygdala (BLA). * Different from the no-test group, # Different from the Day 1 group, p<0.05. Data are mean±SEM. Scale bar: 100 µm. (No-test, n = 15; Day 1, n = 16; Day 15 Forced and Social-induced-abstinence, n = 7 per group). Related to Fig. 5. Statistical details are included in Supplementary Table 1.

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Venniro, M., Zhang, M., Caprioli, D. et al. Volitional social interaction prevents drug addiction in rat models. Nat Neurosci 21, 1520–1529 (2018). https://doi.org/10.1038/s41593-018-0246-6

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