Positive allosteric modulation of the mGlu5 attenuates enhanced D2 signaling and nicotine conditioned place preference in a heritable model of drug abuse vulnerability in psychosis
Location
D.P. Culp Center Ballroom
Start Date
4-5-2024 9:00 AM
End Date
4-5-2024 11:30 AM
Poster Number
35
Name of Project's Faculty Sponsor
Russell Brown
Faculty Sponsor's Department
Biomedical Sciences
Competition Type
Competitive
Type
Poster Presentation
Presentation Category
Health
Abstract or Artist's Statement
Tobacco use is elevated in those suffering from psychiatric disorders, with a usage rate nearly 80% higher than the general population. Our laboratory has established a rodent model of psychosis and drug abuse vulnerability in which F0 generation Sprague-Dawley (SD) rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist from postnatal days 1-21, resulting in lifelong supersensitization of the DAD2 receptor. Increases in DAD2 receptor sensitivity is a hallmark of psychosis. Interestingly, the DAD2 receptor forms a mutually inhibitory heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of either the A(2A) or mGlu5 receptor results in decreased DAD2 signaling. The present study sought to elucidate mechanisms of therapeutic action associated with positive allosteric modulation of the mGlu5 receptor. We also explored epigenetic mechanisms of our model contributing to heritable transmission of substance abuse and psychosis-like phenotypes. This was accomplished by use of F1 generation male and female SD rats that were the offspring of two neonatal quinpirole-treated (QQ) or two saline-treated (SS) animals. QQ and SS treated rats completed nicotine conditioned place preference (CPP), a behavioral task in which animals are conditioned with a reinforcing drug to show preference for a particular environmental context. Our laboratory has previously established that F0 NQ-treated rats display robustly enhanced CPP. Upon the conclusion of behavioral testing, brain tissue from these animals were dissected for Nucleus Accumbens Shell (NAcc), Prelimbic Cortex (PrL), and Infralimbic Cortex (IfL). Tissue was tested on an enzyme-linked immunosorbent assay (ELISA) for Regulator of G protein signaling 9 (RGS9) and β-arrestin 2 (βA2), which mediate G protein-dependent and -independent DAD2 signaling, respectively. Reduced Representation Bisulfite Sequencing (RRBS) was also used to analyze the cytosine methylation in NAcc, PrL, and IfL tissue from QQ and SS animals. In the present study, pretreatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) 20 minutes prior to each nicotine conditioning trial was effective to block the enhanced CPP observed in QQ rats. CDPPB also attenuated aberrant G-protein dependent (RGS9) and G-protein independent (βA2) DAD2 signaling. RRBS revealed region-specific changes in several KEGG pathways, including nicotine addiction and dopamine signaling. The IfL of QQ rats showed a 22-fold increase in the nicotine addiction KEGG pathway compared to SS controls. The present study elucidates significant region-specific mechanistic action of the mGlu5 in a rodent model of drug abuse vulnerability in psychosis. Results further validate the present model and accentuate the efficacy of mGlu5 modulation towards the treatment of comorbid substance abuse in psychosis.
Positive allosteric modulation of the mGlu5 attenuates enhanced D2 signaling and nicotine conditioned place preference in a heritable model of drug abuse vulnerability in psychosis
D.P. Culp Center Ballroom
Tobacco use is elevated in those suffering from psychiatric disorders, with a usage rate nearly 80% higher than the general population. Our laboratory has established a rodent model of psychosis and drug abuse vulnerability in which F0 generation Sprague-Dawley (SD) rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist from postnatal days 1-21, resulting in lifelong supersensitization of the DAD2 receptor. Increases in DAD2 receptor sensitivity is a hallmark of psychosis. Interestingly, the DAD2 receptor forms a mutually inhibitory heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of either the A(2A) or mGlu5 receptor results in decreased DAD2 signaling. The present study sought to elucidate mechanisms of therapeutic action associated with positive allosteric modulation of the mGlu5 receptor. We also explored epigenetic mechanisms of our model contributing to heritable transmission of substance abuse and psychosis-like phenotypes. This was accomplished by use of F1 generation male and female SD rats that were the offspring of two neonatal quinpirole-treated (QQ) or two saline-treated (SS) animals. QQ and SS treated rats completed nicotine conditioned place preference (CPP), a behavioral task in which animals are conditioned with a reinforcing drug to show preference for a particular environmental context. Our laboratory has previously established that F0 NQ-treated rats display robustly enhanced CPP. Upon the conclusion of behavioral testing, brain tissue from these animals were dissected for Nucleus Accumbens Shell (NAcc), Prelimbic Cortex (PrL), and Infralimbic Cortex (IfL). Tissue was tested on an enzyme-linked immunosorbent assay (ELISA) for Regulator of G protein signaling 9 (RGS9) and β-arrestin 2 (βA2), which mediate G protein-dependent and -independent DAD2 signaling, respectively. Reduced Representation Bisulfite Sequencing (RRBS) was also used to analyze the cytosine methylation in NAcc, PrL, and IfL tissue from QQ and SS animals. In the present study, pretreatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) 20 minutes prior to each nicotine conditioning trial was effective to block the enhanced CPP observed in QQ rats. CDPPB also attenuated aberrant G-protein dependent (RGS9) and G-protein independent (βA2) DAD2 signaling. RRBS revealed region-specific changes in several KEGG pathways, including nicotine addiction and dopamine signaling. The IfL of QQ rats showed a 22-fold increase in the nicotine addiction KEGG pathway compared to SS controls. The present study elucidates significant region-specific mechanistic action of the mGlu5 in a rodent model of drug abuse vulnerability in psychosis. Results further validate the present model and accentuate the efficacy of mGlu5 modulation towards the treatment of comorbid substance abuse in psychosis.