آنابولیک نوجوان / استروئیدهای آندروژنی: پرخاشگری و اضطراب در دوران مواجهه با پیش بینی پاسخ رفتاری در طول برداشت در همسترهای سوریه

In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within-subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety-eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time.

The recreational use of anabolic/androgenic steroids (AAS) by adolescent teens has remained a concern for decades yet its use has risen in recent years worldwide (Harmer, 2010 and NIDACapsules, 2007) despite strong evidence for negative acute and long-term physical, psychological and behavioral consequences. While the most common negative behavioral effect of AAS use is increased aggression in adult (Isacsson and Bergman, 1993, Kouri et al., 1995, Kreuz and Rose, 1972, Pope et al., 1988, Pope and Katz, 1994, Pope et al., 2000, Strauss et al., 1983, Strauss et al., 1987 and Su et al., 1993) and youth populations alike (Archer, 1991, Beaver et al., 2008, Dabbs et al., 1987, Dabbs et al., 1991, Johnson, 1990, Johnson et al., 1989, Mattsson et al., 1980, Olweus, 1987, Olweus et al., 1980, Scerbo and Kolko, 1994, Schaal et al., 1996 and Schalling, 1987), an increased incidence of anxiety-related disorders is being diagnosed in AAS users (Bahrke et al., 1990, Daly et al., 2003, Johnson, 1990, Pagonis et al., 2006a, Pagonis et al., 2006b, Pope et al., 1988 and Pope and Katz, 1994), particularly during withdrawal from AAS use (Bahrke et al., 1990, Brower, 1992, Brower, 2002, Corrigan, 1996, Kashkin and Kleber, 1989, Lindqvist et al., 2007, Malone and Dimeff, 1992, Malone et al., 1995, Perry and Hughes, 1992, Perry et al., 1990, Pope et al., 1996 and Su et al., 1993). Interestingly, AAS users in many clinical studies also present with marked increases in both aggression and anxiety ( Hall et al., 2005, Pagonis et al., 2006a, Pope et al., 2000 and Su et al., 1993), suggesting that AAS exposure may promote the development of both negative behavioral phenotypes simultaneously. Yet, while considerable preclinical study has investigated the link between AAS use and aggression ( Lumia et al., 1994, McGinnis, 2004, McGinnis et al., 2002a, McGinnis et al., 2002b and Melloni and Ricci, 2010) or anxiety ( Agis-Balboa et al., 2009, Aikey et al., 2002, Ambar and Chiavegatto, 2009, Barreto-Estrada et al., 2004, Bing et al., 1998, Bitran et al., 1993, Costine et al., 2010, Fernandez-Guasti and Martinez-Mota, 2005, Koukoulas et al., 1999, Minkin et al., 1993, Ovsiukova et al., 2003, Parrilla-Carrero et al., 2009, Ricci et al., 2012, Rocha et al., 2007 and Rojas-Ortiz et al., 2006), no preclinical studies have investigated the effects of AAS administration on the temporal relationship between the expression of the aggressive- and anxiety-related behavioral phenotypes. Here we present the first set of preclinical studies that investigate the consequence of adolescent AAS exposure on the relationship between the expression of aggression and anxiety as they present during AAS exposure and withdrawal. We hypothesized that adolescent AAS exposure would produce behavioral alterations in aggression and anxiety during both the exposure and withdrawal time periods, and that the expression of one behavior would predict the expression of the other over time. More specifically, we hypothesized that adolescent AAS-treated animals would present with high levels of aggression and low levels of anxiety during AAS exposure that would predict low levels of aggression and high levels of anxiety in these same animals during AAS withdrawal. To address these hypotheses we first investigated whether adolescent AAS exposure altered anxiety-like responding immediately (i.e., during AAS exposure) or only during withdrawal from AAS as we previously observed ( Ricci et al., 2012). Next, adolescent AAS-treated animals were tested for aggression and anxiety during AAS exposure, separated into quantitatively unique groups based on their aggression level during the exposure period, and then tested for both aggression and anxiety during AAS withdrawal. Data from these animals were analyzed using between- and within-subjects statistical procedures, along with simple linear regression analyses to evaluate the predictive relationship between aggression and anxiety during adolescent AAS exposure on aggression and anxiety during withdrawal from adolescent AAS exposure.

