# Shifted Balance Between Ventral Striatal Prodynorphin and Proenkephalin Biases Development of Cocaine Place Avoidance

## TL;DR

The study shows that the balance of two opioid peptides in the brain affects how mice respond to the negative effects of cocaine.

## Contribution

The study identifies a novel role for the Pdyn:Penk ratio in the ventral striatum in modulating cocaine-induced aversion.

## Key findings

- Cocaine CPA was associated with low Pdyn:Penk mRNA levels in the ventral striatum.
- Mice with higher Pdyn:Penk levels were more resistant to developing CPA.
- Individual differences, not cocaine dose or apparatus type, influenced CPA expression.

## Abstract

Evidence from human self‐report and rodent models indicate that cocaine can induce a negative affective state marked by panic and anxiety, which may reduce future cocaine use or promote co‐use with opiates. Dynorphin‐mediated signalling within the striatum is associated with negative affect following cocaine withdrawal and stress‐induced cocaine seeking. Here, we used a trace conditioning procedure to first establish the optimum parameters to capture this transient cocaine negative affective state in wild‐type mice, and then we investigated striatal opioid peptides as a substrate mediating cocaine conditioned place avoidance (CPA). Previous reports indicate that trace conditioning, where drug administration occurs after removal from the conditioning chamber, results in CPA to ethanol, nicotine and amphetamine. We tested different cocaine doses, conditioning session lengths and apparatus types to determine which combination yields the best cocaine CPA. Cocaine CPA was moderately larger at the highest cocaine dose (25 mg/kg), but this did not generalize across apparatus types and the effect was transient; thus, data were collapsed across all parameters. Cocaine conditioning scores were variable but also became more polarized across conditioning, with approximately equal proportions developing preference and avoidance. We then correlated cocaine CPA with striatal gene expression levels of the opioid peptides enkephalin (Penk) and dynorphin (Pdyn) using qPCR. Cocaine CPA was correlated with low Pdyn levels and a low Pdyn:Penk ratio in the ventral, but not dorsal, striatum. Consistent with this, mice with higher striatal Pdyn relative to Penk were more resistant to developing cocaine CPA compared with littermate controls. This approach revealed a subset of subjects sensitive to the aversive state immediately following cocaine administration. Our findings suggest that striatal dynorphin has opposing roles in mediating the aversion associated with acute cocaine intoxication versus cocaine withdrawal.

We examined the optimum parameters for producing conditioned place avoidance (CPA) to the acutely aversive effects of cocaine treatment. We discovered that individual differences, rather than cocaine dose, apparatus type, stimulus modality or conditioning time, were important for expression of cocaine CPA. We further discovered that CPA was associated with low Pdyn:Penk mRNA levels in the ventral striatum of wild‐type mice and causally demonstrated that transgenic mice with pre‐existing higher striatal Pdyn:Penk expression levels were more resistant to develop CPA. Created in BioRender. Dobbs, L. (2025) https://BioRender.com/b2agzur.