Behavioral sensitization to cocaine: cooperation between glucocorticoids and epinephrine

Inge E. M. de Jong 0 Peter J. Steenbergen 0 E. Ronald de Kloet 0 0 Present address: I. E. M. de Jong ( 1 ) In Vivo Neurobiology , H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark Rationale Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood. Objectives The present study investigated the role of the two adrenal stress hormones, corticosterone and epinephrine, in sensitization to the locomotor stimulant effects of cocaine. Materials and methods The DBA/2 mouse strain was used, as behavioral sensitization in this strain critically depends on adrenal hormones. Animals were subjected to adrenalectomy (ADX, surgical removal of the adrenals) or SHAM surgery, and ADX mice were given replacement of epinephrine (5 103 mg/kg subcutaneously (s.c.) just prior to each drug administration), corticosterone (20%, s.c., pellet), or both. Mice were subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days followed by a 7.5 mg/kg cocaine challenge after a 5-day withdrawal). Results In agreement with our previous observations, ADX prevented initiation and expression of cocaine-induced locomotor sensitization. Whereas neither corticosterone nor epinephrine alone were sufficient to reverse the ADX effect, both hormones were necessary to fully restore initiation and retention of sensitization to levels observed in SHAM animals. - It is well known that stress, resulting in activation of the hypothalamicpituitaryadrenal axis (HPA-axis) and the autonomic sympathetic nervous system (ANS; De Kloet et al. 2005), can increase sensitivity to the behavioral and reinforcing effects of psychostimulant drugs, a phenomenon known as behavioral sensitization (Piazza and Le Moal 1998; Goeders 2003). Studies in laboratory rodents have demonstrated that stress facilitates acquisition and relapse of psychostimulant self-administration (Piazza et al. 1990; Goeders and Guerin 1994; Haney et al. 1995; Tidey and Miczek 1997) and enhances sensitivity to the locomotor stimulant properties of these drugs (Herman et al. 1984; Sorg and Kalivas 1991; Deroche et al. 1995; Haile et al. 2001; Lepsch et al. 2005). A wealth of data indicates that adrenal glucocorticoids, the output hormones of the HPA-axis, mediate the effects of stress on psychostimulant responsiveness (Marinelli and Piazza 2002; Goeders 2002; Deroche-Gamonet et al. 2003; De Jong and De Kloet 2004) primarily via their actions in the mesencephalic dopamine system (Piazza and Le Moal 1996). By contrast, the role of the ANS in psychostimulant sensitivity has received little attention. This is surprising since catecholamines (epinephrine, norepinephrine) are rapidly released into the general circulation during stress and in response to psychostimulant administration (Chiueh and Kopin 1978). Although the catecholamines are not likely to cross the bloodbrain barrier due to their polar structure (Weil-Malherbe et al. 1959), substantial evidence indicates that peripheral epinephrine can alter brain function and behavior indirectly by activating vagal afferents to the central nervous system (Gold and Van Buskirk 1975; Borrell et al. 1983; Sternberg et al. 1985; Miyashita and Williams 2006). Indeed, it has been shown that in addition to their independent actions, the HPA and ANS components of the stress response can interact to regulate behavior (Borrell et al. 1984; Roozendaal et al. 1996). We have previously identified a mouse strain, the DBA/2 strain, in which sensitization to the locomotor stimulant effects of cocaine is critically dependent on adrenal hormones (De Jong et al. 2007). Interestingly, whereas surgical removal of the adrenals (adrenalectomy, ADX) prevented initiation and expression of psychomotor sensitization, replacement of corticosterone to concentrations similar or even higher than those induced by stress was not sufficient to fully reverse the effects of ADX (De Jong and De Kloet 2009). Similarly, it has recently been reported that glucocorticoids are necessary, but not sufficient, to restore the effects of stress on escalation of cocaine self-administration (Mantsch and Katz 2007) and on morphine-induced conditioned place preference (DerAvakian et al. 2006) in ADX rats. In addition, there is considerable controversy in literature regarding the necessity of adrenal glucocorticoids in psychostimulant-induced behavioral sensitization (Rivet et al. 1989; Badiani et al. 1995; Pauly et al. 1993; Prasad et al. 1996; Przegalinski et al. 2000). Additional evidence for a dissociation between corticosterone secretion and behavioral sensitization comes from a study by Schmidt et al. (1999) who showed that sensitization of the corticosterone response to amphetamine was neither necessary nor sufficient for sensitization of the psychomotor response to the psychostimulant to occur. Collectively, these findings suggest that adrenal glucocorticoids may not be the sole players on the scene. In view of our findings with ADX, we propose an additional role for the adrenal catecholamine epinephrine (De Jong et al. 2007). In the present study, we have therefore investigated the role of adrenal glucocorticoids and epinephrine in sensitization to the locomotor stimulant effects of cocaine in the DBA/2 strain, which has been demonstrated to be highly susceptible to the impact of stress on drug responsiveness (Cabib et al. 2000). Animals were adrenalectomized or SHAM-operated, and ADX mice were given replacement of corticosterone (through release from a s.c. implanted 20% pellet), epinephrine (5 103 mg/kg, s.c., prior to each drug administration), or both. These doses were chosen based on previous findings (Van den Buuse et al. 2004) and pilot studies. The data show that the HPA-axis and the ANS act in a coordinate fashion to facilitate behavioral sensitization of DBA/2 mice to cocaine. Materials and methods Male DBA/2 Rj mice were obtained from Janvier (Le Genest Saint Isle, France) at the age of 8 weeks. Mice were housed in groups of four in perspex cages (351914 cm) with food and water available ad libitum at a 12-h lightdark cycle (lights on at 7 A.M.) in a temperature- (211C) and humidity(555%) controlled room. Surgery was performed 2 weeks after arrival in the animal facility. Animal experiments were performed according to the principles of laboratory animal care as specified in the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003) and in accordance with the EC Council Directive of November 1986 (86/609/EEC). Experiments were approved by the local Committee for Animal Health, Ethics and Research of Leiden University. Animals were either adrenalectomized (ADX) or SHAMoperated. Replacement therapies consisted of corticosterone (ADXcort), epinephrine (...truncated)