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. Author manuscript; available in PMC: 2016 Mar 1.
Published in final edited form as: Horm Behav. 2015 Feb 3;69:132–138. doi: 10.1016/j.yhbeh.2015.01.009

Anabolic/Androgenic Steroid Administration During Adolescence and Adulthood Differentially Modulates Aggression and Anxiety

Thomas R Morrison 1, Lesley A Ricci 1, Richard H Melloni Jr 1
PMCID: PMC4359666  NIHMSID: NIHMS663316  PMID: 25655668

Abstract

Anabolic/androgenic steroid (AAS) use remains high in both teens and adults in the U.S. and worldwide despite studies showing that AAS use is associated with a higher incidence of aggression and anxiety. Recently we showed that chronic exposure to AAS through adolescence increases aggression and decreases anxious behaviors, while during AAS-withdrawal aggression is lowered to species-normative levels and anxiety increases. AAS exposure is known to differentially alter behaviors and their underlying neural substrates between adults and adolescents and thus the current study investigated whether exposure to AAS during adulthood affects the relationship between aggression and anxiety in manner similar to that previously observed in adolescents. Male hamsters were administered a moderate dose of AAS (5.0mg/kg/day × 30days) during adolescence (P27–56) or young adulthood (P65–P94) and then tested for aggression and anxiety during AAS exposure (i.e., on P57 or P95) and during AAS withdrawal (i.e., 30 days later on P77 or P115). Adolescent exposure to AAS increased aggressive responding during the AAS exposure period and anxiety-like responding during AAS withdrawal. Neither behavior was similarly influenced by adult exposure to AAS. Adult AAS exposure produced no difference in aggressive responding during AAS exposure (P95) or AAS withdrawal (P115); however, while AAS exposure during adulthood produced no difference in anxiety-like responding during AAS exposure, adult hamsters administered AAS were less anxious than vehicle control animals following AAS withdrawal. Together these data suggest that the aggression and anxiety provoking influence of AAS are likely a developmental phenomenon and that adult exposure to AAS may be anxiolytic over the long term.

INTRODUCTION

Abuse of anabolic/androgenic steroids (AAS) has remained a concern for decades, yet its use has risen in recent years worldwide (Harmer, 2010; NIDACapsules, 2007) despite strong evidence for negative acute and long-term physical, psychological, and behavioral consequences. While the most common behavioral side effect of AAS use is increased aggression in adult (Kouri, Lukas, Pope, & Oliva, 1995; Pope & Katz, 1994; Pope, Kouri, & Hudson, 2000; Su et al., 1993) and youth populations (Beaver, Vaughn, Delisi, & Wright, 2008; Dabbs, Jurkovic, & Frady, 1991; Johnson, Jay, Shoup, & Rickert, 1989; Johnson, 1990; Mattsson, Schalling, Olweus, Löw, & Svensson, 1980; Olweus, Mattsson, Schalling, & Löw, 1980), there is also a high incidence of anxiety-related disorder diagnoses in AAS users (Bahrke, Yesalis, & Wright, 1990; Johnson, 1990; Pagonis, Angelopoulos, Koukoulis, Hadjichristodoulou, & Toli, 2006; Pagonis, Angelopoulos, Koukoulis, & Hadjichristodoulou, 2006; Pope & Katz, 1994), particularly during withdrawal from AAS use (Bahrke et al., 1990; Brower, 2002; Corrigan, 1996; Lindqvist et al., 2007; Malone, Dimeff, Lombardo, & Sample, 1995; Malone & Dimeff, 1992; Perry, Andersen, & Yates, 1990). Clinical data reflect this incidence showing marked increases in both aggression and anxiety in AAS users (Hall, Hall, & Chapman, 2005; Pagonis, Angelopoulos, Koukoulis, & Hadjichristodoulou, 2006; Pope et al., 2000; Su et al., 1993); suggesting that AAS exposure may promote the development of both negative behavioral phenotypes simultaneously. While a number of preclinical studies have investigated the link between AAS use and the expression of aggression (Farrell & McGinnis, 2004; Lumia, Thorner, & McGinnis, 1994; McGinnis, Lumia, Breuer, & Possidente, 2002; McGinnis, Lumia, & Possidente, 2002; Melloni & Ricci, 2010) less is known regarding the relationship between AAS exposure and anxiety. AAS exposure produces variable effects on anxiety-like responding in animal models (Agis-Balboa, Pibiri, Nelson, & Pinna, 2009; Aikey, Nyby, Anmuth, & James, 2002; Bitran, Kellogg, & Hilvers, 1993; Fernández-Guasti & Martínez-Mota, 2005; Ricci, Morrison, & Melloni, 2012; Rocha, Calil, Ferreira, Moura, & Marcondes, 2007), despite consistent evidence for an anxiolytic effect of testosterone (Bing et al., 1998; Frye, Edinger, & Sumida, 2008; Toufexis, Davis, Hammond, & Davis, 2005; Zuloaga, Morris, Jordan, & Breedlove, 2008). Though evidence between androgen insensitive mice and rats suggests that this inconsistency may involve species differences (Zuloaga et al., 2008; Zuloaga, Poort, Jordan, & Breedlove, 2011), it is also plausible that inconsistent findings can be explained by the age of AAS administration since no preclinical study has investigated the effects of AAS administration on the emergence of these two behaviors during AAS exposure and withdrawal in both adolescent and adult populations – especially as it pertains to experimental, novice use.

