3.1.2 Animals
Testosterone produces positive reinforcing and conditioned rewarding effects in preclinical models. Intact male hamsters reliably self-administer greater amounts of oral testosterone than vehicle in a two-bottle choice test (Johnson & Wood, 2001). Similarly, nose poking can be reliably maintained by intravenous infusions of testosterone in intact male rats (Wood et al., 2004) and intraventricular infusions of testosterone in intact male and female hamsters (Peters & Wood, 2004). Testosterone replacement increases intraventricular intake of exogenous testosterone in castrated male hamsters (DiMeo & Wood, 2004), suggesting that circulating androgens increase sensitivity to testosterone self-administration. Male hamsters will also self-administer the androgenic metabolite of testosterone, dihydrotestosterone (DHT), and low (but not high) doses of its antiandrogenic metabolite, estradiol (DiMeo & Wood, 2006). Testosterone produces a conditioned place preference in intact male rodents following either systemic injections (Alexander et al., 1994; Arnedo et al., 2000, 2002; but see Caladrone et al., 1996) or site-specific injections into the nucleus accumbens shell (Frye et al., 2002; Packard et al., 1997) or medial preoptic area (King et al., 1999). Importantly, the positive reinforcing effects of testosterone are mediated by endogenous opioid activity, given that pretreatment with the opioid antagonist naltrexone blocks the reinforcing effects of testosterone in intact male hamsters (Peters & Wood, 2004).
The effects of androgens on the positive reinforcing and conditioned rewarding effects of opioids vary across species and schedule of reinforcement. Pretreatment with the androgen receptor agonist, nandrolone, enhances morphine-induced place preference in intact male rats (Chow et al., 2016) but reduces morphine-induced place preference in intact male mice (Célérier et al., 2003). Moreover, chronic treatment with nandrolone significantly decreases morphine intake in intact male rats responding on an FR1 schedule of reinforcement but does not alter morphine intake on a PR schedule (Cooper & Wood, 2014).
Testosterone does not reliably serve as a discriminative stimulus in traditional animal models (Wood et al., 2011; but see De Beun et al., 1992), but androgens modulate the discriminative stimulus effects of mu opioids in male rats. For instance, endogenous androgens enhance the discriminative stimulus effects of mu opioid agonists, as evidenced by reductions in the potency and efficacy of mu agonists to substitute for morphine in a drug discrimination assay following castration (Craft et al., 1999). Paradoxically, endogenous androgens attenuate the rate-decreasing effects of mu opioids in drug discrimination tests, as evidenced by increases in sensitivity to the rate-suppressing effects of mu opioids following castration (Craft et al., 1999).
Androgens decrease the development of tolerance to opioids. For instance, chronic treatment with nandrolone attenuates the development of tolerance to the antinociceptive effects of morphine in intact male mice (Célérier et al., 2003) and in gonadectomized male and female rats (Philipova et al., 2003). Similarly, chronic (but not acute) treatment with finasteride, a 5α-reductase enzyme inhibitor that prevents the reduction of testosterone to DHT, attenuates the development of tolerance to the antinociceptive effects of morphine in intact male rats (Verdi & Ahmadiani, 2007).
Chronic treatment with androgens generally increases the severity of naloxone-precipitated withdrawal in morphine-treated male and female rodents (Célérier et al., 2003; Nayebi & Rezazadeh, 2008; Sadeghi et al., 2009; Philipova et al., 2003), suggesting that androgens increase the severity of opioid-induced physical dependence. Lending further support for this premise, treatment with the androgen receptor antagonist, flutamide, attenuates naloxone-precipitated withdrawal in morphine-treated male rats (Nayebi & Rezazadeh, 2008). Similarly, castration attenuates naloxone-precipitated withdrawal in morphine-treated male rodents, and this effect is blocked by supplemental treatment with testosterone (Nayebi & Rezazadeh, 2008; Sadeghi et al., 2009). In contrast, both acute and chronic treatment with finasteride decreases naloxone-precipitated opioid withdrawal in morphine-treated male rats (Verdi & Ahmadiani, 2007).
Androgens do not produce an opioid-mediated withdrawal syndrome in the absence of concurrent mu agonist administration. For instance, opioid antagonists do not precipitate withdrawal in intact male mice treated with nandrolone (Célérier et al., 2003), intact male monkeys treated with testosterone (Negus et al., 2001), or intact male hamsters self-administering testosterone (Peters & Wood, 2004). However, many of the symptoms of AAS withdrawal are qualitatively similar to those of opioid withdrawal, suggesting some overlapping mechanisms may be at play (see Brower et al., 1989; Kashkin & Kleber, 1989; Trenton & Currier, 2005)