Behavioral and neural effects of intranasal cocaine in mice

About This Grant

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.