Keith Trujillo, PhD - US grants

Chronic treatment with opiates leads to three well-known consequences: tolerance, which is a decrease in the effect of a drug with chronic use; sensitization, which is an increase in the effect of a drug with chronic use; and physical dependence, which is a change in functioning produced by chronic use, such that absence of the drug results in an unpleasant withdrawal syndrome. These phenomena are important in both the use of opiates for the treatment of chronic pain and in the development of opiate addiction. Recent experiments suggest that excitatory amino acid systems may have an important role in the development and/or expression of these phenomena. The present studies are designed to explore the potential role of a type of excitatory amino acid receptor, the N-methyl-D-aspartate (NMDA) receptor, in opiate tolerance, sensitization and physical dependence. Adult male Sprague-Dawley rats will be treated chronically with morphine. Tolerance, sensitization and physical dependence will be studied by assessing several indices of locomotor activity. The effects of MK-801, a potent and selective NMDA receptor antagonist, will be examined on the development and expression of all three phenomena. These studies will help to determine the role of NMDA receptors in the behavioral consequences of long-term opiate administration, and may lead to better treatments for chronic pain and opiate addiction.

The global aim of this research is to explore the potential role of excitatory amino acid systems in acute and chronic actions of opiates. Opiates, such as morphine, are very potent pain relievers and are therefore the drugs of choice for the treatment of severe or chronic pain. These drugs are also widely self-administered, and are therefore important drugs of abuse. Long-term treatment with opiates leads to three well-known consequences: tolerance, which is a decrease in the effect of a drug with chronic use; sensitization, which is an increase in the effect of a drug with chronic use, such that absence of the drug results in an unpleasant withdrawal symptom. These phenomena are important in both the use of opiates for the treatment of pain and in the development of opiate addiction. Recent experiments suggest that an excitatory amino acid receptor, known as the N-methyl-D-aspartate (NMDA) receptor, may have a central role in the consequences of long-term treatment with opiates, including tolerance, sensitization and physical dependence. Additionally, there is increasing evidence that this receptor may also be involved in selected acute actions of opiates, including analgesia and locomoter activity. Further research is necessary, however, to more fully understand the role of NMDA receptors in acute and chronic effects of opiates. The studies outlined in this proposal will examine the ability of NMDA receptor drugs to alter the acute analgesic and the acute locomotor effects of opiates in rats, as well as the consequences of long- term opiate administration, including tolerance, sensitization and physical dependence. If NMDA receptors are indeed involved in these opiate- elicited behaviors, then drugs that block NMDA receptors should alter the acute and chronic effects of morphine and other opiates. The results of these studies will be of theoretical importance, toward a better understanding of the neurotransmitter systems involved in critical behavioral effects of opiates. Moreover, these results may be of clinical relevance by elucidating the potential utility of NMDA receptor antagonists in the treatment of pain and opiate addiction.

DESCRIPTION (provided by applicant): The global aim of this research is to explore the development of opiate tolerance and sensitization, using a behavioral pharmacological approach. Opiates, such as morphine, are very potent pain relievers and are therefore the drugs of choice for the treatment of severe or chronic pain. These drugs are also widely self-administered and are therefore important drugs of abuse. Long-term treatment with opiates leads to well-known consequences, including tolerance, which is a decrease in an effect of a drug with chronic use, and sensitization, which is an increase in an effect of a drug with chronic use. These phenomena are important in both the use of opiates for the treatment of pain and in the development of opiate addiction. Recent experiments suggest that glutamate, an excitatory neurotransmitter in the brain, may be involved in the consequences of long-term treatment with opiates, including tolerance and sensitization. However, further research is necessary to better understand the role of glutamate in opiate effects. The present research will examine whether AMPA receptors (a type of glutamate receptor) or glutamate release may be involved in opiate tolerance and sensitization. This will be achieved by exploring the ability of AMPA receptor antagonists and glutamate release inhibitors to alter the development of opiate tolerance and sensitization in rats. Analgesic effects and locomotor effects of opiates will be the behavioral end-points for these studies. This work will extend previous research by the Principal Investigator and others on the role of glutamate in opiate-induced behavioral and neural plasticity. The results of these studies will be of theoretical importance, in understanding the neurotransmitter systems involved in the effects of opiates, and of practical importance in understanding the potential for glutamate drugs in the treatment of pain and opiate addiction.

