Modulation of Metabotropic Glutamate Receptor Type 5 (mGlu5) Reduces the Enhanced Rewarding Effects of Nicotine in a Neonatal Quinpirole Model of Psychosis

Authors' Affiliations

Anthony Cuozzo, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Loren Peeters, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Liza Wills, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Kira Ivanich, College of Arts and Sciences, East Tennessee State University, Johnson City, TN. Seth Turney, Health Sciences, East Tennessee State University, Johnson City, TN. Luke Bullock, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Sam Massey, East Tennessee State University, Johnson City, TN. Justin Gass, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Russell Brown, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Location

Culp Center Ballroom

Start Date

4-25-2023 9:00 AM

End Date

4-25-2023 11:00 AM

Poster Number

16

Faculty Sponsor’s Department

Biomedical Sciences

Name of Project's Faculty Sponsor

Russell Brown

Classification of First Author

Graduate Student-Doctoral

Competition Type

Competitive

Type

Poster Presentation

Project's Category

Neuroscience

Abstract or Artist's Statement

Nicotine has been indicated as a prevalent drug for substance abuse comorbidities in mental illness. Tobacco use is elevated in those suffering from psychiatric disorders, most notably in schizophrenia (SZ), where a three-to-five fold increase in usage compared to the general population is observed. Our laboratory has established a rodent model of psychosis. In this model, male and female rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist for 21 days postpartum, resulting in lifelong supersensitization of the DAD2 receptor. Increases in dopamine D2 receptor sensitivity is a hallmark of psychosis. Interestingly, the dopamine D2 receptor forms a triple mutual inhibitor heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of the A(2A) or mGlu5 receptor results in decreased dopamine D2 signaling. The present study was designed to analyze the role of the mGlu5 receptor in a behavioral task involved in testing the associative aspects of rewarding drugs known as conditioned place preference (CPP). CPP is a behavioral task in which animals are conditioned with a reinforcing drug to prefer a particular environmental context. Male and female rats were neonatally treated with saline (NS) or quinpirole from postnatal day (P) 1 to 21. From P41-51, which is mid-adolescence in a rat, all rats were behaviorally tested on CPP. Results revealed that compared to NS rats, NQ animals administered nicotine demonstrated enhanced CPP, replicating our past work. Groups receiving a positive allosteric modulator to mGlu5, which results in stimulation of the mGlu5 receptor, reduced the enhanced rewarding effects of nicotine in CPP for NQ treated rats equal to control levels. Brain tissue was analyzed for brain-derived neurotropic factor (BDNF), a neurotrophin involved in cell growth, as well cell adhesion molecule cadherin-13 in the ventral tegmental area (VTA), which is a brain area rich in dopamine cell bodies. Results revealed elevations of BDNF in NQ-treated rats given nicotine compared to all other groups, and a sex difference in the increase in cadherin-13, with female NQ rats given nicotine demonstrating increases compared to all other groups. These effects were blocked by the mGlu5 receptor positive allosteric modulator. In addition, we analyzed phospho-p70S6 kinase in the nucleus accumbens (NAcc), which is the dopamine neuronal terminal region in the VTA mitigating drug reward. The NQ group given nicotine demonstrated significant increases in NAcc P70S6 kinase compared to all other groups, suggesting increased synaptic growth, which was also blocked by the positive allosteric modulator to mGlu5. Taken together, these results elucidate mGlu5 as a drug target for reducing the rewarding effects of nicotine via CDPPB administration in a model of substance abuse in psychosis.

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Apr 25th, 9:00 AM Apr 25th, 11:00 AM

Modulation of Metabotropic Glutamate Receptor Type 5 (mGlu5) Reduces the Enhanced Rewarding Effects of Nicotine in a Neonatal Quinpirole Model of Psychosis

Culp Center Ballroom

Nicotine has been indicated as a prevalent drug for substance abuse comorbidities in mental illness. Tobacco use is elevated in those suffering from psychiatric disorders, most notably in schizophrenia (SZ), where a three-to-five fold increase in usage compared to the general population is observed. Our laboratory has established a rodent model of psychosis. In this model, male and female rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist for 21 days postpartum, resulting in lifelong supersensitization of the DAD2 receptor. Increases in dopamine D2 receptor sensitivity is a hallmark of psychosis. Interestingly, the dopamine D2 receptor forms a triple mutual inhibitor heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of the A(2A) or mGlu5 receptor results in decreased dopamine D2 signaling. The present study was designed to analyze the role of the mGlu5 receptor in a behavioral task involved in testing the associative aspects of rewarding drugs known as conditioned place preference (CPP). CPP is a behavioral task in which animals are conditioned with a reinforcing drug to prefer a particular environmental context. Male and female rats were neonatally treated with saline (NS) or quinpirole from postnatal day (P) 1 to 21. From P41-51, which is mid-adolescence in a rat, all rats were behaviorally tested on CPP. Results revealed that compared to NS rats, NQ animals administered nicotine demonstrated enhanced CPP, replicating our past work. Groups receiving a positive allosteric modulator to mGlu5, which results in stimulation of the mGlu5 receptor, reduced the enhanced rewarding effects of nicotine in CPP for NQ treated rats equal to control levels. Brain tissue was analyzed for brain-derived neurotropic factor (BDNF), a neurotrophin involved in cell growth, as well cell adhesion molecule cadherin-13 in the ventral tegmental area (VTA), which is a brain area rich in dopamine cell bodies. Results revealed elevations of BDNF in NQ-treated rats given nicotine compared to all other groups, and a sex difference in the increase in cadherin-13, with female NQ rats given nicotine demonstrating increases compared to all other groups. These effects were blocked by the mGlu5 receptor positive allosteric modulator. In addition, we analyzed phospho-p70S6 kinase in the nucleus accumbens (NAcc), which is the dopamine neuronal terminal region in the VTA mitigating drug reward. The NQ group given nicotine demonstrated significant increases in NAcc P70S6 kinase compared to all other groups, suggesting increased synaptic growth, which was also blocked by the positive allosteric modulator to mGlu5. Taken together, these results elucidate mGlu5 as a drug target for reducing the rewarding effects of nicotine via CDPPB administration in a model of substance abuse in psychosis.