Effects of Long-acting Kappa-opioid Receptor Antagonism on Compulsive Cocaine Self-administration

Authors' Affiliations

Stephen Foster, Department of Biomedical Sciences, East Tennessee State University Quillen College of Medicine, Johnson City, TN Brooke Schmeichel, PhD., Department of Biomedical Sciences, East Tennessee State University Quillen College of Medicine, Johnson City, TN.

Location

Culp Ballroom

Start Date

4-7-2022 9:00 AM

End Date

4-7-2022 12:00 PM

Poster Number

111

Faculty Sponsor’s Department

Biomedical Sciences

Name of Project's Faculty Sponsor

Brooke Schmeichel

Classification of First Author

Undergraduate Student

Competition Type

Competitive

Type

Poster Presentation

Project's Category

Neuroscience

Abstract or Artist's Statement

Abstract

Cocaine addiction, or stimulant use disorder (SUD) is a prevalent issue in the United States, with 5.5 million people being polled as having used cocaine in 2019 (SAMHA, 2020). This broad reaching issue highlights the need for the elucidation of the neurological mechanisms of reward and stress and how they contribute to SUD. One neuropeptide, dynorphin, which activates the kappa opioid receptors (KOR) has been shown to mediate negative mood states and dysphoria, which likely occur during drug withdrawal to reinforce subsequent drug seeking (Chavkin & Koob, 2016). To investigate the role of the KOR and dynorphin complex in drug addiction, this experiment examines the effects of KOR blockade on cocaine self-administration in rats.

Male rats were first trained to self-administer cocaine intravenously and split into short access (ShA; 1 hour; N=15) and long access (LgA; 6 hours; N=16) groups. Rats were given either vehicle or a long-acting KOR antagonist, norbinaltorphimine (NBI). After 15 self-administration sessions under a fixed ratio 1 (FR1) schedule, rats were also tested on a progressive-ratio (PR) schedule of reinforcement as a test of motivated behavior. We predicted that treatment with NBI would attenuate cocaine self-administration in LgA rats under both FR1 and PR schedules.

Results show the escalation of cocaine intake in saline-treated LgA rats, an increase that was attenuated in NBI-treated LgA rats. NBI-treated LgA rats also show a decrease in the PR breakpoint compared to saline-treated LgA rats. These results suggest dynorphin is necessary for compulsive cocaine seeking associated with drug dependence. Additional ongoing studies seek to determine the brain regions where dynorphin acts to modulate compulsive cocaine self-administration through measures of dynorphin density using an ELISA assay.

References

Chavkin, C., & Koob, G. F. (2016). Dynorphin, Dysphoria, and Dependence: the Stress of Addiction. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(1), 373–374. https://doi.org/10.1038/npp.2015.258

Substance Abuse and Mental Health Services Administration. (2020). Key substance use and mental health indicators in the United States: Results from the 2019 National Survey on Drug Use and Health (HHS Publication No. PEP20-07-01-001, NSDUH Series H-55). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf

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Apr 7th, 9:00 AM Apr 7th, 12:00 PM

Effects of Long-acting Kappa-opioid Receptor Antagonism on Compulsive Cocaine Self-administration

Culp Ballroom

Abstract

Cocaine addiction, or stimulant use disorder (SUD) is a prevalent issue in the United States, with 5.5 million people being polled as having used cocaine in 2019 (SAMHA, 2020). This broad reaching issue highlights the need for the elucidation of the neurological mechanisms of reward and stress and how they contribute to SUD. One neuropeptide, dynorphin, which activates the kappa opioid receptors (KOR) has been shown to mediate negative mood states and dysphoria, which likely occur during drug withdrawal to reinforce subsequent drug seeking (Chavkin & Koob, 2016). To investigate the role of the KOR and dynorphin complex in drug addiction, this experiment examines the effects of KOR blockade on cocaine self-administration in rats.

Male rats were first trained to self-administer cocaine intravenously and split into short access (ShA; 1 hour; N=15) and long access (LgA; 6 hours; N=16) groups. Rats were given either vehicle or a long-acting KOR antagonist, norbinaltorphimine (NBI). After 15 self-administration sessions under a fixed ratio 1 (FR1) schedule, rats were also tested on a progressive-ratio (PR) schedule of reinforcement as a test of motivated behavior. We predicted that treatment with NBI would attenuate cocaine self-administration in LgA rats under both FR1 and PR schedules.

Results show the escalation of cocaine intake in saline-treated LgA rats, an increase that was attenuated in NBI-treated LgA rats. NBI-treated LgA rats also show a decrease in the PR breakpoint compared to saline-treated LgA rats. These results suggest dynorphin is necessary for compulsive cocaine seeking associated with drug dependence. Additional ongoing studies seek to determine the brain regions where dynorphin acts to modulate compulsive cocaine self-administration through measures of dynorphin density using an ELISA assay.

References

Chavkin, C., & Koob, G. F. (2016). Dynorphin, Dysphoria, and Dependence: the Stress of Addiction. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(1), 373–374. https://doi.org/10.1038/npp.2015.258

Substance Abuse and Mental Health Services Administration. (2020). Key substance use and mental health indicators in the United States: Results from the 2019 National Survey on Drug Use and Health (HHS Publication No. PEP20-07-01-001, NSDUH Series H-55). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf