Behavioral and neural effects of intranasal cocaine in mice
openNIDA - National Institute on Drug Abuse
Project Summary. Many drugs of abuse are inhaled by users to achieve a more immediate or intense high
including cocaine, amphetamine, prescription stimulants (e.g., Adderall), heroin, prescription opioids,
benzodiazepines, and ecstasy. Nasal inhalation of these drugs (viz., “snorting”, “taking a bump”, “sniffing”, or
“blowing”) holds substantial public health and treatment implications in addition to destruction and necrosis of
oral, nasal, and facial structures. Despite the widespread use of the nasal route of administration by human
drug users, there lacks an established model to capture this route of administration preclinically. Thus,
there is a critical gap in our understanding of the mechanisms of these drugs on the brain and behavior. We
reason that the lack of safe and effective therapies to combat drug addiction is due in part to this fundamental
knowledge gap. Indeed, inhalation of drugs into the nose exposes them to unique entry points whereby they can
eventually reach the CNS, including a unique enzymatic milieu which will impact metabolism and unique plasma
permeability which altogether will influence the total amount of drug to reach the brain in addition to the kinetics
of how it does so. While we are learning more about how routes of drug administration can influence brain circuits
recruited by those drugs as well as dopamine increases, we have no benchmark for outcomes from intranasal
delivery. To overcome this knowledge gap, a paradigm is needed which achieves reliable and precise delivery
of drugs into the nose in preclinical models. We have developed a surgical device, that when implanted upon
the nasal bone of mice, accesses the nasal cavity to allow reliable and precise intranasal (IN) drug
delivery during freely-moving behavior. We validated that this device (called the Nasal Access Port or NAP)
achieves precise and reliable administration of drugs. In this R21 we seek to compare the outcomes of cocaine
when administered intranasally (IN) versus intravenously (IV) or intraperitoneally (IP) on common behavioral and
neurobiological measures. Our hypothesis is that IN cocaine will induce distinct behavioral and neural alterations
compared to other routes of administration. Data to support this hypothesis will highlight a unique liability profile
and specific neurobiological mechanisms underlying cocaine’s effects when inhaled. In Aim 1 we will determine
differences in how IN cocaine administration impacts behavior and then in Aim 2 determine differences in
activation of the mesolimbic dopaminergic system by IN cocaine. From the results in Aim 1 we will also generate
an integrated PK/PD model to bolster rigor and outcomes. The results from this pilot R21 study will establish
a valuable platform for investigating the long-term effects of IN drug use, including addiction liability,
neurotoxicity, and the development of targeted interventions.
Up to $422K
health research