Cocaine abuse by human mothers is correlated with a high incidence of child neglect and abuse. Gestational cocaine (COC) treatment has been shown to increase aggression towards an intruder (maternal aggression) and reduce the levels of oxytocin (OXY) in the amygdala of rats on postpartum days (PPD) 6-10. Blocking OXY receptors in the central amygdala results in an increase in aggression parallel to that seen following COC treatment. COC likely decreases OXY in the amygdala and increases maternal aggression through its reuptake inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE). These studies are designed to elucidate the specific mechanisms through which COC may work to alter OXY and maternal aggression in rats.
Specific Aim 1 will determine if gestational treatment with a combination treatment of selective DA and 5-HT uptake inhibitor will increase maternal aggression as does COC. To test this hypothesis, groups of rat dams will be treated gestationally (days 1-20) with COC, control vehicle buffer (VCB), selective DA, 5-HT, or NE reuptake inhibitors or combinations of selective inhibitors. Dams will be tested for maternal aggression on PPD 6.
Specific Aim 2 will determine if gestational treatment with a combination of a selective DA and 5-HT uptake inhibitor will alter OXY dynamics as does COC. To test this hypothesis, groups of rat dams will be treated gestationally (days 1-20) with vehicle buffer (VCB), COC, selective DA, 5-HT, or NE reuptake inhibitors or combinations of the selective inhibitors and sacrificed on PPD 6. OXY levels and receptor binding will be measured by radioimmunoassay, in situ hybridization and autoradiography in the amygdala, medial preoptic area and paraventricular nucleus of the hypothalamus, all of which have been implicated in OXY regulation of maternal aggression.
Specific Aim 3 will determine if gestational COC treatment reduces OXY synthesis in the medial preoptic area and paraventricular nucleus and oxytocin receptor (OTR) synthesis in the amygdala, medial preoptic area and paraventricular nucleus. To test this hypothesis, rat dams will be treated gestationally with VCB or COC, and these brain regions removed for in situ hybridization and autoradiography for assessment of OXY and OTR messenger ribonucleic acid on PPD 6.
Specific Aim 4 will determine if prenatal exposure to COC and being raised by a COC treated mother as compared to being raised by mothers treated with control vehicle increases maternal aggression displayed by female offspring and decreases OXY in the amygdala of the offspring as adults. To test this hypothesis, female offspring of dams gestationally treated with COC or control vehicle buffer (2 groups, buffer with no pair feeding and buffer with pair feeding), will be raised by their natural dams or foster dams that are vehicle-treated (pair-fed and non-pair-fed) or COC and then bred and tested for maternal aggression in the presence of their own litters on PPD 6. OXY levels in the amygdala will be assessed following the behavioral testing.
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