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Abstract
Nitric oxide synthase 1 (NOS1) within the interpeduncular nucleus (IPN) is upregulated by chronic nicotine and oxycodone exposure. Disrupting Nos1 in the IPN abolishes nicotine place preference in mice. The IPN receives input from the medial habenula (MHb) and IPN-released nitric oxide (NO) inhibits glutamate release from the MHb, providing feedback inhibition. We hypothesize that behaviorally this reduces the strength of aversion mediated by the MHb, promoting the development of tolerance to nicotine and possibly opioids. In support of this hypothesis, previous work has demonstrated a role for NO in drug abuse, where systemic administration of a NOS1 inhibitor can prevent development of analgesic tolerance to opioids, reverse established tolerance, and modulate withdrawal. Our present study investigates whether behavioral tolerance to oxycodone coincides with increased NOS1 in the IPN, if NOS1 in the IPN is necessary for behavioral tolerance and develops tools for direct visualization of NO in behaving animals.
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