Jerrold S. Meyer, B.S., M.S., Ph.D. - US grants

Glucocorticoids are hormones secreted from the adrenal glands of animals and human beings. These hormones are known to influence brain function and behavior in both adult and developing organisms. The hippocampus, a brain area involved in memory and learning, is a particularly important target site of glucocorticoid action. Previous research has demonstrated that altered glucocorticoid levels early in life significantly modify the development of the hippocampus, yet few studies have examined the functional consequences of these changes in brain organization. Dr. Meyer will perform experiments in which young laboratory rats will be exposed to either very low glucocorticoid levels (by surgically removing their adrenal glands) or high levels (produced by injection of hormones into non-operated animals). Appropriate control procedures will also be performed. All subjects will subsequently be tested in a spatial-learning task, the Morris water maze, that critically depends on the hippocampus for normal performance. Separate animals from each group will be studied at different ages, thereby enabling Dr. Meyer to detect disturbances in the normal developmental appearance of spatial-learning ability. These experiments will provide important new information about the role of glucocorticoids in normal behavioral development as well as the potential deleterious effects of early exposure to high levels of hormones, as sometimes occurs in human clinical situations.

Newborn infants exposed to cocaine in utero exhibit behavioral and neurological abnormalities that may hamper their subsequent development. Enabling clinicians to effectively predict and treat these deficits requires knowledge about the mechanisms of cocaine action on the fetal brain, which can be obtained most readily from neurobiological research on animals. Previous studies in our laboratory using the rat as a model animal have shown that cocaine binding sites are present in fetal brain and that cocaine inhibition of synaptic dopamine (DA) uptake occurs prenatally, but that cocaine does not acutely inhibit catecholamine synthesis as it does in adults. The deleterious effects of prenatal cocaine exposure may arise in part from interaction of the drug with these binding sites and subsequent interference with monoaminergic development. Therefore, the overall goals of the proposed studies are to further define the fundamental prenatal mechanisms of cocaine action, to investigate the neurochemical affects of chronic prenatal cocaine treatment, and to relate these effects to possible behavioral alterations in cocaine-exposed animals. Specifically, we will first determine the kinetic characteristics of cocaine receptors pre- and postnatally and localize these receptors autoradiographically using 3H-CFT, a newly available cocaine analog well suited for binding studies. As cocaine receptors in adult organisms have been related to membrane transport systems for DA, norepinephrine (NE), and serotonin (5-HT), we will look for a similar relationship in fetuses by examining the effects of lessening monoaminergic nerve terminals with selective neurotoxins, and by correlating drug inhibition of synaptosomal monoamine uptake with inhibition of CFT binding. Because of the central role of uptake inhibition in mediating the physiological and behavioral effects of cocaine, we will study the prenatal developmental of synaptosomal uptake processes or DA, NE, and 5-HT, and determine the ontogeny of cocaine action on these processes and its potency at various developmental stages. Finally, we will investigate the short- and long- term effects of chronic prenatal cocaine treatment on cocaine receptors, transmitter uptake systems and uptake inhibition by cocaine, D1 and D2 receptors, and selected behaviors that are stimulated by cocaine and mediated by dopaminergic mechanisms. The potency of cocaine in suppressing isolation-induced distress vocalizations will be studied in prenatally cocaine-exposed pups, whereas other animals maintained into adulthood will be tested for place conditioning using i.v. cocaine injection as the reinforcer. By examining a multitude of related neurochemical parameters along with cocaine-stimulated behavioral responses in our prenatally- treated subjects, we expect to find specific neural alterations that have demonstrable functional consequences for the animals.

biomedical equipment purchase;

