Russell W. Brown - US grants

DESCRIPTION (provided by applicant): The purpose of this proposal is to request funds to support a one day satellite symposium entitled "Nicotine: Potential therapies and possible pitfalls" to the 2004 International Behavioral Neuroscience Society (IBNS) Conference in Key West, FL. The dates for this meeting are from June 16th to June 20th, 2004. The recent and exciting developments in nicotine research represent a specific need for this symposium. Although there have been several other symposia focused on nicotine over the past few years, most of these have focused on a specific research area, such as nicotine as an addictive drug or on its effects relative to a specific behavioral disorder or neurodegenerative disease. The proposed symposium is designed to convene experts from across the diverse areas of nicotine research to identify nicotine's therapeutic potential, the possible pitfalls of utilizing nicotine as a therapeutic agent, and potential mechanisms of action. A primary goal for this meeting is to encourage discussion amongst scientists from diverse research backgrounds and with wide-ranging interests that can reveal commonalities of approach regarding nicotine as a potential therapy, as well as the positive and negative consequences of nicotine administration in a variety of behavioral, cognitive and neurological research models. However, because nicotine is a psychostimulant, the psychoactive ingredient in tobacco and believed to be the primary ingredient responsible for nicotine addiction, there are obvious potential pitfalls to using nicotine as a therapeutic agent. On the other hand, nicotine and agonists to the acetylcholinergic nicotinic receptor have been shown to eliminate anxiety when given at low doses, enhance cognition, and to significantly reduce, or even eliminate cognitive deficits produced by brain injury and sensory deficits in schizophrenics. Nicotine also increases neurotrophic factor expression and this effect of the drug may have an important role in neuroprotection in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therefore, several topics across this field will be covered, including underlying mechanisms of nicotine addiction, the role of the nicotinic receptor in behavior and neuroprotection, nicotine's potential therapeutic effects in Alzheimer's and Parkinson's disease, nicotine's role in anxiety, and it's effects on behavior in schizophrenia and brain trauma in animal models as well as humans. The symposium is also designed to bring together a group of scientists at all career levels including graduate students, post-doctoral fellows, assistant, associate, and full professors. In doing this we hope to provide a stimulating environment for the more senior researchers and a nurturing environment for the more junior participants. Additionally, the scientific background of these scientists is also very diverse. The research disciplines of the invitees to the symposium range from molecular neuroscience to behavioral neuroscience and neurology that also work with a variety of species, ranging from rodent to primate to human. Although speakers and session leaders will provide an introduction suited for the less acquainted attendee, presentations will be geared to late-breaking, novel and often unpublished findings to bring as many people to the forefront of the field as possible. In addition to the organizers, eleven scientists have accepted invitations to this symposium, and each will present their latest research in a 30-minute talk. Additionally, we plan a final roundtable discussion with all speakers to discuss the commonalities of the positive effects, underlying mechanisms, and adverse effects of nicotine as a potential therapy.

DESCRIPTION (provided by applicant): This proposal is designed to analyze the effects of amphetamine sensitization on dopamine release in the nucleus accumbens in a rodent model of schizophrenia. Research has shown that substance abuse in the schizophrenic population is approximately 2-5 times higher than that of the general public. The abuse of drug in the psychostimulants class, such as amphetamine and nicotine, are the most frequently abused drugs in the schizophrenic population. There is not a definitive explanation as to why there is a high level of drug abuse in this population, as substance abuse in schizophrenia has not been a well-investigated issue. Although there is typically higher overall functioning in women schizophrenics, this disappears with substance abuse, and women are more vulnerable to the negative effects of psychostimulant abuse. The rodent model of schizophrenia utilized in this proposal is based on long-term priming of the dopamine D2 receptor through neonatal administration of quinpirole, a dopamine D2/D3 agonist. Past research has demonstrated that neonatal quinpirole administration produces priming of the dopamine D2 receptor throughout the animal's lifetime. Preliminary data of this proposal demonstrates that an acute injection of amphetamine to D2-primed rats produced a 4-fold increase in dopamine microdialysate in the neostriatum compared to animals non-D2-primed rats neonatally treated with saline. The increase in dopamine release induced by amphetamine may be important in explaining the increased incidence of psychostimulant abuse in the schizophrenic population, and may lead to reduction in anhedonia, a negative symptom of the disorder. The proposal is designed to analyze three specific aims: 1) Compare the effects of amphetamine sensitization and analyze amphetamine's effects on dopamine release in the nucleus accumbens core utilizing microdialysis in D2-receptor-primed versus non-D2-receptor primed rats;2) Investigate the role of dopamine D1 and D2 receptors in sensitization and dopamine release in the nucleus accumbens core in D2- versus non-D2-primed rats;3) Analyze sex differences in amphetamine-induced behavioral sensitization and its relationship to dopamine microdialysis in the NAcc in D2- versus non-D2-primed rats. Plain language description: Schizophrenia affects approximately 1% of the U.S. population, and this population is 2-5 times more likely to use or abuse stimulants than the general public. This proposal is designed to investigate the effects of chronic amphetamine (street name: Speed) administration on behavior and neurochemistry of rats that been given a drug manipulation during development that mimics the neurochemistry of schizophrenia.

