HIV-1 AND COCAINE: MOTIVATION AND SYNAPTIC FUNCTION
Molecular and behavioral assays were used to examine the effects of HIV-1 on synaptodendritic integrity, motivated behavior and the therapeutic potential of natural isoflavones in ameliorating both synaptodendritic injury in vitro and changes in motivation in vivo. The overarching hypothesis of the present dissertation is twofold: 1. HIV-1 causes a decrease in motivation for sucrose and cocaine and the change in motivational state is driven by compromised synaptic integrity as evaluated by F-actin and DAT function and, 2. Treatment with phytoestrogens will prevent synaptodendritic damage, normalize the internal motivational state of the HIV-1 Tg rat for sucrose and cocaine, and alter dendritic spine morphology.
Primary neuronal cell cultures were utilized to evaluate the effects of HIV-1 Tat and cocaine on synaptodendritic integrity and the therapeutic potential of phytoestrogens. We demonstrate that the cysteine rich domain of Tat is required to initiate synaptodendritic injury, and damage can be prevented by pre-treatment with phytoestrogens daidzein, liquiritigenin, and equol in an estrogen receptor dependent manner. Addition of daidzein and liquiritigenin to the cell culture medium following Tat exposure resulted in a significant restoration of the fine network which was an estrogen receptor mediated mechanism. Simultaneous treatment with Tat and cocaine, at independently non-damaging concentrations, resulted in significant synaptodendritic injury. Tat + cocaine induced damage is prevented by S/R-equol treatment in an estrogen receptor beta dependent mechanism.
The HIV-1 transgenic rat was utilized to evaluate the effects of HIV-1 on motivated behavior for sucrose and cocaine, and the ability of equol treatment to potentially modulate changes in goal-directed behavior. HIV-1 Tg rats respond less overall for sucrose (0-30%; w/v) and may be more sensitive to cocaine. Equol treatment resulted in a differential response to sucrose and cocaine in both HIV-1 Tg and F344 rats. Control animals respond in a functionally linear manner for higher sucrose concentrations, but equol treatment produced a quadratic response. Equol increased cocaine intake in F344 rats but resulted in a decrease in responding in HIV-1 Tg rats. Finally, equol treatment shifted choice behavior in F344 animals. Together, these studies indicate equol may be a beneficial treatment for HIV-1+ individuals, but may not be suitable for seronegative individuals.