Schizophrenia is a neurodevelopmental disorder which has distinct gender differences in age of onset, symptom severity, type of symptoms, and response to neuroleptics. However, due to the difficulties involved in working with females at different stages of the reproductive cycle, most studies have been done in males. During development, testosterone exerts organizational effects on brain differentiation. Pertubations of perinatal brain sexual differentiation which affect the dopaminergic and serotonergic systems may be contributing factors in some cases of schizophrenia. In conjunction with the late adolescence/early adulthood dopamine peak, organizational effects of steroids may become manifested in the overt symptoms of schizophrenia. Conventional neuroleptics produce a strong D2 receptor blockade in the prefrontal cortex and striatum, among other brain regions, which inhibits dopamine action and is effective against positive symptoms (psychosis) but which is largely ineffective against negative symptoms (flat affect, lack of motivation). Several of the atypical neuroleptics produce a weaker D2 blockade and a strong 5-HT2 blockade, and are effective against both positive and negative symptoms. This study will examine the organizational and activational effects of gonadal steroids on development and function of dopamine D2 and serotonin 5-HT2 receptors in the prefrontal cortex and striatum in male and female rats. In addition, organizational effects of gonadal steroids on the actions of a typical neuroleptic and an atypical neuroleptic will be investigated. Scatchard analyses of D2 and 5-HT2 binding sites and affinity, and HPLC analyses of dopamine turnover will be done.
