No abstract

Most studies agree that males and females respond differently to drugs of abuse. In females, estradiol enhances the behavioral response to cocaine. However, studies on the role of testosterone and the locomotor response to psychostimulants in the male rat are inconclusive. Our study was designed to determine the behavioral effects of testosterone on the development and persistence of cocaine sensitization in male rats. We tested different doses of cocaine (10, 15 and 30mg/kg) to determine which dose induced locomotor sensitization in intact (INT) and gonadectomized (GDX) animals. We also investigated if GDX males with testosterone replacement (GDX-T) showed a similar locomotor response to cocaine as INT males. Our data showed that gonadectomy enhanced the locomotor response to a single cocaine injection. This effect was not observed in gonadectomized rats that received testosterone replacement. However, GDX rats did not show a progressive increase in their locomotor response to repeated cocaine administration (15 and 30 mg/kg) (sensitization) as did INT and GDX-T animals. It is possible that in GDX males, the initial high locomotor response to cocaine creates a ceiling effect that limits further increase in cocaine-induced hyperactivity. These findings indicate that testosterone not only modulates the behavioral response to a single and to repeated cocaine injections, but is essential for male rats to become sensitized to cocaine.

Preclinical studies show that estradiol enhances sensitization to cocaine in females by mechanisms not fully understood. These studies consistently show that ovariectomized (OVX) rats exhibit little or no sensitization to cocaine compared to OVX rats administered estradiol. In this study we varied the dose of cocaine (10, 15, and 30 mg/kg), the length of cocaine treatment (from 5 to 10 days) and the context of cocaine injections to determine if these factors play a role on estradiol's effects on cocaine sensitization. Because OVX rats are hormonally compromised, they are not representative of the natural state of the animal, and thus the physiological context of these studies remains unclear. To address this issue, we blocked ERs in gonadally intact females by icv administration of the antiestrogen ICI-182,780. Varying the dose or length of exposure to cocaine does not alter estradiol's effect on cocaine sensitization. In contrast, a highly context-dependent sensitization protocol results in robust sensitization even in OVX rats. Interestingly, using this protocol, sensitization in OVX rats diminished with time, suggesting that estradiol is necessary for the maintenance of cocaine sensitization. Blocking brain ERs with ICI completely abolishes the development and expression of cocaine sensization in gonadally intact female rats, even when tested in a highly context-dependent sensitization protocol. Given these findings, we propose that activation of brain ERs is required for the development and maintenance of sensitization and CPP.

Background Insulin resistance occurs in HIV-infected individuals and is associated with HIV-associated neurocognitive disorders (HAND). However, the mechanisms involved are not well understood. Previously we showed a correlation between soluble insulin receptor (sIR) and HAND. Here we investigated if binding of free insulin to sIR and soluble insulin-like growth factor-1 receptor (sIGF1-R) levels are associated with sIR in HAND. Methods Thirty-four (34) HIV-seropositive women stratified by cognitive status and 5 HIV-seronegative women were evaluated. In a subgroup of 20 HIV positive and 5 donors, binding of plasma insulin to sIR was determined by ELISA assay of residual insulin levels in plasma immuno-depleted with anti–IR-monoclonal antibody-Sepharose beads. sIR and sIGF1-R levels were determined by ELISA. Nonparametric statistics were used. Results Higher percentages of insulin bound to sIR significantly correlated with sIR levels and were associated with HAND status. Higher levels of plasma sIGF1-R had a positive correlation with sIR levels (p=0.011) and were associated with HAND (p=0.006). No correlations were observed with age, viral-immune profile, antiretroviral therapy, or TNF. Conclusion This study suggests that changes in sIGF1-R levels and insulin binding to sIR may contribute to HAND.