Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice.

Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone's capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior.

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-Based Antagonists and Kappa Opioid Receptor.

The kappa opioid receptor (KOR) is involved in the regulation of both the reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and the overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), have been shown to stop depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to a relapse in drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Furthermore, their persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein, we report our studies of the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N male mice for spontaneous cocaine withdrawal. Assessment of pharmacokinetics showed that 1 is a short-acting compound with an average half-life of 3.75 h across different compartments (brain, spinal cord, liver, and plasma). Both 1 (5 mg/kg) and nor-BNI (5 mg/kg) were shown to reduce spontaneous withdrawal behavior in mice, with 1 producing additional anti-anxiety-like behavior in a light-dark transition test (however, no mood-related effects of 1 or nor-BNI were observed at the current dosing in an elevated plus maze or a tail suspension test). Our results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Furthermore, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insight into the design of future selective, potent, and short-acting salvinorin-based KOR antagonists.

Allopregnanolone and neuroHIV: Potential benefits of neuroendocrine modulation in the era of antiretroviral therapy.

Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as 'neuroHIV.' Although combination antiretroviral therapy (cART) has been a tremendous success, in its present form, it cannot eradicate HIV. Reservoirs of virus reside within the central nervous system, serving as sources of HIV virotoxins that damage mitochondria and promote neurotoxicity. Although understudied, there is evidence that HIV or the HIV regulatory protein, trans-activator of transcription (Tat), can dysregulate neurosteroid formation potentially contributing to endocrine dysfunction. People living with HIV commonly suffer from endocrine disorders, including hypercortisolemia accompanied by paradoxical adrenal insufficiency upon stress. Age-related comorbidities often onset sooner and with greater magnitude among people living with HIV and are commonly accompanied by hypogonadism. In the post-cART era, these derangements of the hypothalamic-pituitary-adrenal and -gonadal axes are secondary (i.e., relegated to the brain) and indicative of neuroendocrine dysfunction. We review the clinical and preclinical evidence for neuroendocrine dysfunction in HIV, the capacity for hormone therapeutics to play an ameliorative role and the future steroid-based therapeutics that may have efficacy as novel adjunctives to cART.