HIV and estrogen effects on hypothalamic regulation of cocaine-related behavior

PROJECT SUMMARY HIV infection results in abnormal menstruation and alterations in circulating hormones. HIV infection is also highly comorbid with drug use. Women who use drugs are at an elevated risk of HIV infection and show accelerated HIV progression. In rodents, estrous cyclicity and cocaine-related behaviors are both regulated by the medial

preoptic area (mPOA) of the hypothalamus. The mPOA regulates gonadal hormone release which feeds back onto the mPOA to regulate its activity. The mPOA regulates cocaine-related behaviors through primarily GABAergic projections to the ventral tegmental area (VTA), which modulates dopamine release in the nucleus

accumbens (NAc). Lesion of the mPOA disrupts estrous cycling and enhances cocaine-induced locomotion. These mPOA lesion-induced changes are associated with increased cFos expression and dopamine release in the NAc, together implicating mPOA in both estrous cyclicity and cocaine-related behavior. Our preliminary data

in the EcoHIV mouse model of HIV infection indicate disruptions in estrous cycle following inoculation with EcoHIV. Further, EcoHIV infection enhanced cocaine-induced locomotor sensitization, a model of cocaine- related behavioral plasticity, and increased cocaine-induced cFos expression in the NAc. Thus, the mPOA may

represent a common site of dysregulation following EcoHIV infection, leading to alterations in both estrous cycle and cocaine-related behavior. Consistent with this, we have observed that EcoHIV-infected female mice exhibit attenuated cFos expression in the mPOA. This R21 proposal will test the overarching hypothesis that EcoHIV

infection dysregulates the mPOA estradiol system, leading to enhanced cocaine-induced locomotor sensitization. Aim 1 will determine the effects of EcoHIV inoculation and cocaine exposure on estradiol levels and receptor expression in the mPOA. Aim 2 will determine the effects of EcoHIV inoculation on engagement of

mPOA→VTA and VTA→NAc projections in cocaine-induced locomotor sensitization. Aim 3 will determine the effect of chemogenetic activation of mPOA→VTA projections on cocaine-induced locomotor sensitization following EcoHIV infection. It will also determine the effect of an estrogen receptor α antagonist on cocaine-

induced locomotor sensitization following EcoHIV infection. The results of these experiments will identify a mechanism by which EcoHIV infection alters behavioral response to cocaine and the contribution of the mPOA→VTA→NAc pathway to cocaine-related behavior following EcoHIV infection. Further, we will gain

significant knowledge of sex differences in the regulation of cocaine-related behavior by the hypothalamus.