Influence of the Anabolic-Androgenic Steroid Nandrolone on Cannabinoid
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Neuropharmacology 50 (2006) 788e806 www.elsevier.com/locate/neuropharm Influence of the anabolic-androgenic steroid nandrolone on cannabinoid dependence Evelyne Ce´le´rier a, Therese Ahdepil b, Helena Wikander b, Fernando Berrendero a, Fred Nyberg b, Rafael Maldonado a,* a Laboratori of Neurofarmacologia, Facultat de Cie´ncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain b Department of Pharmaceutical Biosciences, University of Uppsala, Box 591 Biomedicum, S751 24 Uppsala, Sweden Received 8 April 2005; received in revised form 29 November 2005; accepted 29 November 2005 Abstract The identification of the possible factors that might enhance the risk of developing drug addiction and related motivational disorders is crucial to reduce the prevalence of these problems. Here, we examined in mice whether the exposure to the anabolic-androgenic steroid nandrolone would affect the pharmacological and motivational effects induced by D9-tetrahydrocannabinol (THC), the principal psychoactive component of Cannabis sativa. Mice received nandrolone using pre-exposure (during 14 days before THC treatment) or co-administration (1 h before each THC injection) procedures. Both nandrolone treatments did not modify the acute antinociceptive, hypothermic and hypolocomotor effects of THC or the development of tolerance after chronic THC administration. Nandrolone pre-exposure blocked THC- and food-induced condi- tioned place preference and increased the somatic manifestations of THC withdrawal precipitated by the CB1 cannabinoid antagonist rimona- bant (SR141617A). The aversive effects of THC were not changed by nandrolone. Furthermore, nandrolone pre-exposure attenuated the anxiolytic-like effects of a low dose of THC without altering the anxiogenic-like effects of a high dose in the lit/dark box, open field and elevated plus-maze. Biochemical experiments showed that chronic nandrolone treatment did not modify CB1 receptor binding and GTP-binding protein activation in the caudate-putamen and cerebellum. Taken together, our results suggest that chronic nandrolone treatment alters behavioural re- sponses related to cannabinoid addictive properties. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Anabolic-androgenic steroid; Nandrolone; THC; Dependence; Anxiety; Mice 1. Introduction (AAS), used as doping substances, as a risk factor for the con- sumption of drugs of abuse such as cannabis. Considerable efforts are now devoted to the study of risk Derivates from Cannabis sativa, whose main psychoactive factors that may increase individual vulnerability to drugs of constituent is the D9-tetrahydrocannabinol (THC) (Mechoulam abuse. An important factor that could enhance the risk for et al., 1970), are today the most consumed illicit drugs world- an addictive process and motivational related disorders is the wide (Smart and Ogborne, 2000). Cannabinoid effects are exposure to pharmacological compounds able to modify the mediated by the activation of two receptors, the CB1 cannabi- physiological equilibrium of the rewarding system (Koob noid receptor highly abundant in the central nervous system, and Le Moal, 2001). The purpose of the present study was and the CB2 receptor, mainly located in the cells of the to investigate the effects of anabolic-androgenic steroids immune system (Ameri, 1999). The cannabinoid system is closely related to several neurobiological pathways involved in motivation, mood and addictive behaviours, particularly the dopaminergic and the opioid system (for reviews, see * Corresponding author. Tel.: þ34 93 542 28 45; fax: þ34 93 542 28 02. Manzanares et al., 1999; Maldonado and Rodrı´guez de E-mail address: [email protected] (R. Maldonado). Fonseca). Accordingly, cannabinoids have been reported to 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2005.11.017 E. Ce´le´rier et al. / Neuropharmacology 50 (2006) 788e806 789 produce behavioural and biochemical changes in animals treatment with THC were evaluated. In order to mimic human similar to other drugs of abuse and leading to dependence abuse regimes, supraphysiologic doses of nandrolone were ad- (Maldonado and Rodrı´guez de Fonseca, 2002). However, ministered using two different protocols, i.e. co-administration one important aspect of marijuana activity is the complexity during THC treatment and pre-exposure before THC of evoked emotional/affective responses and the possibility treatment. of dual euphoric-dysphoric effects (Halikas et al., 1985). In- deed, reinforcing and aversive as well as anxiolytic and anxio- 2. Methods genic effects have been reported after the administration of THC and other cannabinoid agonists (Chaperon and Thie´bot, 