For over a decade we have used pubertal male Syrian hamsters (Mesocricetus auratus) as an adolescent animal model to investigate the effects of adolescent AAS exposure on the behavioral neurobiology of two of the most common side effects of AAS exposure, i.e., offensive aggression (DeLeon, Grimes, & Melloni, 2002; Harrison, Connor, Nowak, Nash, & Melloni, 2000; Melloni & Ricci, 2010) and anxiety (Ricci et al., 2012, 2013). Behavioral data from these studies show that adolescent hamsters repeatedly exposed to moderate doses of AAS (5.0 mg/kg/day) display significant increases in aggression during the adolescent AAS exposure period followed by significant increases in anxiety during withdrawal. Linear regression analysis revealed that the difference in aggressive responding between the AAS exposure and withdrawal periods was a significant predictor of changes in anxiety-like behavior between these two periods, indicating that moderate adolescent AAS 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 (Ricci et al., 2013). While these alterations in aggressive and anxiety-like responding exist for adolescents exposed to AAS, it is unknown whether adults exposed to moderate doses of AAS experience similar behavioral side effects in parallel. To determine whether adult exposure to moderate dose AAS alters aggression and anxiety in a manner similar to adolescent exposure, the current study compares the effect(s) of moderate dose AAS administration between adolescents and adults on the expression of aggression during AAS exposure and anxiety during withdrawal.

METHODS

Animals

Intact male Syrian hamsters (Mesocricetus auratus) postnatal day 21 (P21; pubertal hamsters) or postnatal day 59 (P59; young adult hamsters) were obtained from Charles River Laboratories (Wilmington, MA), individually housed in polycarbonate cages, and maintained at ambient room temperature (22–24°C with 55% relative humidity) on a reverse light/dark cycle (14L:10D; lights off at 7:00). Food and water were provided ad libitum. For aggression testing, stimulus (intruder) males of equal size and weight to the experimental animals were obtained from Charles River one week prior to the behavioral test, group housed at 5 animals/cage in large polycarbonate cages, and maintained as above to acclimate to the animal facility. All intruders were evaluated and prescreened for low aggression (i.e., disengage and evade) and submission (i.e., tail-up freeze, flee, and fly-away) one day prior to the aggression test to control for behavioral differences between stimulus animals, as previously described in a number of our studies (Ferris et al., 1997; Grimes & Melloni, 2002; Ricci, Schwartzer, & Melloni, 2009). Intruders displaying significantly low aggression and/or submissive postures were excluded from use in the behavioral assay. All experimental treatments and behavioral tests described below were administered during the first four hours of the dark cycle under dim-red illumination to control for circadian influences. All studies using live animals were approved by the Northeastern University Institutional Animal Care and Use Committee (NU-IACUC), and all methods used were consistent with guidelines provided by the National Institute of Health for the scientific treatment of animals.

Anabolic/Androgenic Steroid Treatment

Postnatal day 27 (P27; pubertal) and postnatal day 65 (P65; adult) hamsters were weighted and received daily subcutaneous (SC) injections (0.1ml – 0.2ml) for 30 consecutive days (P27 – P56, pubertal; P65 – P94, adult) of a mixture (or “stack”) of 3 commonly used AAS (Hall et al., 2005) in doses consistent with repeated, moderate use in humans as described (see Melloni & Ricci, 2010 for a review). The AAS cocktail was composed of 2 mg/kg testosterone cypionate, 2 mg/kg nortestosterone and 1 mg/kg dihydrotestosterone undecyclate (Steraloids, Newport, RI) dissolved in sesame oil (SO). As a control, a separate set of P27 and P65 male hamsters received daily SC injections (0.1ml – 0.2ml) for 30 consecutive days (P27 – P56 or P65 – P94) of SO (vehicle control).