DESCRIPTION (provided by applicant): The broad goal of this research is to better understand the behavioral effects of dissociatives, with a particular focus on their effects in adolescents. Dissociatives, including phencyclidine (PCP) and ketamine were originally developed as anesthetics, but are being increasingly used at subanesthetic doses for both clinical and non-clinical purposes. These drugs have been used in human clinical studies and preclinical animal models to better understand and treat two major psychiatric disorders, schizophrenia and major depression. In addition, evidence indicates that subanesthetic doses of dissociatives are useful in the treatment of pain. Dissociatives are also an important class of abused drugs, often classified as 'club drugs'. Dissociatives are of special interest and importance to adolescents. These drugs are often used by teens in dance club or "rave" settings. Survey research shows increased use of dissociatives by teens in recent years, as well as decreased age for initiation of use. This is true for both PCP and ketamine, as well as the over-the-counter cough suppressant, dextromethorphan. Despite all of this, no published research has systematically examined differences between adolescents and adults in the behavioral effects of dissociatives. The current project will compare the behavioral effects of dissociatives (including ketamine, PCP and dextromethorphan) in adolescent and adult laboratory rats. In addition to examining differences in the acute response to these drugs, the studies will also explore differences following repeated administration, and in particular, a phenomenon known as behavioral sensitization. Sensitization is an increase in an effect of a drug following repeated use, and is thought to be important to the development of addiction. The following specific aims will be examined: 1) to compare the acute behavioral effects of dissociatives in adolescent and adult rats;2) to compare the development of sensitization to dissociatives in adolescent and adult rats;3) to assess the role of glutamate release in the behavioral effects of dissociatives in adolescent and adult rats;and 4) to compare the plasma concentrations of dissociatives in adolescent and adult rats. Together, the research will lead to a better understanding of the effects of dissociatives in adolescents and adults, and may lead to better treatments for schizophrenia, depression, pain and drug abuse.

? DESCRIPTION (provided by applicant): The CSU San Marcos MARC U-STAR Program has a strong record of success, with over 93% of MARC Scholars in recent years transitioning to graduate school, including PhD programs at Stanford, Yale, Harvard, Northwestern, UC San Diego and other top institutions. Given the past success and rigorous set of activities, renewal of this program will help increase the pool of underrepresented minority students who pursue research careers in the biomedical and behavioral sciences. We have three overall measurable objectives for the program, which are informed by our recent success: 1) 100% of MARC Scholars will graduate with a Bachelor's Degree; 2) 95% of MARC Scholars will enter graduate school in the biomedical or behavioral sciences; and 3) 80% of MARC Scholars will pursue a PhD program in the biomedical or behavioral sciences. We plan to achieve these objectives through eight goals: 1) to increase the pool of students eligible for MARC through a set of Pre-MARC activities, assure that our scholars participate in a laboratory-rich curriculum, enhance academic performance; 2) to assure that all MARC Scholars participate in a strong, laboratory-rich curriculum that prepares them for graduate study; 3) to enhance academic performance; 4) to enhance scientific communication skills; 5) to enhance experimental design and statistical analysis tools; 6) to empower students for success; 7) to participate in biomedical research; and 8) to prepare competitive applications for graduate school. Activities within these goals include participation in a challenging curriculum supported by a range of academic support services, skills development, research seminars, and supervised original research leading to scientific presentations and publications. Through these activities, Scholars will develop strong skills in critical thinking, problem solving, writing and oral communication, experimental design and statistics, and teamwork. We will select twelve Scholars to participate in the program in years 1 and 2 and fourteen Scholars in years 3-5. Our Evaluation Plan provides clearly stated goals and measurable objectives to assess project success. The commitment of CSUSM to diversity and to student development is in perfect alignment with the goals of the national MARC Program. This alignment, together with rapid student population growth (especially that of underrepresented minority students), the success of the current MARC Program, the supportive faculty, the experience of the program director, and new facilities with modern scientific instruments and powerful instructional resources, collectively make CSUSM an ideal location to operate a successful MARC Program.

