The goal of these studies is to understand the neurobiological basis for cocaine's effects on the developing brain. Previous work has shown that ontogenic cocaine exposure produces gender-specific alterations in behavioral responses and brain metabolic activity associated with the mesolimbic dopamine (DA) system and the basal ganglia. The proposed work will determine the neuroanatomic basis for these gender differences.
Specific Aim 1 : To determine plasma and brain cocaine levels in male and female pups.
Specific Aim 2 : To determine the neuroanatomic basis for the gender-specific responses to cocaine observed following stimulation of the dopaminergic system. Rates of glucose utilization in discrete brain nuclei will be quantified to determine the neuroanatomical distribution of the functional response to challenge with SKF 82958 and subjected to correlational analysis with the ongoing behaviors.
Specific Aim 3 : To determine the specific cell types in the circuits affected by cocaine exposure. The activation of efferent systems such as the striato-nigral, striato-pallidal, accumbal-vendral pallidal neurons will be assessed by quantification of the mRNAs encoding for dynorphin, substance P and enkephalin using in situ hybridization histochemistry (ISHH).
Specific Aim 4 : To determine the activational effects of gonadal hormones in the production of the gender-related differences observed in response to cocaine exposure. Using gonadectomy and hormonal replacement, we will determine whether the presence of gonadal steriods during the period of drug administration is necessary for the production of the gender-specific cocaine effects. By assessing the functional components of the basal ganglia and the mesolimbic DA system using in vivo functional mapping (quantitative autoradiography) and ISHH of molecular markers in weanling rats during the time of drug exposure and adult males and females which received the drug during the postnatal period, these studies will determine the neuroanatomic basis for cocaine's gender-specific ontogenic effects.
