The Role of Beta-Endorphin in Cocaine-Induced Conditioned Place Preference, Its Extinction, and Reinstatement in Male and Female Mice

Abstract

Endogenous opioids have been implicated in cocaine reward. However, the role of each opioid peptide in this regard is unknown. Notably, the role of each peptide in extinction and reinstatement is not fully characterized. Thus, we assessed whether cocaine-induced conditioned place preference (CPP) and its extinction and reinstatement would be altered in the absence of beta-endorphin. We also examined if sex-related differences would exist in these processes. Male and female mice lacking beta-endorphin and their respective controls were tested for baseline place preference on day 1. On day 2, mice were treated with saline/cocaine (15 mg/kg) and confined to the vehicle- or drug-paired chamber for 30 min, respectively. In the afternoon, mice were treated with the alternate treatment and confined to the opposite chamber. Mice were then tested for CPP on day 3. Mice then received additional conditioning on this day as well as on day 4. Mice were then tested for CPP on day 5. Mice then received extinction training on day 9. On day 10, mice were tested for extinction and then reinstatement of CPP following a priming dose of cocaine (7.5 mg/kg). Male and female mice lacking beta-endorphin did not exhibit CPP following single conditioning with cocaine. On the other hand, only male mice lacking beta-endorphin failed to show CPP after repeated conditioning. Nonetheless, reinstatement of CPP was blunted in both male and female mice lacking beta-endorphin compared to controls. The present results suggest that beta-endorphin plays a functional role in cocaine-induced CPP and its reinstatement, and sex-related differences exist in the regulatory action of beta-endorphin on the acquisition but not reinstatement of cocaine CPP.

Endogenous opioid system modulates conditioned cocaine reward in a sex‐dependent manner

“…One potential candidate is the opioid peptide β‐endorphin, which is released into the striatum and has high affinity for MORs. Furthermore, mice lacking β‐endorphin show attenuated cocaine preference 30,31 . Systemic naloxone could also be acting to prevent enkephalin‐mediated disinhibition of dopamine neurons in the ventral tegmental area, 32,33 which could potentially lead to attenuated cocaine preference 2 …”

“…Furthermore, mice lacking β-endorphin show attenuated cocaine preference. 30,31 Systemic naloxone could also be acting to prevent enkephalin-mediated disinhibition of dopamine neurons in the ventral tegmental area, 32,33 which could potentially lead to attenuated cocaine preference. 2 We also observed consistent sex differences in the extinction of cocaine place preference.…”

Striatal enkephalin supports maintenance of conditioned cocaine reward during extinction

“…The copyright holder for this preprint this version posted February 24, 2023. ; https://doi.org/10.1101/2023.02. 23.529807 doi: bioRxiv preprint Systemic administration of the non-selective opioid receptor antagonists naloxone and naltrexone attenuates acquisition and expression of conditioned place preference to cocaine [6][7][8] . This effect appears to be mediated by MORs, as intracerebroventricular injection of the MOR antagonist CTAP also blocks acquisition of cocaine place preference 9 .…”

“…The copyright holder for this preprint this version posted February 24, 2023. ; https://doi.org/10.1101/2023.02.23.529807 doi: bioRxiv preprint Single-dose naloxone also attenuated cocaine preference in D2-PenkKOs, suggesting that naloxone suppresses cocaine preference by blocking the action of a striatal opioid peptide other than enkephalin or that it is acting in a different brain region. The opioid peptide β-endorphin is released into the striatum, has high affinity for the MOR, and mice lacking β-endorphin show attenuated cocaine preference 22,23 . Systemic naloxone could also prevent enkephalin-mediated disinhibition of dopamine neurons in the ventral tegmental area 24,25 , which could potentially lead to attenuated cocaine preference 2 .…”