The sex difference in onset of schizophrenic illness occurring during late adolescence and early adulthood is inadequately understood. As a group, men develop symptoms during late adolescence or very early adulthood. In contrast, the mean onset of symptoms in women occurs during their late twenties and women appear to have better treatment prognosis. A complete neurobiological understanding of schizophrenia must account for these observations and their relationship to dopamine, the neurotransmitter most frequently linked to the severity of schizophrenia. The recently isolated peptide, galanin, is colocalized in some dopamine neurons and potently influenced by estrogen. The link between estrogen, galanin and dopamine provides a rationale to begin exploring this ternary relationship. This proposal outlines the strategy to investigate the unique biology of galanin as a means of determining its relationship to catecholamine systems, particularly dopamine, and the gonadal steroid, estrogen. These studies will employ animal models to test the hypotheses that galanin is an antidopaminergic neuroeffector, that galanin influences sexual maturation of the brain at puberty and that galanin participates in the mediation of estrogen feedback. The relationships between estrogen, galanin and catecholamines will be evaluated in vitro using monolayer cultures of anterior pituitary cells and perifused medial basal hypothalamic fragments and in vivo using blood sampling and passive immunization techniques. The metabolism of the galanin precursor and other galanin-like peptides will be investigated in an effort to enhance findings based on the above hypotheses. It is expected that these studies will provide basic information about inhibitory mechanisms, estrogenic modulation of central nervous system function, and provide a basis for understanding sexual and developmental influences in schizophrenia.