Aggression and anxiety during adolescent AAS exposure and withdrawal Aggressive behavior As reported in a number of our prior studies (see Melloni and Ricci, 2010 for a review), adolescent AAS administration results in a significant increase in offensive aggression during the adolescent exposure period (i.e., on P57) compared to SO-treated control animals (t(44) = 5.29, p < 0.001) ( Fig. 1). During adolescent exposure, AAS-treated animals exhibited a greater than six-fold increase in the number of attacks compared to SO-treated controls. Also, consistent with our previous data ( Carrillo et al., 2011, Grimes and Melloni, 2006, Grimes et al., 2006 and Ricci et al., 2012), behavioral data from the current study showed that the aggression-stimulating effects of adolescent AAS exposure were no longer present at 3 weeks of AAS withdrawal (i.e., on P77), i.e., a time at which AAS-treated animals were no longer aggressive and displayed a non-aggressive phenotype identical to SO-treated control animals (t(43) = 1.98, p > 0.1). Further, within-treatment group comparisons revealed that AAS-treated animals displayed a significantly lower level of aggression during withdrawal from adolescent AAS exposure (i.e., on P77) as compared to that observed during the AAS exposure period (i.e., on P57) (t(37) = 2.471, p < 0.05) ( Fig. 1, upper inset). During withdrawal from adolescent AAS exposure (i.e., on P77), residents executed nearly 3-fold fewer attacks onto intruders placed in their home cage compared to animals tested during adolescent AAS exposure. Conversely, however, no significant difference was observed in aggression between the exposure and withdrawal periods in SO-treated control animals. In this case, SO-treated animals directed a nearly identical number of attacks onto intruders (i.e., 2.6 ± 0.1.3 attacks) during the withdrawal period (i.e., on P77) as compared to the exposure period (i.e., 2.67 ± 0.97 attacks on P57) (t(16) = 0.076, p > 0.1). Full-size image (42 K) Fig. 1. Adolescent AAS exposure alters aggression and anxiety during adolescent AAS exposure and withdrawal. Top Graphs. The number of attacks of control- (SO; white bars) and AAS- (black bars) treated hamsters in a resident/intruder (R/I) test during adolescent exposure (i.e., on P57) and withdrawal (i.e., on P77). Top Inset. The number of attacks of AAS-treated hamsters during adolescent AAS exposure (i.e., on P57, striped bars) and withdrawal (i.e., on P77, black bars). Bottom Graphs. The duration of time control- (SO; white bars) and AAS- (black bars) treated hamsters spent in the open arm of the elevated plus maze (EPM) during adolescent exposure (i.e., on P57) and withdrawal (i.e., on P77). Bottom Inset. The duration of time spent in the open arm of the EPM of AAS-treated hamsters during adolescent AAS exposure (i.e., on P57, striped bars) and withdrawal (i.e., on P77, black bars). Bars denote SEM; *p < 0.05, **p < 0.01, ***p < 0.001. Figure options Anxiety Adolescent AAS-treated animals displayed a significantly lower level of anxiety-like behavior during adolescent AAS exposure (i.e., on P57) compared to SO-treated control animals as measured by the duration of time spent in the open arms of the EPM (t(40) = 2.22, p < 0.05) ( Fig. 1). Indeed, during adolescent AAS exposure, AAS-treated animals spent significantly more time (> 30% more time) in the open arms of the EPM compared to SO-treated control animals. However, behavioral data from the current study showed that the anxiolytic effects of adolescent AAS exposure were no longer present at 3 weeks of AAS withdrawal (i.e., on P77). Rather, consistent with our recent findings ( Ricci et al., 2012), during withdrawal from adolescent AAS administration (i.e., on P77), AAS-treated animals displayed a higher level of anxiety-like responding in the EPM compared to SO-treated controls. Specifically, during withdrawal from adolescent AAS exposure, AAS-treated animals spent significantly less time (< 20% less time) in the open arms of the EPM compared to SO-treated control animals (t(45) = 2.05, p < 0.05) ( Fig. 1). Within treatment group comparisons revealed that AAS-treated animals displayed a significantly higher level of anxiety-like behavior in the EPM test during withdrawal from adolescent AAS exposure (i.e., on P77) as compared to that observed during AAS exposure (i.e., on P57) ( Fig. 1, lower inset). During withdrawal from adolescent AAS exposure, the animals spent significantly less time in the open arms of the EPM compared to the duration of time spent in the open arms of the EPM during the AAS exposure period (t(41) = 4.65, p < 0.001). During AAS withdrawal, the animals spent less than 50% of the time in the open arms of the EPM compared to the animals tested during adolescent AAS exposure. Conversely, however, no significant difference was observed in anxiety-like behavior between the exposure and withdrawal periods in SO-treated control animals. In this case, SO-treated animals spent an average of 81.52 ± 9.8 s in the open arms of the EPM during the withdrawal period (i.e., on P77) as compared to 80.79 ± 4.3 s in the open arms of the EPM during the exposure period (i.e., on P57) (t(19) = 0.081, p > 0.1). Adolescent AAS-induced aggression: Quantitative separation of responders Based on our hypothesis that aggression and anxiety are inversely related in adolescent AAS-treated animals, the animals were divided into adolescent AAS-induced No/Low (NL), Species Normative (SN) and Excessive (E) responder groups as defined by their aggression level displayed during the adolescent AAS exposure period (i.e., on P57) as compared to SO-treated littermates.