2.1. Animals 1999; Ghozland et al., 2002; Berrendero and Maldonado, e 2002). Albino male CD-1 mice (CRIFFA, France) weighing 20 22 g were housed five per cages and maintained at a controlled temperature AAS are synthetic derivates of testosterone widely used in (21 Æ 1 C) and humidity (55 Æ 10%) environment. The mice were given ac- the clinic as androgen replacement therapy and as chemother- cess to food and water ad libitum. Lighting was maintained at 12-h cycles (on apy for certain types of cancer (Wilson and Griffin, 1980). at 7 a.m. and off at 7 p.m.). All the experiments were performed during the During the last five decades, AAS has been used at doses light phase of the dark/light cycle. The animals were habituated to the exper- 10e100 times the therapeutic range by many athletes and imental room and handled for 1 week before the start of the experiments. All animal procedures met the guidelines of the National Institute of Health de- bodybuilders to enhance their physical performance, increase tailed in the ‘‘Guide for the Care and use of Laboratory Animals’’, the Euro- muscle mass and intensify training regimens (Wilson, 1988; pean Communities directive 86/609/EEC regulating animal research and were Lukas, 1993; Yesalis and Bahrke, 1995). The chronic use of approved by the Local Ethical Committees. All experiments were performed high doses of AAS has been reported to cause several physical with the investigators being blind to the treatment conditions. and psychological side-effects such as liver dysfunction, coro- nary heart disease, reproductive dysfunction, acne, depression, 2.2. Drugs personality changes and aggressive behaviour (Williamson and Young, 1992; Pope and Katz, 1994; Bahrke et al., THC and the AAS nandrolone decanoate were purchased from Sigma (Poole, UK). The selective CB1 cannabinoid receptor antagonist 1996). Interestingly, a concurrent abuse of AAS has also SR141617A (rimonabant) was generously provided by Sanofi Research been reported among addicts and others not connected to (France). Nandrolone was dissolved in vehicle (10% ethanol/10% cremophor sports (DuRant et al., 1993; Lukas, 1993; Yesalis and Bahrke, EL/80% distilled water) and injected intramuscularly (i.m.) in a volume of 1995; Kindlundh et al., 1999). Several studies have suggested 2 ml/g body weight. THC was dissolved in vehicle (5% ethanol/5% cremophor the association between use of AAS and consumption of alco- EL/90% distilled water) and injected intraperitoneally (i.p.) in a volume of 10 ml/g body weight. Rimonabant was dissolved in vehicle (10% ethanol/ hol, tobacco and illicit drugs, such as cannabis, opiates, am- 10% cremophor EL/80% distilled water) and injected i.p. in a volume of phetamine and ecstasy (DuRant et al., 1993; Yesalis and 20 ml/g body weight. Control mice received equivolumic vehicle injections. Bahrke, 1995; Kindlundh et al., 1999; Kanayama et al., 2003). Based on these clinical and epidemiological studies, 2.3. Behavioural experiments AAS exposure has been proposed to serve as a ‘‘gateway’’ for the misuse of other drugs of abuse (Arvary and Pope, The effects of nandrolone treatment on acute and chronic THC effects 2000). In line with this hypothesis, recent animal studies were evaluated. Two different protocols (pre-exposure or co-administration) have shown that AAS can be self-administered by laboratory were used for nandrolone administration in an attempt to mimic conditions similar to those used during human abuse regimes: drug intake concomitant animals (Ballard and Wood, 2005). AAS have also been re- to nandrolone use or drug intake with a past of long-term consumption of nan- ported to evoke neurobiochemical and behavioural alterations drolone. In the first protocol (pre-exposure), nandrolone was chronically ad- related to dependence, mood and motivation in rodents espe- ministered once daily during 14 days before starting THC treatment. In the cially by affecting the endogenous opioid and dopamine sys- second protocol (co-administration), nandrolone was administered 1 h before tem (Lukas, 1993; Menard et al., 1995; Clark et al., 1996; each THC injection. The i.m. injections of nandrolone were given alternatively ` in the left and the right hind leg when repeated administration was required. A Le Greves et al., 1997; Johansson et al., 1997, 2000a,b; supra-therapeutic dose of nandrolone (15 mg/kg) was chosen (i) because it Thiblin et al, 1999; Hallberg et al., 2000; Schlussman et al., mimics the dose self-administered by heavy nandrolone abusers (Williamson 2000; Ce´le´rier et al., 2003; Kindlundh et al., 2003 and for re- and Young, 1992) and (ii) because it has been previously shown to induce bio- view, see Clark and Henderson, 2003). chemical changes in the endogenous opioid and dopamine system in rodents Interactions