[unreadable] DESCRIPTION (provided by applicant): This proposal seeks support for an interdisciplinary predoctoral training program in Neuroscience and Behavior at the University of Massachusetts Amherst. The Neuroscience and Behavior (NSB) Program is an interdepartmental doctoral program that provides broad-based instruction and research training to prepare students for careers in academia, industry, and related areas within the health sciences. NSB Program faculty are drawn from seven different departments and form five clusters of research focus: (1) Molecular and Cellular Neuroscience, (2) Neural and Behavioral Development, (3) Neuroendocrinology, (4) Animal [unreadable] Behavior, Learning, and Computational Neuroscience, and (5) Sensory and Motor Systems. Many faculty members are associated with more than one of these research clusters. Trainees in the proposed program will be supported for their first two years of predoctoral work. During this time, they will participate in two to three laboratory rotations and will take required coursework including a 1-year intensive core course in neuroscience, a proseminar that introduces the students to the program and teaches other skills such as grant writing, a newly developed course in the responsible conduct of research, and at least one course in quantitative methods. Other resources available to NSB Program students include the NSB Colloquium series, a noon-time seminar series, and journal clubs organized around a variety of topics. Other programs that contribute to NSB student training are the Center for Neuroendocrine Studies, the Molecular and Cellular Biology (MCB) Program, the Organismic and Evolutionary Biology (OEB) Program, and the UMass Amherst - Baystate Medical Center Collaborative Biomedical Research Program. Together with NSB, these programs provide an extremely rich intellectual environment as well as state-of-the-art research facilities for predoctoral students in the life sciences at the University of Massachusetts. The proposed training program will enable the NSB Program to continue to attract highly qualified applicants and it will enable the best students to conduct their rotate laboratory rotations without the time commitment required by a teaching assistantship. The training program will be managed by an NSB Training Executive Committee, which will have full [unreadable] responsibility for trainee selection and evaluation throughout the period of predoctoral training. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Use of 3,4-methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a significant health problem in the United States. High doses of MDMA damage the serotonergic system in adult animals, and similar consequences may occur in heavy Ecstasy users. Many studies have also found an association between Ecstasy use and cognitive deficits, heightened anxiety, and increased impulsivity. However, interpretation of these findings is confounded by the fact that most heavy Ecstasy users also regularly use cannabis, thus raising important questions as to the source of the cognitive and neuropsychiatric abnormalities observed in Ecstasy/cannabis co-users. Because Ecstasy use typically begins during adolescence and commonly occurs intermittently (e.g., on weekends at dances), our laboratory has developed a novel rat model of intermittent adolescent MDMA exposure. Animals treated using this model show a relatively modest serotonergic neurotoxicity (compared to high-dose binge regimens) that resembles the results obtained from neuroimaging studies of the serotonergic system in Ecstasy users. In subsequent behavioral testing, the MDMA-treated animals showed memory impairment as well as other effects that may be indicative of increased impulsivity. The proposed studies represent a pilot project designed to investigate the separate and combined behavioral and neurotoxic effects of MDMA and ?9-tetrahydrocannabinol (THC; the main psychoactive ingredient in cannabis) given repeatedly to adolescent male and female rats. Beginning at 1 week following the end of the dosing period, we will test drug-treated and control animals for their performance in several tests of spatial and non-spatial learning and memory, or for their behavioral and adrenocortical responses in several tests of anxiety or impulsivity. The effects of the treatments on regional brain serotonin transporter expression will be ascertained to determine possible relationships between behavioral and hormonal responses and serotonergic neurotoxicity in key brain areas involved in learning, memory, and anxiety. These studies will provide important new information on the separate and combined effects of MDMA and THC exposure during adolescence, thereby helping to resolve a controversial issue that has continued to plague the clinical Ecstasy literature. PUBLIC HEALTH RELEVANCE: Many young people regularly use the drug "Ecstasy", and there is scientific evidence that such use has adverse effects on the users' brain function and behavior. Because most Ecstasy users also smoke marijuana, researchers have had difficulty determining whether some of the negative consequences of Ecstasy, especially those involving memory deficits, might instead be related to repeated marijuana exposure. The proposed research will help answer this important problem by using controlled studies of experimental animals to determine the influence of these two drugs separately or together on learning, memory, and anxiety. [unreadable] [unreadable] [unreadable]