This application involves a systematic investigation of the pharmacology of chronic high dose anabolic steroid treatment. A comprehensive evaluation i necessary in order to determine the deleterious consequences associated wit anabolic steroid abuse in humans. Uncertainties associated with human abus of steroids include concerns over the development of side effects (psychosis, aggression, mania), potential dependence problems, and depression following drug abstinence. The development of such phenomena could be due to a direct effect of chronic abuse, due to an unrecognized neurotoxicity, or conceivably due to a """"""""withdrawal"""""""" syndrome. Three hypotheses are to be investigated: 1) chronic anabolic steroid treatment produces behavioral manifestations (possibly indicative of either direct effects, neurotoxicity, or dependence and withdrawal); 2) chronic treatment produces alterations in the androgen receptor KD and/or Bmax in the central nervous system (possibly indicative of behavioral manifestations), and 3) chronic treatment produces alterations in brain biogenic amine transmitter systems measurable as fluctuations in the KD and/or Bmax of the reuptake sites (possibly indicative of a psychotic side effect or of depression associated with steroid abuse).
The specific aims to be accomplished are: 1)the investigation of potential steroid-induced behaviors by evaluating multiple non-specific measures and aggression (in a resident-intruder paradigm) following chronic (16 week) treatment of adult males, adult females and juvenile rodents with nandrolon testosterone, and fluoxymesterone at doses which mimic the abuse pattern of humans; 2) the investigation in brain tissue of steroid-induced changes in nuclear and synaptic plasma membrane androgen receptors; and 3) the investigation in brain tissue of the dopamine, norepinephrine, and serotoni reuptake sites. The non-specific behaviors include direct and indirect measures. Direct effects include: observational measures (Straub tail, piloerection, jumping, tremors, and convulsions), temperature, and locomoto activity (forced activity and spontaneous activity). Indirect measures are anabolic steroid-mediated alterations of responses induced by non-steroid drugs such as stimulant-induced hyperactivity/hyperthermia, barbiturate- induced sleep induction/duration, and cannabinoid-induced catalepsy. Attempts will also be made to precipitate """"""""withdrawal"""""""" behaviors (observational, temperature, and locomotor) by treatment with steroid antagonists. Little is known concerning the behavioral or neurochemical consequences of chronic exposure to pharmacological doses of anabolic steroids. The studie proposed here will provide basic information critical to our understanding of the potential hazards of anabolic steroid abuse in humans.