Experimental Design

The day following the last AAS injection (P57 or P95), AAS-treated animals (P57, n=7; P95, n=10) and SO-treated controls (P57, n=7; P95, n=10) were randomly assigned to one of two counterbalanced groups and tested for anxiety-like responding using the Elevated Plus Maze (EPM) test and aggressive behavior using the Resident/Intruder (RI) test. At the completion of behavioral testing on P57 or P95, animals were placed back into their home cage and withdrawn from AAS (or SO) for 21 days (i.e., until P77 or P115) and then tested again for anxiety and aggression.

Behavior Testing

Aggression

Hamsters were tested for offensive aggression using the resident-intruder (RI) paradigm, a well-characterized and ethologically valid model of offensive aggression in Syrian hamsters (Floody & Pfaff, 1977; Lerwill & Makings, 1971). For this measure, a novel intruder of similar size and weight was introduced into the home cage of the experimental animal (resident) and the resident was scored for specific and targeted aggressive responses observed as lateral, flank-directed attacks as previously described (Grimes, Ricci, & Melloni, 2003; Ricci, Rasakham, Grimes, & Melloni, 2006). An attack was scored each time the resident animal would pursue and then either [1] lunge toward and/or [2] confine the intruder by upright and sideways threat; each generally followed by a direct attempt to bite the intruder's dorsal rump and/or flank target area(s). The latency to attack was defined as the period of time between the beginning of the behavioral test and the first attack the residents made toward an intruder. In the case of no attacks, latencies to attack were assigned the maximum latency (i.e., 600s). Each aggression test lasted for 10 minutes and was videotaped and scored manually by two observers unaware of the hamsters' experimental treatment. Inter-rater reliability was set at 95%. No intruder was used for more than one behavioral test, and all subjects were tested during the first 4 hours of the dark cycle under dim red illumination to control for circadian influences on behavioral responding.

Anxiety

Hamsters were tested for anxiety-related behavior using the elevated plus maze (EPM) test as in our previous studies (Ricci et al., 2012, 2013) and elsewhere (Gannon et al., 2011; Prendergast & Nelson, 2005). The EPM has been used extensively in rodents as a reliable test of anxiety-like responding, with particular use as a sensitive behavioral test to screen for anxiolytic drug effects (Gannon et al., 2011; Pellow, Chopin, File, & Briley, 1985; Pellow & File, 1986). The apparatus consisted of two open arms and two closed arms (30 × 5 cm) elevated to a height of 38.5 cm and intersecting in a central platform (5 × 5 cm). The closed arms had black Plexiglas walls (15 cm high) covered with a black Plexiglas lid on the roof. The apparatus was arranged such that the open arms were opposite to each other. Animals were individually placed in the center of the apparatus facing one of the closed arms. The duration of time (sec) spent beyond a complete body length in the open arms was calculated for each animal over a 5-minute period. An increase in the duration of time spent in the open arms of the EPM was used as an index of anxiolytic behavior (Lister, 1987; Pellow et al., 1985). Each anxiety test was videotaped and coded by two observers unaware of experimental treatment. Animals were tested during the first four hours of the dark cycle under dim-red illumination to control for circadian influences in behavioral responding.

Statistical Analyses

Behavioral results from aggression (i.e., attacks and latency to attack) and anxiety (i.e., number of entries and duration of time spent within the open arms of the EPM) during AAS exposure (P57 and P95) and AAS withdrawal (P77 and P115) measures were compared between AAS and SO treatment groups using paired Student’s t-test (two-tailed). The α level for all statistical analyses was set at 0.05.

RESULTS

Adolescent AAS Exposure and Withdrawal

Figure 1a (Left) shows that during adolescent exposure (P57), AAS-treated animals were significantly more aggressive than SO-treated control animals. Adolescent AAS-treated animals directed significantly more rump/belly attacks (t(12)=4.15, p<0.01) and were faster to attack (t(12)=3.92, p<0.01) intruders than SO-treated control animals. In fact, AAS animals exhibited a greater than tenfold increase in number of rump/belly attacks and were four times faster to attack intruders compared to SO-treated controls. Conversely, during the adolescent AAS exposure period (i.e., on P57), animals showed no change in anxiety-like responding compared to SO-treated controls (Figure 1a, Right). During this time, there were no differences in the number of entries into- (t(12)=0.51, p>0.1) and the duration of time within- (t(12)=1.35, p>0.1) the open arms of the EPM between AAS- and SO-treated animals.

