The developmental consequences of exposure to drugs of abuse and/or withdrawal on interactions between the immune, endocrine, and nervous systems that are essential for the proper execution of the host defense response have not been well studied. This proposal seeks to study these interactions in rats and chicks exposed prenatally to opiates, and opiate or quasi-opiate withdrawal to determine short and long term adverse consequences which could compromise the organism's ability to prevent and survive infection by pathogens. The research is important and timely considering the recent increases in the use of heroin among adolescents, which is likely to increase the number of infants exposed to opiate and opiate withdrawal in utero. In addition, since a common route of heroin administration (and other abused drugs) is intravenous injection, likelihood of exposure to infectious agents, such as HIV, that can be vertically transmitted to the fetus is increased. Thus, it is important to examine how drugs of abuse can affect the development of and interactions between the immune, endocrine, and nervous systems. The proposed studies will examine behaviors influenced by immune system activation (sickness behaviors, autoshaping, and operant responding), endocrine function (hypothalamic-pituitary-adrenal (HPA) axis hormones and their response to acute and chronic stress), and immune function (serum concentrations and tissue gene expression of pro-inflammatory cytokines, macrophage metalloproteinase activity, and antibody response to antigenic challenge) will be examined following opiate exposure and/or withdrawal. Immune system modulation of opiate and quasi-opiate withdrawal will be investigated using both unconditioned and conditioned behavioral measures. Comparisons between true opiate and quasi-opiate withdrawal will permit conclusions as to whether opiate exposure per se is sufficient, in contradistinction to opiate exposure and or withdrawal and associated stresses by itself. Studies will begin to determine causal mechanisms for altered interactions by examining similarities between cocaine exposure and opiate withdrawal and the role of the neurotransmitters serotonin and norepinephrine, since alterations in their activity affect/mediate opiate action, withdrawal phenomena, endocrine, and immune system function. Alterations in HPA axis function will also be examined, as well as immune system activation or suppression concurrent with opiate or withdrawal exposure. This proposal draws on the candidate's past research history studying developmental psychobiology and neural-immune interactions. However, since the candidate has little formal training in pharmacology, appropriate coursework and seminars, along with guidance from an experienced psychopharmacology mentor and consultations/collaborations with researchers in various disciplines will be conducted during the project period. These experiences, coupled with the proposed research project, will help to train and guide the candidate to an independent career studying the developmental consequences of abused drugs, and in particular the complex interactions between the immune, nervous, and endocrine systems.
