Imbalanced Direct and Indirect Pathway Activity Underlies Heroin Conditioned Place Preference

O’Neal TJ, Bernstein MX, MacDougall DJ, Ferguson SM. A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens. J Neurosci 2022;42(10):2011-2024. doi: 10.1523/JNEUROSCI.1451-21.2021.

Background: Addiction arises when neutral cues acquire motivational significance through repeated pairing with drug exposure. The nucleus accumbens (NAc) integrates dopaminergic and striatal inputs to encode reward-related learning, but how heroin alters NAc signaling remains unclear. Direct (dMSN) and indirect (iMSN) pathway medium spiny neurons have opposing roles in motivation and action selection, yet their specific contributions to heroin reinforcement are not well defined.

Hypothesis: This study tested the hypothesis that heroin conditioned place preference (CPP) is driven by increased dopamine and dMSN activity and decreased iMSN activity in the NAc, forming an imbalance that encodes the reinforcing value of heroin-paired contexts.

Methods: The authors used fiber photometry (FP3001) to measure dopamine and calcium activity in NAc dMSNs and iMSNs during heroin CPP in male and female rats. Neural activity was recorded during conditioning and test sessions as rats entered or exited heroin- or saline-paired chambers. Additional experiments examined whether buprenorphine pretreatment affected heroin CPP and NAc Fos expression.

Results: Rats developed robust CPP and showed increased NAc Fos activation. During heroin conditioning, dopamine and dMSN signals increased while iMSN signals decreased before entry into heroin-paired contexts, with reversed patterns before exit. Across conditioning, dopamine and dMSN activity sensitized, and iMSN activity declined. Buprenorphine pretreatment blocked CPP formation and reduced NAc Fos levels.

Conclusions: Heroin reward learning depends on enhanced dopamine and direct pathway activity with concurrent suppression of indirect pathway signaling in the NAc. This imbalance encodes heroin-cue associations, while buprenorphine prevents their development.