Testosterone is essential for cocaine sensitization in male rats

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.

Cocaine-induced sensitization correlates with testosterone in male Japanese quail but not with estradiol in female Japanese quail

“…Other studies have reported increased cocaine-induced locomotor activity and striatal dopamine in CAST male rats relative to intact rats (Camp & Robinson, 1988a, b; Hernandez et al, 1994; Purvis-Tyson et al, 2014; Robinson, 1984). In contrast, Menendez-Delmestre and Segarra (2011) observed cocaine-induced sensitization at 15 and 30 mg/kg in intact and CAST male rats with testosterone replacement but not in CAST male rats. Thus, it is difficult to decipher the role of testosterone on cocaine-induced locomotor based on the current literature.…”

“…Similar to the current experiment, Martinez-Sanchis et al (2002) did not find an effect of testosterone at doses greater than 10 mg/kg cocaine. Furthermore, Menendez-Delmestre and Segarra (2011) found that 15 and 30 mg/kg of cocaine progressively increased locomotor activity in intact and CAST male rats with testosterone replacement but not in CAST male rats. In contrast, several studies examining the role of testosterone in the behavioral effects of cocaine have failed to find differences between castrated (CAST) and intact male rodents (Becker et al, 2001; Forgie & Stewart, 1994; Hu & Becker, 2003; Hu et al, 2004; Robinson et al, 1981; van Haaren & Meyer, 1991).…”

Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

“…Sex differences have been reported for sensitization to psychostimulants in rodents, which is likely related to augmented DA responses [249,250], with females showing a higher level of sensitization than males. E2 increases sensitization in OVX females [251-253], whereas the effects of CAST and T replacement are more variable [249,252,254-256]. We are unaware of any studies investigating sex differences in tolerance.…”

Sex differences in drug addiction and response to exercise intervention: From human to animal studies

“…For example, estradiol facilitates positive subjective effects of drugs, while progesterone and its metabolite allopregnanolone attenuate drug-related responses and protect against the aversive effect of drugs in females (Becker et al , 2012; Carroll and Anker, 2010). Similarly, testosterone has been shown to modulate drug-related awarding effects and behavioral response differently in males and females (Menendez-Delmestre and Segarra, 2011; Bawor et al , 2014). …”