Psychopharmacology (2004) 171:298–305 DOI 10.1007/s00213-003-1587-7
ORIGINAL INVESTIGATION
Ruth I. Wood · Luke R. Johnson · Lucy Chu · Christina Schad · David W. Self
Testosterone reinforcement: intravenous and intracerebroventricular self-administration in male rats and hamsters Received: 22 March 2003 / Accepted: 27 June 2003 / Published online: 14 October 2003 Springer-Verlag 2003
Abstract Rationale: Anabolic steroids are drugs of abuse. However, the potential for addiction remains unclear. Testosterone induces conditioned place preference in rats and oral self-administration in hamsters. Objectives: To determine if male rats and hamsters consume testosterone by intravenous (IV) or intracerebroventricular (ICV) selfadministration. Methods: With each nose-poke in the active hole during daily 4-h tests in an operant conditioning chamber, gonad-intact adult rats and hamsters received 50 mg testosterone in an aqueous solution of b-cyclodextrin via jugular cannula. The inactive nosepoke hole served as a control. Additional hamsters received vehicle infusions. Results: Rats (n=7) expressed a significant preference for the active nose-poke hole (10.0€2.8 responses/4 h) over the inactive hole (4.7€1.2 responses/4 h). Similarly, during 16 days of testosterone self-administration IV, hamsters (n=9) averaged 11.7€2.9 responses/4 h and 6.3€1.1 responses/4 h in the active and inactive nose-poke holes, respectively. By contrast, vehicle controls (n=8) failed to develop a preference for the active nose-poke hole (6.5€0.5 and 6.4€0.3 responses/4 h). Hamsters (n=8) also self-administered R. I. Wood ()) · L. Chu Department of Cell and Neurobiology, Keck School of Medicine at the University of Southern California, 1333 San Pablo Street, BMT 401, Los Angeles, CA, 90033, USA e-mail:
[email protected] Tel.: +1-323-4421980 Fax: +1-323-4423158 L. R. Johnson Center for Neural Science, New York University, New York, NY 10003 USA C. Schad Department of Neurobiology, Chicago Medical Center, North Chicago, IL 60064 USA D. W. Self Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
1 mg testosterone ICV (active hole:39.8€6.0 nose-pokes/ 4 h; inactive hole: 22.6€7.1 nose-pokes/4 h). When testosterone was replaced with vehicle, nose-poking in the active hole declined from 31.1€7.6 to 11.9€3.2 responses/ 4 h within 6 days. Likewise, reversing active and inactive holes increased nose-poking in the previously inactive hole from 9.1€1.9 to 25.6€5.4 responses/4 h. However, reducing the testosterone dose from 1 mg to 0.2 mg per 1 ml injection did not change nose-poking. Conclusions: Compared with other drugs of abuse, testosterone reinforcement is modest. Nonetheless, these data support the hypothesis that testosterone is reinforcing. Keywords Androgens · Self-administration · Operant behavior · Testosterone · Hamsters · Rats · Intravenous · Intracerebroventricular
Introduction Androgens have powerful effects in the body and brain. Through their androgenic, anabolic, and psychotropic actions, androgens enhance performance, both athletic achievement and “competition” in non-athletic social situations (Goldstein 1990). Not surprisingly, androgenicanabolic steroids (AAS) are abused, both by athletes and casual users. Although AAS were banned from Olympic competition in 1975, steroid abuse continues. In unannounced drug tests at national competitions, up to 50% of athletes tested positive for AAS (Yesalis et al. 1990). Moreover, steroid abuse is not confined to athletes and body builders: as many as 7% of male high school seniors have tried AAS (Yesalis et al. 1990). In response to widespread abuse, testosterone was declared a controlled substance in 1991. Like opiates and psychostimulants, AAS abuse has negative health consequences for users, including endocrine, hepatic, and cardiovascular disturbances (Friedl 1990). In addition, traffic in illegal steroids has negative societal impact, including ingestion/injection of impurities mixed with steroids, crime from selling and
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purchasing, and disease (AIDS, hepatitis) from needlesharing (Goldstein 1990). While it is clear that AAS are abused, the potential for positive reinforcing effects and addiction is not fully understood. Recently, Brower (2002) proposed a twostage model of AAS dependence. According to the model, anabolic effects of AAS on muscle growth account for the initial stage of steroid use. However, with chronic exposure, users develop dependence on the psychoactive effects of AAS. In this regard, there are reports that AAS may possess euphorigenic effects (Cicero and O’Connor 1990; Brower et al. 1991; see also Kashkin and Kleber 1989; Galloway 1997; Leshner 2000; Doweiko 2002). Nonetheless, it is difficult in humans to separate direct psychoactive effects of AAS from the user’s psychological dependence on the anabolic effects of AAS. Thus, studies in laboratory animals are useful to explore androgen reinforcement. Testosterone induces a conditioned place preference in rats (De Beun et al. 1992; Alexander et al. 1994) and mice (Arnedo et al. 2000), and is self-administered by oral routes in hamsters (Johnson and Wood 2001; Wood 2002). Conditioned place preference with testosterone appears to involve dopamine release in the nucleus accumbens (Packard et al 1997, 1998), which acts on D1 and D2 types of dopamine receptors (Schroeder and Packard 2000). AAS users self-administer steroids orally, transdermally, and by intramuscular injection. While oral selfadministration in rodents has parallels with AAS use in humans, there are behavioral and physiologic limitations to this method. In particular, we cannot eliminate potential effects of taste or gut fill on oral testosterone consumption. Physiologically, it is difficult to achieve a rapid elevation in brain androgen with oral intake due to absorption across the gut and first-pass liver metabolism. To further evaluate the abuse potential of testosterone, we tested whether intravenous (IV) or intracerebroventricular (ICV) testosterone would support self-administration behavior. Rats were used in a pilot study to test IV testosterone self-administration according to established procedures for drug self-administration (Schmidt et al. 2001). IV self-administration was then adapted to hamsters, since we previously found that hamsters selfadminister testosterone orally (Johnson and Wood 2001; Wood 2002).
Materials and methods Subjects Adult male rats and hamsters were studied. Sprague-Dawley rats [300–325 g body weight (BW)] and hamsters (120–160 g) were obtained from Charles River Laboratories (Kingston, N.Y., USA). All animals remained gonad-intact to more closely approximate AAS use in humans. Animals were singly housed with food and water available ad libitum. Rats were maintained under a 12:12 light-dark cycle (lights on at 8 a.m.). Hamsters were exposed to a long-day photoperiod (14:10 LD, lights on at 10 p.m.) to maintain endogenous testosterone. Hamsters are seasonal breeders, and short-day photoperiods (
