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)