MGlu5 modulation reduces alcohol self-administration in an animal model of THC and alcohol co-use

Authors' Affiliations

Britta Schwartz, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee University, Johnson City, TN. Dr. Liza Wills, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee University, Johnson City, TN. Dr. Justin Gass, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee University, Johnson City, TN.

Location

D.P. Culp Center Ballroom

Start Date

4-5-2024 9:00 AM

End Date

4-5-2024 11:30 AM

Poster Number

75

Name of Project's Faculty Sponsor

Justin Gass

Faculty Sponsor's Department

Biomedical Sciences

Classification of First Author

Graduate Student-Doctoral

Competition Type

Competitive

Type

Poster Presentation

Presentation Category

Health

Abstract or Artist's Statement

Cannabis is one of the most used illicit drugs, particularly in vulnerable populations such as veterans diagnosed with PTSD, adolescents, and chronic alcohol users. Indeed, patients diagnosed with cannabis use disorder (CUD) are 10x more likely to develop alcohol use disorder (AUD). With increased legalization of recreational marijuana use across the United States, it is vital to understand the combined effects of THC and other commonly used drugs. Delta 9 -tetrahydrocannabinol (THC), the psychoactive compound found in the cannabis plant, has been shown to significantly impact both physiological and behavioral outcomes when used concomitantly with alcohol. Therefore, the current study aims to investigate the hypothesis that combined THC and alcohol exposure exacerbates alcohol self-administration behaviors. Additionally, since we have previously shown the beneficial effects of the mGluR5 positive allosteric modulator CDPPB on alcohol behaviors, we will also test its ability to recover behavioral changes associated with THC and alcohol exposure. Rats were exposed to THC vapor for 5 days, followed by a chronic intermittent ethanol exposure (CIE) procedure for 10 days to model alcohol dependency. Next, rats underwent a Two-Bottle Choice (TBC) task in which they were given access to two bottles in their home cages. One bottle contained water, and the other contained a 20% ethanol solution. Bottles were weighed daily to assess alcohol intake. A separate group of rats was trained to operantly self-administer alcohol. Each lever press resulted in a 45L ethanol solution, stimulus light, and tone presentation. Following training, rats entered an extinction phase in which each lever press resulted in the tone/light presentation, but no ethanol delivery. Twenty minutes prior to an extinction trial, a subset of rats received a subcutaneous injection of CDPPB (30mg/kg) or a vehicle. Our results indicate rats exposed to THC+CIE displayed significantly higher alcohol consumption compared to air controls on days 2, 4, and 5 of the TBC task. Furthermore, THC+CIE rats also showed significantly increased alcohol intake in the operant (lever-pressing) self-administration task. In this same task THC+CIE exposed rats showed deficits in their ability to extinguish alcohol-seeking behavior. Importantly, this effect was prevented with CDPPB treatment. Specifically, THC+CIE exposed rats who received CDPPB treatment displayed significantly less lever presses on days 2-5 of extinction training compared to vehicle treated animals. Together, these data suggest that THC and alcohol co-use may lead to exacerbated drinking behaviors and a diminished ability to quit drinking. Deficits in extinction learning due to THC+CIE exposure can be prevented through modulation of mGlu5 via CDPPB treatment. Future studies conducted in our lab will examine neurological substrates involved in THC+CIE induced behavioral changes using optogenetic manipulation of specific neuronal circuitry. Furthering our understanding of the consequences of THC and alcohol co-use is vital due to the frequency in which these drugs are used together and the vulnerable populations that are affected.

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Apr 5th, 9:00 AM Apr 5th, 11:30 AM

MGlu5 modulation reduces alcohol self-administration in an animal model of THC and alcohol co-use

D.P. Culp Center Ballroom

Cannabis is one of the most used illicit drugs, particularly in vulnerable populations such as veterans diagnosed with PTSD, adolescents, and chronic alcohol users. Indeed, patients diagnosed with cannabis use disorder (CUD) are 10x more likely to develop alcohol use disorder (AUD). With increased legalization of recreational marijuana use across the United States, it is vital to understand the combined effects of THC and other commonly used drugs. Delta 9 -tetrahydrocannabinol (THC), the psychoactive compound found in the cannabis plant, has been shown to significantly impact both physiological and behavioral outcomes when used concomitantly with alcohol. Therefore, the current study aims to investigate the hypothesis that combined THC and alcohol exposure exacerbates alcohol self-administration behaviors. Additionally, since we have previously shown the beneficial effects of the mGluR5 positive allosteric modulator CDPPB on alcohol behaviors, we will also test its ability to recover behavioral changes associated with THC and alcohol exposure. Rats were exposed to THC vapor for 5 days, followed by a chronic intermittent ethanol exposure (CIE) procedure for 10 days to model alcohol dependency. Next, rats underwent a Two-Bottle Choice (TBC) task in which they were given access to two bottles in their home cages. One bottle contained water, and the other contained a 20% ethanol solution. Bottles were weighed daily to assess alcohol intake. A separate group of rats was trained to operantly self-administer alcohol. Each lever press resulted in a 45L ethanol solution, stimulus light, and tone presentation. Following training, rats entered an extinction phase in which each lever press resulted in the tone/light presentation, but no ethanol delivery. Twenty minutes prior to an extinction trial, a subset of rats received a subcutaneous injection of CDPPB (30mg/kg) or a vehicle. Our results indicate rats exposed to THC+CIE displayed significantly higher alcohol consumption compared to air controls on days 2, 4, and 5 of the TBC task. Furthermore, THC+CIE rats also showed significantly increased alcohol intake in the operant (lever-pressing) self-administration task. In this same task THC+CIE exposed rats showed deficits in their ability to extinguish alcohol-seeking behavior. Importantly, this effect was prevented with CDPPB treatment. Specifically, THC+CIE exposed rats who received CDPPB treatment displayed significantly less lever presses on days 2-5 of extinction training compared to vehicle treated animals. Together, these data suggest that THC and alcohol co-use may lead to exacerbated drinking behaviors and a diminished ability to quit drinking. Deficits in extinction learning due to THC+CIE exposure can be prevented through modulation of mGlu5 via CDPPB treatment. Future studies conducted in our lab will examine neurological substrates involved in THC+CIE induced behavioral changes using optogenetic manipulation of specific neuronal circuitry. Furthering our understanding of the consequences of THC and alcohol co-use is vital due to the frequency in which these drugs are used together and the vulnerable populations that are affected.