DESCRIPTION (provided by applicant): This proposal is based around a rodent model of schizophrenia that is accomplished through neonatal injection of the dopamine D2/D3 agonist quinpirole to rats from postnatal days (P) 1-21, which results in increased dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. Increased dopamine D2 sensitivity is consistent with increased D2 activation in schizophrenia. Nicotine is the most frequently abused drug in schizophrenics. Preliminary data report four major findings: 1) Neonatal quinpirole treatment results in a significant increase in ¿7 nicotinic receptors (nAChRs) in the striatum, a brain area important in drug reward; 2) neonatal quinpirole treatment results in a sensitized dopamine response to nicotine in the nucleus accumbens core of adolescent rats as analyzed by microdialysis; 3) we have reported enhanced behavioral sensitization and place conditioning to nicotine in rats neonatally treated with quinpirole; 4) neonatal quinpirole enhanced the response of brain-derived neurotrophic factor (BDNF) to nicotine in several brain areas, and resulted in a substantial increase in accumbal phosphorylated cAMP response element binding protein (pCREB). Regarding this final finding, robust increases in accumbal pCREB have been hypothesized to be a physiological measure of anhedonia, a negative symptom of schizophrenia. Interestingly, nicotine reduced pCREB, which suggests nicotine may self-medicate anhedonia in schizophrenia, consistent with a sensitized dopamine response. We hypothesize that ¿7nAChR upregulation produced by neonatal quinpirole treatment is critical to the enhanced behavioral and dopamine response to nicotine because of its pivotal role in nicotine's role in dopamine function in brain regions that mediate reward. The primary hypothesis of this proposal is that ¿7nAChRs and changes in proteins related to neural plasticity are central to the sensitized behavioral and dopaminergic response to nicotine in rats neonatally treated with quinpirole. Aim 1 will investigate the role of ¿7 and ¿4¿2 nAChRs in nicotine behavioral sensitization and place conditioning. A sub-aim will analyze the roles of nAChRs on BDNF and pCREB in response to nicotine behavioral sensitization. This aim will test the hypotheses that enhanced nicotine sensitization and place conditioning in neonatal quinpirole-treated rats is mediated by the ¿7 nAChR, and the ¿7 nAChR antagonist MLA will reduce nicotine-induced increased of BDNF and p-CREB protein in neonatal quinpirole rats. Aim 2 will investigate the role of ¿7 and ¿4¿2 nAChRs in the accumbal dopamine response to nicotine using the microdialysis technique. This aim will test the hypothesis that dopamine overflow in response to nicotine pretreatment will depend on ¿7nAChRs in neonatal quinpirole rats, but not controls. Aim 3 will analyze nicotine self-administration in adult male rats neonatally treated wit quinpirole. The critical hypothesis tested is that adult rats neonatally treated with quinpirole wil self-administer more nicotine than animals neonatally treated with saline.

A major issue in schizophrenia (SZ) is tobacco smoking, which leads to lung cancer, poor quality of life,  and negative health outcomes. The adenosine system represents a novel pharmacological treatment target,  because adenosine may contribute to both psychosis and substance abuse comorbidity in SZ. Adenosine A2A  receptors form a heteromeric complex with dopamine D2 receptors in the brain that is mutually inhibitory.  Adenosine A2A agonists reduce D2 receptor sensitivity, whereas D2 agonists reduce A2A receptor sensitivity.  This is important, because increased D2 receptor sensitivity underlies psychosis in SZ. This application centers  around a rodent model of SZ of D2 sensitivity, with rats neonatally treated with the dopamine D2/D3 agonist  quinpirole (neonatal quinpirole treatment, NQ). NQ treatment results in increased D2 receptor sensitivity  throughout the animal?s lifetime without altering D2 density, consistent with SZ.  In sum, preliminary data  revealed that NQ enhanced the rewarding associative aspects of nicotine as well as the brain-­derived  neurotrophic factor (BDNF) and glial cell-­line derived neurotrophic factor (GDNF) response to nicotine. These  responses were reduced by adenosine A2A agonist CGS 21680 as well as the antipsychotic clozapine. In  addition, NQ treatment has been shown to result in auditory sensorimotor gating deficits, a behavioral hallmark  of SZ. The overall hypothesis is that NQ-­induced enhancement of the behavioral response to nicotine and  auditory sensorimotor gating deficits can be mitigated by adenosine A2A activation in combination with  clozapine and changes in BDNF and GDNF signaling cascades. Aim 1 will analyze potential synergistic  effects of the A2A receptor agonist CGS 21680 and clozapine on nicotine CPP and auditory  sensorimotor gating in adolescent NQ-­treated male and female rats. Aim 1a will then test the hypothesis  that CGS 21680 combined with clozapine will most effectively reduce NQ-­induced enhancement of nicotine  CPP.  Aim 1b will test the hypothesis that CGS 21680 alone will reduce, and in combination with clozapine will  alleviate, sensorimotor gating deficits produced by NQ, showing that adenosine A2A receptor activation is  effective to treat both nicotine abuse and psychosis-­like symptoms. Aim 2 will investigate whether CGS  21680 will reduce enhanced dopamine and glutamate release in the NAcc in adolescent NQ-­treated  male and female rats. We hypothesize that A2A receptor activation via reverse microdialysis infusion into the  brain will reduce enhanced dopamine and glutamate release in response to nicotine in NQ-­treated rats tested  in adolescence. Aim 3 will analyze common downstream neurobiological targets of BDNF and GDNF in  NQ-­treated animals administered CGS 21680 in adolescence. We hypothesize that A2A receptor activation  combined with clozapine will mitigate the downstream response of proteins common to both the BDNF and  GDNF signaling cascades in the nucleus accumbens and hippocampus, brain areas that are implicated in drug  addiction and psychosis respectively.