RESUMO
Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17ß-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4mg/kg), but not 17ß-estradiol (0.09mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17ß-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice.
Assuntos
Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Ovariectomia , Progesterona/farmacologia , Progestinas/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/biossíntese , Animais , Química Encefálica/efeitos dos fármacos , Doxiciclina/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genéticaRESUMO
The HIV-1 trans-activator of transcription (Tat) protein, interacts with psychostimulants to potentiate cocaine-reward in rodents. Sex steroids may protect against Tat-induced deficits. Female GT-tg transgenic mice conditionally-expressed Tat protein targeted to brain via a doxycycline-dependent, GFAP-linked promoter. Mice were tested for cocaine-conditioned place preference (CPP) and cocaine-induced locomotion when in the proestrous (high-hormone) or diestrous (low-hormone) phases of their estrous cycle. Cocaine-CPP was potentiated by Tat induction via 50, 100, or 125 (but not 25) mg/kg doxycycline daily treatment for 7 days. Diestrous mice exposed to Tat protein demonstrated significantly greater cocaine-CPP than did proestrous mice. Tat induction interacted with estrous cycle to decrease acute cocaine-induced locomotion among Tat-induced diestrous mice, but not their uninduced or proestrous counterparts, and attenuated cocaine-sensitization. In a cocaine-challenge, previously cocaine-sensitized mice demonstrated greater cocaine-locomotion over cocaine-naive counterparts and Tat-induction attenuated locomotion. Altogether, data demonstrate Tat and circulating sex steroid influences over cocaine-reward and psychostimulation.
Assuntos
Cocaína/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Ciclo Estral , HIV-1/fisiologia , Locomoção/efeitos dos fármacos , Entorpecentes/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Camundongos TransgênicosRESUMO
The synthesis of conformationally constrained RGD-containing integrin ligands via an efficient solid-phase intramolecular thioalkylation reaction is described. The reaction of S-nucleophiles with newly generated N-terminal 4-chloromethyl thiazoles leads to the desired cyclic RGD products 5 in high purities and good overall yields.
RESUMO
Macrocyclization via an efficient high-yielding solid-phase intramolecular thioalkylation reaction is described. The reaction of S-nucleophiles with newly generated N-terminal 4-chloromethyl thiazoles led to the desired macrocyclization products 5 in high purities and good overall yields.
Assuntos
Peptídeos Cíclicos/síntese química , Tiazóis/síntese química , Ciclização , Estrutura Molecular , Peptídeos Cíclicos/química , Tiazóis/químicaRESUMO
Macrocyclization via an efficient high-yielding solid-phase intramolecular thioalkylation reaction is described. The reaction of S-nucleophiles with newly generated N-terminal 4-chloromethyl thiazoles led to the desired macrocyclization products 5 in high purities and good overall yields.