Carmen Maldonado-Vlaar - US grants

DESCRIPTION: (Applicant's Abstract) Drug abuse has become a major social and medical problem in the United States, South America and Europe. Presently, it is estimated that there are over 2 million regular drug users in the USA. One of the main goals of neurobiological research is to study the different neural systems and molecular mechanisms involved in drug addiction. The nucleus accumbens and other areas of the corpus striatum have previously been implicated in mediating the motor activation and reinforcing effects of psychostimulant drugs such as cocaine. In addition, studies have demonstrated that these subregions of the striatum also regulate different learning and memory functions and that excitatory amino acid (EAA) neurotransmission from cortical and limbic projections to these striatal regions modulate these functions. The metabotropic glutamate receptor (mGluRs) is a type of EAA receptor found in the striatum that seems to have modulatory effects in synaptic plasticity and learning. The current proposal seeks to further investigate EAA neurotransmission and the role of protein kinase C within the different subregions of the corpus striatum, using a behavioral-pharmacological-molecular approach in the rat. To accomplish this goal, direct brain microinfusions of experimental drugs will be utilized in conjunction with behavioral paradigms that measure: spatial learning, intravenous cocaine self-administration responding and the reinstatement of cocaine seeking behavior. There are two major goals of the proposed experiments: 1) To characterize the role that mGluRs within the corpus striatum play in controlling learning related to both normal and cocaine-induced behavioral response. 2) To examine the role of Protein Kinase C activation within different striatal regions in distinct striatal learning functions. Results from the proposed research plan may provide new knowledge on: 1) the functional roles of EAA-receptors and, specifically the mGluRs, in the corpus striatum, 2) the molecular mechanisms controlled by PKC that are involved in the modulation of different forms of striatal learning, and 3) the role of EAA receptors and PKC activity within the nucleus accumbens in mediating cocaine reinforcement and eliciting cocaine seeking behavior.

substance abuse related behavior; cocaine; glutamate receptor; conditioning; nucleus accumbens; psychological reinforcement; association learning; craving; cues; neuroregulation; NMDA receptors; excitatory aminoacid; AMPA receptors; behavioral /social science research tag; behavior test; laboratory rat; neurochemistry;

substance abuse related behavior; craving; neuropeptide receptor; neurotensin; cholecystokinin; gene expression; cocaine; prefrontal lobe /cortex; nucleus accumbens; cues; neurochemistry; association learning; microarray technology; laboratory rat; nucleic acid hybridization; nucleic acid probes; behavioral /social science research tag;

? DESCRIPTION (provided by applicant): This proposal entitled Neuroscience Research Opportunities to Increase Diversity (NeuroID) from the University of Puerto Rico Rio Piedras Campus aims to increase the opportunities available for undergraduate students in the area of Neurosciences. This proposal builds upon the experiences gathered during the current funding period to enhance and strengthen the mentoring and training activities of the NeuroID program, incorporating an emphasis in developing active-learning skills and strengthen emotional competence. NeuroID takes advantage of the strong Neuroscience expertise among UPR investigators and fortifies the underlying neuroscience network that joins undergraduate students, island investigators and their collaborators in mainland institutions. The main goal of the NeuroID program is to increase diversity in the neurosciences by establishing a cohort of interested students that will receive academic and professional training in neuroscience-related research. The selected students will be Hispanics from different gender, race, social status and physical needs. The core of the program is a comprehensive research experience for undergraduate students based on a research-with-purpose training philosophy. The training program consists of three major components: (1) Research Experience - An intense research experience during the academic year and two research summer experiences: one at the UPR and the other in a laboratory at an institution in the mainland USA that have active T32 training grants in neuroscience and/or excellent track record in recruiting and training underrepresented minorities. (2) Academic training - an academic program based on active learning activities, seminars, workshops and selected courses to enhance their knowledge in neurobiology, quantitative biology and understanding of a research career. (3) Student development activities - Participants will enter a mentoring program that includes community outreach activities, writing in science, oral presentations and career counseling to enhance their professional capabilities. The proposed activities together with an established mentoring program with ethnic and race-representative members of the Neuroscience community as role models will serve to increase the student competitiveness and enhance their interest in continuing a research career in neuroscience. The NeuroID program will extend the impact of other successful programs at the University of Puerto Rico, not only by focusing on the neuroscience field but also by greatly expanding the program to students from primarily-undergraduate institutions in the San Juan metropolitan areas, which increases the pool of available applicants as well as providing an inclusive and broader training program.

PROJECT SUMMARY Oxytocin (OT) is a neuropeptide secreted by the hypothalamic paraventricular nucleus (PVN) and commonly associated with social behaviors, stress responses and drug-addiction. Previous studies have shown that OT has anxiolytic properties associated with cues in a cocaine seeking behavior paradigm, but the underlying mechanism remains unknown. Clinical studies show that cocaine abuse has long-term effects in the brain reward circuitry of those who use it. These changes might be responsible for a high risk of relapse even after years of abstinence. Given the fact that persons, places, paraphernalia and stress can induce the drug relapse, cocaine abuse elicit strong memories with its use. Our published data previously showed a role for OT in modulating the anxiety behavior elicited by the drug-paired environment. However, further experimentation is required to elucidate what other neurochemical substrates interact with OT within the mesolimbic system. One possible neuromodulatory substrate for this interaction is the endocannabinoid system (ECS), in particular the cannabinoid receptor type 1 (CB1) and the transient receptor potential vanilloid type-1 (TRPV1) receptors. The present sets of experiments aim to investigate the interactions between OT, CB1 and TRPV1 receptors within the dopamine mesolimbic system in the anxiogenic response triggered by cue- elicited cocaine seeking behavior. Our proposal is two-fold: first, we propose to determine the role of intranasal OT treatment in the anxiety response triggered by cue-elicited cocaine seeking behavior; second to establish CB1 and TRPV1 receptors interactions with OT actions within the NAc and medial prefrontal cortex in the anxiety response triggered by cue-elicited cocaine seeking behavior. The outcome of our proposal may contribute to a more detailed understanding of the cross-talk between OT and ECS on the anxiety elicited by the drug-associated cues. The present proposal further broadens the understanding of OT physiological actions as a novel therapeutic alternative for cocaine addiction. If funded, the present proposal will also provide our underrepresented minority undergraduate students at our Department of Biology with an intense research experience during the academic year and summer months. As mentor, I will offer student mentees with a strong scientific mentoring program that will promote active learning experiences, critical thinking, best practices in the ethical conduct in science, how to prepare successful applications to summer internships and graduate school abroad, effective writing skills in science, oral presentations in scientific forums and career counseling to enhance their professional capabilities. Moreover, the proposed experiments will further promote a strong research platform for successful training of Hispanic undergraduate students from the University of Puerto Rico Rio Piedras in the field of the neurobiology of drug addiction.