Robert Smith - US grants

animal developmental psychology; ethology; gestational age; lidocaine; embryo /fetus drug adverse effect; postnatal growth disorder; avoidance behavior; dosage; teratogens; drug administration routes; prenatal stress; behavior test; orientation; parent offspring interaction; conditioning;

Recent human data, and very limited animal data, suggest that cocaine useage in gestation is associated with adverse outcomes in the infant, including altered neurobehavioral development. Our laboratory has recently published data indicating that several postweaning behaviors are altered in rats exposed to 10 mg/kg/d cocaine in utero, and we have unpublished data indicating that this dose may alter hippocampal morphology of offspring. we now propose to establish a dose-effect curve for neurobehavioral effects of prenatal cocaine exposure, expand the range of behaviors tested, establish whether such effects persist when offspring are fostered to undosed surrogate dams, and further investigate neuroanatomical correlates of the altered behavior. Rats will be dosed during gestation with 5, 10, 20, or 40 mg/kg/d cocaine; controls will include uninjected and injected/pairfed controls. All pups will be fostered to undosed surrogates at birth. Offspring will be evaluated on a number of different measures of behavioral development and adult behavior (including representatives of each category suggested for testing by the Collaborative Behavioral Teratology Study), and on several aspects of hippocampal neuromorphology. The proposed work will expand the body on data on neurobehavioral effects of prenatal cocaine exposure (particularly on effects in adult offspring), and will provide a basis for continuing, more detailed studies on mechanisms of prenatal cocaine in our laboratory.

DESCRIPTION: (Applicant's Abstract) Although studies with humans confirm that there is a typical progression from tobacco and alcohol through marijuana to other drugs such as cocaine and heroin (the "gateway" hypothesis), no data exist on whether this is a purely social phenomenon, or whether there are underlying neurobiological substrates for this drug progression. Recent work on common substrates for different addictive drugs, and on drug interactions, make it plausible that there may be a biological component to drug progression. At least three possible such mechanisms may exist: (1) use of one drug may alter brain substrates [persistently] in such a way that later use of another drug is more reinforcing, (2) withdrawal from one drug may trigger behavior to seek relief from those symptoms, including consumption of another drug, or (3) cues conditioned to the use of one drug may elicit cravings which can be satisfied by another drug. Using adolescent rats as subjects, we propose to attempt an animal model of adolescent drug progression, and to determine whether any of the above three alternatives may underlie such progression. Subjects will be preexposed to alcohol during the juvenile period, and later evaluated on three tests (schedule-induced polydipsia of cocaine solution, cumulative cocaine dosing effects on activity, and conditioned place preference) to determine if reactions to cocaine are altered in any of three conditions: during the acute withdrawal phase from alcohol, long after acute withdrawal is concluded, and in the presence of cues formerly associated with alcohol. The proposed work will be the first attempt to develop an animal model of drug progression, and may have implications for both understanding and treatment of adolescent substance abuse, as well as continuing to define the plasticity of the CNS during later development.

Long-term objective. Improved care at the same or reduced costs for chronic somatizing patients, those patients without disease explanations for their prominent physical symptoms. Specific aims. It is predicted that a comprehensive, multidimensional management intervention will lead to the following changes: 1) improvement in mental health, physical health, satisfaction with care, and economic productivity; 2) decrease in pain, nonpain physical symptoms, anxiety, depression, and health care utilization. 3) We expect no change in costs for health services used. Significance. Chronic somatizing patients present a paradox: excessive utilization that results in poor care. This is due in part to poor recognition of the problem, disinterest among physicians, and the absence of research-based guidelines -- in light of a 5-10 percent prevalence. Design and Method. In a managed care setting we will generate a list of likely somatizers from computerized data systems, based on number of visits and types of symptoms. By chart review, a medical student will then identify which patients are somatizers. Of these somatizers, two groups of 100 each will be randomly assigned to a usual care control group and an intervention group. Intervention patients will be referred to a nurse practitioner (backed-up by a usual care physician) for confirmation of somatization and intitiation of treatment. The nurse practitioner will be trained for managing somatizing patients and their psychiatric comorbidities and will manage the intervention group. Measures of health related quality of life and economic cost will be used to assess the effectiveness of the 12 month treatment intervention. Outcome. If the prediction is supported, an important step towards developing research-based management guidelines for one of the most common and difficult problems in primary care will have been taken.