Dynorphin Blockade Attenuates Cocaine Seeking in Male Rats.
Location
D.P. Culp Center Ballroom
Start Date
4-5-2024 9:00 AM
End Date
4-5-2024 11:30 AM
Poster Number
70
Name of Project's Faculty Sponsor
Brooke Schmeichel
Faculty Sponsor's Department
Biomedical Sciences
Competition Type
Competitive
Type
Poster Presentation
Presentation Category
Health
Abstract or Artist's Statement
As of 2021, nearly 41 million people in the United States had reported cocaine use, resulting in a nearly 7-fold increase in cocaine-involved overdoses in the past decade. Long-term cocaine use can lead to a chronically relapsing substance use disorder characterized by persistent drug-seeking behaviors despite physical, mental, and social harm to the individual. To date, there are no FDA-approved medications for treatment of cocaine addiction and there is a critical need for further expositions on the neurobiological mechanisms that underlie cocaine use and addiction. One potential pharmaceutical target for the treatment of cocaine addiction is the endogenous neuropeptide dynorphin that preferentially binds at kappa opioid receptors (KOR). The activation of KORs has been shown to mediate negative emotional states (anhedonia, dysphoria, irritability, etc.) during drug withdrawal. These withdrawal symptoms heavily contribute to the negatively reinforcing actions of drugs like cocaine. To research the role of the dynorprhin-KOR system in cocaine addiction, the effects of long-term κOR antagonism was studied using a rodent-model of cocaine dependence. Male Wistar rats were first trained to self-administer cocaine intravenously, then split into two groups: short access (ShA; 1hr sessions; n=15) and long access (LgA; 6hr sessions; n=16) to emulate non-dependent and dependent-like drug-taking conditions, respectively. Rats in each group were given a single, systemic injection of either vehicle or a long-acting KOR antagonist, norbinaltorphimine (nor-BNI), prior to undergoing 15 consecutive self-administration sessions under a fixed ratio (FR1) schedule of reinforcement. The rats were subsequently tested on a progressive ratio (PR) schedule of reinforcement to measure motivated behavior. It was predicted that KOR antagonism with nor-BNI would attenuate escalation of cocaine self-administration under both FR1 and PR schedules of reinforcement. Results indeed showed attenuated cocaine self-administration in nor-BNI-treated LgA rats compared to the uninhibited escalation of cocaine intake in saline-treated LgA rats. Nor-BNI-treated LgA rats also show a decrease in the PR breakpoints, compared to saline-treated LgA rats. There was no effect of nor-BNI on cocaine self-administration in ShA rats. These results suggest that dynorphin is a determining component underlying compulsive cocaine seeking behaviors associated with drug dependence. Additional ongoing studies seek to determine the specific brain regions where dynorphin acts to modulate compulsive cocaine self-administration through measures of pro-dynorphin density using immunohistochemistry assays on stress-sensitive brain regions in cocaine dependent rats.
Dynorphin Blockade Attenuates Cocaine Seeking in Male Rats.
D.P. Culp Center Ballroom
As of 2021, nearly 41 million people in the United States had reported cocaine use, resulting in a nearly 7-fold increase in cocaine-involved overdoses in the past decade. Long-term cocaine use can lead to a chronically relapsing substance use disorder characterized by persistent drug-seeking behaviors despite physical, mental, and social harm to the individual. To date, there are no FDA-approved medications for treatment of cocaine addiction and there is a critical need for further expositions on the neurobiological mechanisms that underlie cocaine use and addiction. One potential pharmaceutical target for the treatment of cocaine addiction is the endogenous neuropeptide dynorphin that preferentially binds at kappa opioid receptors (KOR). The activation of KORs has been shown to mediate negative emotional states (anhedonia, dysphoria, irritability, etc.) during drug withdrawal. These withdrawal symptoms heavily contribute to the negatively reinforcing actions of drugs like cocaine. To research the role of the dynorprhin-KOR system in cocaine addiction, the effects of long-term κOR antagonism was studied using a rodent-model of cocaine dependence. Male Wistar rats were first trained to self-administer cocaine intravenously, then split into two groups: short access (ShA; 1hr sessions; n=15) and long access (LgA; 6hr sessions; n=16) to emulate non-dependent and dependent-like drug-taking conditions, respectively. Rats in each group were given a single, systemic injection of either vehicle or a long-acting KOR antagonist, norbinaltorphimine (nor-BNI), prior to undergoing 15 consecutive self-administration sessions under a fixed ratio (FR1) schedule of reinforcement. The rats were subsequently tested on a progressive ratio (PR) schedule of reinforcement to measure motivated behavior. It was predicted that KOR antagonism with nor-BNI would attenuate escalation of cocaine self-administration under both FR1 and PR schedules of reinforcement. Results indeed showed attenuated cocaine self-administration in nor-BNI-treated LgA rats compared to the uninhibited escalation of cocaine intake in saline-treated LgA rats. Nor-BNI-treated LgA rats also show a decrease in the PR breakpoints, compared to saline-treated LgA rats. There was no effect of nor-BNI on cocaine self-administration in ShA rats. These results suggest that dynorphin is a determining component underlying compulsive cocaine seeking behaviors associated with drug dependence. Additional ongoing studies seek to determine the specific brain regions where dynorphin acts to modulate compulsive cocaine self-administration through measures of pro-dynorphin density using immunohistochemistry assays on stress-sensitive brain regions in cocaine dependent rats.