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0 4 - 0 1 - 2 0 0 5 Androgen Dependence in Hamsters: Overdose, Tolerance and Potential Opioidergic Mechanisms
K. D. Peters, R. I. Wood
When steroid use is discontinued, many anabolic-androgenic steroids users experience withdrawal symptoms characterized by a hyperadrenergic state resembling opioid withdrawal. Other studies suggest that anabolic-androgenic steroids users may possess euphorigenic effects. While these data suggest that anabolic-androgenic steroids users are rewarding independent of their anabolic effects, defining the potential for anabolic-androgenic steroids users addiction in humans has been difficult.
This study used i.c.v. testosterone selfadministration and controlled infusions of testosterone or vehicle in hamsters to explore central mechanisms of androgen overdose.
A total of 42 hamsters have been tested for i.c.v. testosterone self-administration in our laboratory. Of these, 10 (24%) died during testing. None of the deaths occurred in the operant chambers. Instead, hamsters often died during the night, several hours after removal from the operant chamber.
Deaths correlated with peak daily intake of testosterone. Of the hamsters that self-administered a peak intake of <20 mug/day, there was 100% survival (10/10). Survival decreased to 86% (19/22) when daily testosterone intake peaked at 20–60 mug/day. Only 30% (three of 10) survived when daily testosterone intake exceeded 60 mug/day.
Deaths are not due to volume or vehicle because i.c.v. infusions of 80 ml vehicle had no effect. Testosterone overdose resembles opiate intoxication.
When male hamsters received infusions of 40 mug testosterone, locomotion (25.1 +/- 18.8 gridcrossings/10 min), respiration (72.7 +/- 5.4 breaths/min) and body temperature (33.5 +/- 0.4 °C) were significantly reduced, compared with males receiving vehicle infusions (186.1 +/- 8.1 crossings/10 min, 117.6 +/- 1.0 breaths/min, 35.9 +/- 0.1 °C, P<0.05).
However, males developed tolerance to continued daily testosterone infusion. After 15 days, locomotion (170.2 +/- 6.3 crossings), respiration (118.4 +/- 1.3 breaths/min), and body temperature (35.3 +/- 0.3 °C) in testosterone-infused males were equivalent to that in vehicle controls (P>0.05).
The depressive effects of testosterone infusion are blocked by the opioid antagonist, naltrexone.
With naltrexone pretreatment (10 mg/kg s.c.), locomotion (183.7 +/- 1.8 crossings/10 min), respiration (116.9 +/- 0.3 breaths/min), and body temperature (36.1 +/- 0.4 °C) during testosterone infusion were equivalent to vehicle controls.
Likewise, naltrexone prevents the reinforcing effects of i.c.v. testosterone selfadministration. These results indicate that testosterone at high doses causes central autonomic depression, which may be a factor in deaths during self-administration. As well, the depressive effects of large quantities of testosterone may be mediated, at least in part, by an opioidergic mechanism.
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