A Hormonal, Neuronal, And Behavioural Approach To The Augmentation Of Heroin Seeking In Chronically Food-Restricted Rats Under Withdrawal

Why can’t we stop? Despite one’s greatest efforts to remain abstinent, re-exposure to drug- associated cues can elicit drug-craving and promote relapse after withdrawal. Interestingly, hunger can increase the vulnerability to relapse. In chronically food-restricted, compared to sated rats, we demonstrated augmented heroin seeking under withdrawal. However, the mechanisms responsible for this susceptibility remain unclear. Here, we evaluated the hormonal, neuronal, and behavioural processes that may contribute to the enhanced vulnerability to drug seeking in calorically-restricted rats. Estradiol (E2) may facilitate, while progesterone may attenuate drug seeking; however, we are the first to assess these hormones’ role in calorically-restricted, heroin-seeking rats. Removal of the ovaries and subsequent progesterone replacement yielded no effects. However, E2 replacement attenuated the augmented heroin seeking observed in food-restricted rats, providing a therapeutic target for drug-addiction treatment in females. Next, we investigated the role of the glutamate GluA1 and phosphorylated GluA1 (p-Ser845- GluA1) subunits, which contribute to the long-term relapse vulnerability of abused drugs. Re- exposure to heroin cues, compared to heroin-trained rats not re-exposed to the cues, increased p-Ser845-GluA1 protein levels in the nucleus accumbens (NAc) shell. Reduced NAc shell GluA1 and p-Ser845-GluA1 protein levels were also observed in heroin-trained compared to drug- naïve rats. No changes were observed due to dietary restriction. As we did not dissociate membrane-bound and cytoplasmic receptors, our findings may be a limitation of the iii procedure employed. Further work is needed to clarify the role of the GluA1 receptor in chronically food-restricted, heroin-seeking rats. Lastly, we investigated whether augmented heroin seeking in our food-restricted rats was a function of the cues’ association with the drug, or the inherent value of light cues alone. While some light-cue-specific effects were observed, we concluded that caloric restriction contributes to the motivational properties of light cues as a result of their heroin association. Collectively, we demonstrate the value of a multi-dimensional approach to the understanding a novel behavioural procedure. While we have answered some questions on the hormonal, neuronal, and behavioural mechanisms underlying the enhanced vulnerability to drug abuse in calorically-restricted rats, we have importantly presented many questions to drive future research