Molecular and Cellular Profiling of the Habenulointerpeduncular Circuit in Opioid Tolerance and Withdrawal

ABSTRACT The present crisis of opioid addiction in the United States highlights how an initial exposure to opioids, often oxycodone, as a medical patient can lead to escalation of use, misuse and eventually addiction. Chronic exposure to oxycodone produces tolerance to many of its effects, and it is this development of tolerance that

leads to taking increasingly higher doses and to withdrawal upon abstinence. Drug-induced adaptations in gene expression and neuronal function are thought to underlie the development of tolerance and withdrawal, but the mechanisms by which this occurs remain unclear. We have found that the habenula-interpeduncular nucleus

(IPN), which plays a prominent role in limiting nicotine intake and in nicotine withdrawal responds to chronic nicotine by upregulating nitric oxide synthase 1 (NOS1), and that this same adaptation occurs in response to chronic oxycodone exposure. Acute exposure to oxycodone is not sufficient to upregulate NOS1 in the IPN.

Using viral approaches, purification of tagged ribosomes followed by next gen sequencing and oral oxycodone in the drinking water of adult male and female mice, we will examine gene expression in the IPN – both in the presynaptic terminals and postsynaptic IPN neurons - and correlate neuronal calcium dynamics with intoxication

and withdrawal behavior. We will also examine the contribution of NOS1 to drug-induced changes in gene expression in neuronal activity and axon terminals from the medial habenula within the interpeduncular nucleus. Together these aims will establish a preclinical model of opioid tolerance that may provide a basis for evaluating

potential new therapeutics in the treatment of opioid use disorder.