DESCRIPTION (provided by applicant): The California State University San Marcos (CSUSM) RISE Program is well-aligned with the national goal of RISE to increase diversity in the biomedical workforce. With more than 10 years of experience we've revised and updated our program to achieve a rigorous set of activities designed to develop thoughtful and creative scientists who not only have the tools and skills to be successful in doctoral studies, but also have the opportunity to become leaders in their respective fields. As a young and rapidly growing campus situated in north San Diego County, CSUSM is well-positioned to influence an increasing number of students from underrepresented minority (URM) groups, helping them find their way to research careers. The CSUSM RISE Program consists of four key components: 1) The Pre-Rise Program, which is designed to enhance awareness of careers in biomedical research and to increase the number of students eligible for, and interested in, the Undergraduate RISE Program. 2) The Undergraduate RISE Program, which includes a broad set of activities designed to increase the number of students from underrepresented minority groups who are competitive for admission to graduate school in the biomedical sciences. 3) The Graduate RISE Program, which parallels our Undergraduate RISE Program to prepare Master's Degree students for admission to doctoral programs in the biomedical sciences. 4) Institutional Impact identifies broader benefits of the RISE Program, and in particular how the program has impacted on the CSUSM campus with shifts in the campus culture and perspective, and the institutionalization of activities. Student development activities include participation in a challenging curriculum supported by a range of academic support services, research training, research seminars, and supervised original research leading to scientific publications. Our students will develop strong skills in critical thinking, problem solving, writing and oral communication, leadership, and teamwork. Finally, students will participate as a cohort in a set of activities designed to prepare and place them into graduate school and to track completion of their graduate degrees. The CSUSM RISE Program has shown increasing success over the years. In recent years, 90% of CSUSM undergraduate RISE Scholars have gone to graduate programs in the biomedical and behavioral sciences and 80% of graduate RISE Scholars have gone to PhD programs. Taken as a whole, the CSUSM RISE Program will prepare underrepresented minority students to be thoughtful scientists who have the knowledge, skills, research experience and personal character that prepare them for doctoral studies in the biomedical and behavioral sciences and that will allow them to become future leaders in science and academia.

PROJECT SUMMARY As a young, rapidly growing campus in North San Diego County, California State University San Marcos (CSUSM) is well-positioned to prepare motivated students from underrepresented (UR) groups for graduate studies and research careers. A large proportion of CSUSM students is Hispanic (47%), which exceeds the non-Hispanic White population (26%). The campus is both a Hispanic Serving Institution (HSI) and an Asian American, Native American and Pacific Islander-Serving Institution (AANAPISI). In addition, 54% are from families in which they will be the first to complete a college degree and 48% are Pell Grant recipients. Thus, CSUSM is home to a rapidly growing diverse student body, many of whom are low income and/or the first in their family to attend college. We?ve specifically developed our program to meet the needs of the student population at CSUSM. The program will use evidence-based practices to achieve the following 8 objectives: 1) to prepare, recruit and select U-RISE scholars who show significant promise for success; 2) to assure strong academic performance; 3) to enhance quantitative and methodological skills; 4) to enhance scientific communication skills; 5) to engage students in biomedical research; 6) to develop knowledge, skills and persistence necessary to succeed in a doctoral program and beyond; 7) to expose students to a culturally validated pedagogy to increase belonging and persistence; and 8) to prepare competitive applications for graduate school. A capstone project, to prepare a graduate research fellowship proposal will utilize many of the skills learned by the scholars. The program is two years in length. We propose to engage 20 undergraduate students in year 1 of the program, 22 in year 2, and 24 in years 3-5. Our major goals, informed by past success rates, are for 90% of CSUSM U-RISE Scholars to enter the PhD pathway in the biomedical and behavioral sciences, and 65% to enter PhD programs. Taken as a whole, the U-RISE at CSUSM Program, in concert with a highly supportive campus environment, will prepare students from UR groups to be thoughtful scientists who have the knowledge, skills, research experience and character that prepare them for doctoral studies in the biomedical and behavioral sciences and that allow them to become future leaders in science and academia. By doing this we will help advance the goals of the National Institutes of Health to diversify the research workforce. A more diverse research workforce will better address the research needs of a diverse nation and thereby contribute to better health for all.