Investigation of the Adenosine A(2A) Receptor on the Enhanced Rewarding Effects of Nicotine and Dopamine D2 Receptor Signaling in a Novel Heritable Model of Drug Abuse Vulnerability

Investigation of the adenosine A(2A) receptor on the enhanced rewarding effects of nicotine and dopamine D2 receptor signaling in a novel heritable model of drug abuse vulnerability Seth E. Turney, Loren D. Peeters, Olivia A. Jennings, Liza J. Wills, Russell W. Brown Many years ago, our laboratory along with a collaborator established that neonatal treatment of the dopamine (DA)D2-like receptor agonist quinpirole (NQ) to rats induces an increase in DAD2 receptor sensitivity throughout the animal’s lifetime, which has validity to schizophrenia (SZ) and a number of clinical conditions. These clinical conditions, which include SZ but also bipolar disorder, obsessive-compulsive disorder, panic disorder, and major depression all demonstrate increased drug abuse vulnerability, especially to cigarette smoking. Based on this permanent change in DAD2 sensitivity, we bred NQ-treated male and female rats with their NQ-treated or neonatal saline (NS)-treated counterparts. This F1 generation also demonstrated increases in DAD2 signaling, both behaviorally as well as through DAD2 signaling mechanisms. We have shown both d enhanced behavioral responding to nicotine on the conditioned place preference (CPP) and behavioral sensitization paradigms. These F1 offspring of NQ-treated rats also demonstrated increases of G-protein dependent and G-protein independent DAD2 signaling. Interestingly, the adenosine A(2A) receptor forms a mutual inhibitory heteromer with the DAD2 receptor. Adenosine is a known neuromodulator that can increase or decrease synaptic transmission in the brain, and there exists a hypothesis that adenosine dysfunction is the primary system which is disrupted in SZ which leads to changes in the dopamine and other neurotransmitter systems. The drug CGS 21680, an A(2A) agonist which stimulates the A(2A) receptor, is known to decrease DAD2 signaling and has been shown to block nicotine behavioral sensitization. A major focus in this project is on the adenosine A(2A) receptor as a novel pharmacological treatment target, since it is known that antipsychotic drugs which are often used to treat SZ and these other clinical conditions which have increased DAD2 signaling produce deleterious side effects, and novel medications are needed. Results here revealed that a 0.09 mg/kg dose of CGS 21680 was effective to block enhanced nicotine CPP and changes in DAD2 G-protein independent signaling in F1 generation rats. Interestingly, CGS 21680 did not affect G-protein dependent signaling in F1 generation animals, suggesting that the mechanism through which it is working may not be through the traditional DAD2 signaling mechanism. Future work is designed to analyze underlying mechanisms of this effect

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Metabotropic Glutamate Receptor Type 5 (Mglu5) as a Therapeutic Target Towards the Enhanced Rewarding Effects of Nicotine and Deficits in Sensorimotor Gating in a Heritable Model of Drug Abuse Vulnerability in Psychosis

Heritable and environmental factors contribute to an individual’s risk of substance abuse and psychosis. Individuals diagnosed with a mental disorder have greater vulnerability for substance abuse. Our laboratory established that neonatal treatment of rats with quinpirole (NQ), a dopamine (DA) D2-like agonist, results in a significant increase of DAD2 receptor sensitivity throughout the animal’s lifetime. An increase of DAD2 receptor sensitivity is relevant to a model of schizophrenia (SZ), although increases of DAD2 receptor activity also occur in a number of clinical disorders, including bipolar disorder, obsessive-compulsive disorder, panic disorder, and major depression. Common amongst these clinical conditions is a dramatic increase in cigarette smoking compared to the general population. We bred NQ-treated male and female rats with their NQ-treated or neonatal saline (NS)-treated counterparts once they reached adulthood to determine whether increases in DAD2 sensitivity were passed to the next generation. Offspring of these animals, regardless of whether one or both founders received NQ-treatment, also demonstrated increases of DAD2 receptor sensitivity both behaviorally and neurobiologically. RNASeq preliminary data revealed an increase in cortisol synthesis and release in F1 generation animals, demonstrating an enhanced response to stress, consistent with a model of drug abuse vulnerability. Consistent with this finding, F1 generation rats demonstrated enhanced nicotine conditioned place preference (CPP) and had an enhanced brain derived neurotrophic factor (BDNF) response to nicotine in the nucleus accumbens (NAcc), a brain area critical to drug reward. The DAD2 receptor forms a triple heteromer with the adenosine A(2A) and metabotropic glutamate type 5 (mGlu5) receptor, such that stimulation of either receptor results in a decrease of DAD2 activity. Therefore, we analyzed whether use of a positive allosteric modulator (PAM) of mGlu5 in the F1 generation would block nicotine CPP and improve sensorimotor gating deficits, which is a hallmark of psychosis. In both experiments, the mGlu5 PAM effectively blocked the enhanced rewarding effects of nicotine and also alleviated sensorimotor gating deficits in this model. In essence, we demonstrate in results reported here that there may be a common therapeutic target for the dual treatment of substance abuse and psychosis

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

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