# Olanzapine Attenuates the Morphine‐Induced Conditioned Place Preference: The Involvement of the D2‐Like Dopamine Receptors

## TL;DR

Olanzapine reduces morphine-induced drug-seeking behavior in mice by affecting dopamine receptors in the brain.

## Contribution

Olanzapine's effect on morphine dependence via D2-like dopamine receptors is demonstrated in a CPP model.

## Key findings

- Olanzapine reduced morphine-induced conditioned place preference in a dose-dependent manner.
- Olanzapine decreased D2R protein expression in the hippocampus during expression and extinction phases.
- Olanzapine accelerated the extinction of morphine-induced CPP without impairing locomotor activity.

## Abstract

Opioid use disorder is associated with persistent molecular and cellular changes in the brain, leading to compulsive drug‐seeking behaviors. This study aimed to evaluate the effects of olanzapine (OLZ), a D2‐like dopamine receptor (D2R) antagonist, on morphine dependence using the conditioned place preference (CPP) model.

Morphine‐induced CPP was established by subcutaneous (sc) administration of morphine (5 mg/kg) for three consecutive days. OLZ at doses of 1.5, 3, and 4.5 mg/kg was administered intraperitoneally (ip) during different phases of CPP: acquisition, expression, and extinction. Behavioral assessments included measurement of conditioning scores and locomotor activity. D2R protein expression in the hippocampus (HIP) was evaluated using western blotting.

OLZ reduced both acquisition and expression of morphine‐induced CPP in a dose‐dependent manner. Additionally, OLZ facilitated extinction by shortening the duration of the extinction phase. Western blot analysis showed a significant reduction in D2R protein expression in the expression and extinction phases in the OLZ‐treated groups compared to the morphine‐only group. Importantly, effective doses of OLZ did not impair locomotor activity.

OLZ attenuates morphine‐induced CPP and downregulates D2R expression in the HIP without affecting general locomotor function. These findings suggest a potential therapeutic role for OLZ in the management of opioid‐related behaviors. Further research is needed to determine its clinical relevance.

The results of this study demonstrated that olanzapine can inhibit morphine‐induced CPP behavior during the acquisition, expression, and extinction phases. These effects are likely mediated by the inhibition of dopamine receptors and a reduction in D2R protein expression in the HIP. Additionally, the use of olanzapine during the extinction phase accelerated the extinction process of CPP. These findings suggest that olanzapine may hold therapeutic potential in managing psychological dependence on drugs through D2R‐dependent pathways.