Iyer, M. R. | bioRxiv Science

bioRxiv2022

Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder

RationaleCurrent medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known. ObjectivesHere, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder. MethodsOver 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement. ResultsWe found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index. ConclusionsThese results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.

neuroscience↗

bioRxiv2022

The onset of hearing triggers nuclear translocation in inner hair cells

Nuclear position is precisely orchestrated during cell division, migration, and maturation of cells and tissues. Here we report a previously unrecognized, programmed movement of the nucleus in rat cochlear inner hair cells. This cell-type specific nuclear movement among hair cells of the inner ear offers a new glimpse into the cellular mechanisms involved in the functional maturation of inner hair cells. In early post-natal days, the nucleus sits at the very basal pole of the hair cell, far from the apically located mechano-transducing stereocilia, but close to where synapses with primary afferent and efferent neurons are forming. By maturity, the nucleus moves to occupy a new position half-way along the length of the cell. Remarkably, nuclear translocation happens quickly over the course of 1-2 post-natal days, coinciding with the onset of hearing. The movement of the nucleus likely signals the closing of a critical period correlated with the forming and refining of synapses at the onset of hearing. Significance StatementThe misplacement of a cells nucleus has been implicated in hearing, vision, and muscular pathologies. In this study, we report a remarkably abrupt change in nuclear position in cochlear inner hair cells that coincides with the onset of hearing in rats, when hair cells switch from producing sensory-independent action potentials to sensory-dependent graded potentials. This work suggests that post-mitotic nuclear migration may be critical to the final phase of post-natal development in mammalian hearing.

neuroscience↗