Neuroscience

Large-scale characterization of cocaine addiction-like behaviors reveals that escalation of intake, aversion-resistant responding, and breaking-points are highly correlated measures of the same construct

Department of Psychiatry, University of California, San Diego, San Diego, USA
Department of Neuroscience, The Scripps Research Institute, San Diego, USA
Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille, France
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, USA
Institute for Genomic Medicine, University of California, San Diego, San Diego, USA

https://doi.org/10.7554/eLife.90422.2

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Figures and data

Individual differences in addiction-behaviors in HS rats following intravenous cocaine self-administration.
A) Timeline of the behavioral paradigms. B) Number of cocaine infusions in the first hour of cocaine self-administration during short (2 h, ShA) and long (6 h, LgA) access (N=567, *** p < 0.0001 vs the first LgA session). C) Average number of daily infusions for the last 3 days of LgA (N=567). D) Violin plot of number of cocaine infusions under progressive ratio (PR) tested after ShA (1) and LgA, before (2) and after (3) the Shock session (N= 560, *** p < 0.0001). E) Number of infusions despite footshock after LgA compared to a 1 h preshock session (N=466, *** p < 0.0001). F) Correlation of responding during the shock and preschock session is reproduced in each of 10 color coded cohorts (N=466, p < 0.0001). G) Difference in irritability scores after LgA and at baseline (N=380 + 49 naive, behavior *** p < 0.0001, ** p < 0.001 vs naive) H) Principal component analysis of cocaine infusions over all sessions ShA1-10, LgA1-14, PR1-3, Shock with escalation, motivation, and compulsivity indices.

Sex differences in addiction-like behaviors.
A) Cocaine infusions during short (2h, ShA) and long (6h, LgA) access of cocaine self-administration (N = 275 F and 292 M, ^### p <0.0001 vs males) B) Average number of daily infusions for the last 3 days of LgA in male and female rats. C) Violin plot of number of cocaine infusions under progressive ratio (PR) test after ShA and LgA (N = 273 F and 291 M). D) Number of infusions despite footshock after LgA (N= 275 F and 292 M, ^### p < 0.0001). E) Increase in irritability-like behavior in males and females after LgA compared to naive rats, no significant sex differences were detected (N = 186 F + 194 M + 23 naive F + 26 naive M).

Addiction-like behaviors in resilient and vulnerable HS rats.
A) Number of cocaine infusions during short (2h, ShA) and long (6h, LgA) access of cocaine self-administration in resilient and vulnerable animals (N = 122 resilient and 445 vulnerable, *** p < 0.001 vs LgA day 1, ^### p < 0.0001, ^## p < 0.001 vs resilient). B) Average number of infusions over the last 3 days for the individual animals). C) Number of cocaine infusions under progressive ratio (PR) at the end of ShA and LgA (^### p < 0.0001 vs resilient). D) Number of infusions despite footshock after LgA (^### p < 0.0001 vs resilient). E) Irritability scores after LgA (N=79 resilient, 301 vulnerable).

Normalizing and combining addiction like behaviors into an addiction index.
A) Z-score for escalation (N=566), B) motivation (N=512), C) compulsivity (N=567) and D) irritability-like behavior (N=380) in the whole population. E) Representation of the individual rats (N=377), resilient (green) or vulnerable (red) along the two first principal components, based on escalation, motivation, compulsivity, and irritability z-scores. F) Representation of the addiction index for the individual rats with the constituting individual z-scores and their identification as resilient or vulnerable and male or female (N=511).

Different degrees of vulnerability to cocaine addictive behaviors.
A) Cocaine infusions during short (2h, ShA) and long (6h, LgA) access of cocaine self-administration (N = 128 Low + 128 Mild + 127 Moderate + 128 Severe; *** p <0.0001). B) Average number of cocaine infusions over the last 3 days for the individual animals in the low, mild moderate and severe vulnerable groups. C) Number of cocaine infusions under progressive ratio (PR) test at the end of the ShA and LgA phases (*** p < 0.0001 vs low, ^### p <0.0001 vs ShA) D) Number of infusions despite footshock after LgA for the resilient and vulnerable groups (** p <0.001 and *** p <0.0001).

Additional representations of the intake and lever presses associated with figure 1B. A) Total number of cocaine infusions during short (2h, ShA) and long (6h, LgA) access. B) Percent of active or inactive lever presses of the total presses during short access is significantly different in every session. Mixed effects analysis shows a significant interaction between the levers and days (F_{(9, 2620)} = 55.57, p < 0.0001), the Bonferroni corrected post-hoc pairwise comparison between the percentages of both levers was significantly different on every day (***p<0.0001).

Motivation (A) and compulsivity (B) for the vulnerable and resilient populations split by sex

Additional PCA analysis with the representation of the individual rats (N=377) along the first two principal components. A) Rerun the PCA from Fig. 4E without irritability shows escalation, motivation, and compulsivity loading onto the first PC that explains a significant portion of the variance. B) Same PCA as in Fig. 4E, but with the data colored according to sex [female (yellow) or male (blue)], showed no sex differences. C-D) Same PCA as in Fig. 4E but run on females (D) or males (D) only. E-F) Rerun the PCA from Fig. 4E without irritability on females (E) or males (F) only.

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