Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence

Abstract

Background: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. Aims: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Methods: A cocaine-CPP paradigm in male Sprague–Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference. Results: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes ( Fos, Egr2, Nr4a1, and Zbtb37) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP. Conclusion: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine’s rewarding effects.

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

“…Notably, the identified transcription factors were particularly driven by the Ctx condition in the NAc core, suggesting elevated transcriptional regulation. We identified enriched putative motifs for ZNF263 (Ctx group) and RRBE1 (HC group), proteins previously associated with drug exposure 46,47 (Fig. 5B, left/middle panels).…”

Quantifying conditioned place preference: a review of current analyses and a proposal for a novel approach

“…The tolerance interval is used to determine a range of values within which a specified proportion of the sampled population falls. Atehortua Martinez et al (2022) built two tolerance intervals: [70, 95] and [90, 95]. The intervals indicate that one can be 95% confident that either 70% (first interval) or 90% (second interval) of the CPP scores for the control subjects are represented.…”

“…This makes dissociating these subjects as nCPPE or CPPE difficult. Atehortua Martinez et al (2022) also characterized rats with scores below −128 s as unclear as they appear to have developed CPA.…”

“…Using the same data from the Ro 63-1908/methamphetamine CPP experiment described above, I built tolerance intervals as described in Atehortua Martinez et al (2022) using the control data reported in Yates et al (2021a) . The [70, 95] interval includes the range of −104.498 s to 95.166 s. The [90, 95] interval includes the range of −163.103 s to 153.771 s. Applying the same protocol as Atehortua Martinez et al (2022) , CPPE rats are those that have an adjusted CPP score of >153.771 s. Rats with a score between −104.498 and 95.166 s are nCPPE. All other rats are considered unclear.…”

“…However, one advantage of this approach over CART is that it allows one to determine if subjects have developed an aversion to the CS + compartment. While Atehortua Martinez et al (2022) labeled rats with scores below −128 s as unclear, one could classify these subjects as CPA-expressing (CPAE). If I apply the same logic to the data presented in Figure 9 , one male rat pretreated with Ro 63-1908 (3.0 mg/kg) has a score less than −163.103 s, indicating CPA.…”