Figure 1.

Figure 1

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Adolescent AAS exposure produced increased rump/belly targeted attacks and decreased latency to attack during adolescent exposure testing period (P57) (a - Left), but not during withdrawal (P77) (b - Left). There were no changes in entries into the open arms or duration of time spent in the open arms of the EPM during AAS exposure (P57) (a - Right), but decreases in the number of entries into the open arms and a reduction in the amount of time spent in the open arms of the EPM were observed following withdrawal from adolescent AAS exposure (P77) (b - Right). (**p<0.01, ***p<0.01).

Consistent with our previous data (Carrillo, Ricci, & Melloni, 2011; Grimes & Melloni, 2006; Ricci et al., 2012), the aggression-stimulating effects of adolescent AAS exposure were no longer present at 3 weeks of AAS withdrawal (i.e., on P77), i.e., AAS-treated animals displayed a non-aggressive phenotype identical to SO-treated control animals (Figure 1b, Left). During withdrawal from AAS (P77), adolescent animals were no longer aggressive as evidenced by nearly identical numbers of rump/belly attacks (i.e., 2.14±0.9 attacks) and an attack latency period (i.e., 409.3±78 seconds) similar to SO-treated controls (i.e., 1.14±0.5 attacks and 444±73 seconds). Neither of these behavioral differences were statistically significant (attacks; t(12)=0.94, latency to attack; t(12)=0.32, p>0.1 each). In contrast, adolescent AAS-treated animals had significantly fewer open arm entries (t(12)=3.75, p<0.01) and spent significantly less time in the open arms (t(12)=5.17, p<0.001) than SO-treated control animals during withdrawal (Figure 1b, Right). In fact, AAS animals exhibited threefold fewer entries into-, and spent nearly half the time (>42% of time) within- the open arms of the EPM compared to SO-treated control animals.

Adult AAS Exposure and Withdrawal

Figure 2a and 2b show the effects of AAS exposure and withdrawal (respectively) on aggression and anxiety measures in adult animals. During exposure, both AAS- and SO- treated animals directed a high number of rump/belly attacks onto- (i.e., 27.6±4.4 vs. 27.8±3 attacks, respectively) and were quick to attack intruders (i.e., 85.3±12 vs. 92.6±11 seconds, respectively). Neither of these behavioral measures were statistically significantly different between SO and AAS animals (attacks; t(18)=0.11: latency to attack; t(18)=0.4, p>0.1 each). Similar to adolescent animals, adult AAS exposure had no significant effect on anxiety-like responding during the exposure period (i.e., on P95), i.e., AAS-treated animals showed no change in anxiety-like responding compared to SO-treated controls (Figure 2a, Right). During this time, there were no differences in the number of entries into- (t(18)=0.41, p>0.1) and the duration of time within- (t(18)=0.05, p>0.1) the open arms of the EPM between AAS- and SO- treated animals.

Figure 2.

Figure 2

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During the AAS-exposure testing period (P95), adults administered AAS showed no differences in targeted attacks, latency to attack, entries or time spent in the open arms of the EPM compared to vehicle-treated controls (a). During the AAS-withdrawal testing period (P115), AAS adults showed no differences in aggression measures, but did have a greater number of entries into- and spent significantly more time than vehicle treated controls within- the open arms of the EPM (b) (*p<0.05, **p<0.01).

During withdrawal from AAS (i.e., on P115), adults displayed an aggressive phenotype that was identical to SO-treated control animals (Figure 2b, Left). AAS-treated adults had similar numbers of rump/belly attacks (i.e., i.e., 29.4±4 vs. 23.6±4, respectively) and similar attack latency times (i.e., 90.3±13 vs. 81.4±12 seconds, respectively) to that of SO-treated controls during the withdrawal period. Neither of these behavioral differences were statistically significant (attacks; t(18)=0.98, latency to attack; t(18)=0.53, p>0.1 each). Conversely, during withdrawal from AAS administration (i.e., on P115), adult animals displayed a lower level of anxiety-like responding compared to SO-treated controls by showing a higher frequency of open-arm entries (t(18)=2.6, p<0.05) and spending significantly more time within the open arms of the EPM (t(18)=3.63, p<0.01). In fact, adult AAS animals exhibited twice the number of entries into- and spent nearly seven times the amount of time within- the open arms of the EPM compared to SO-treated control animals.

DISCUSSION

Here we present the first set of preclinical studies that investigate the effect of adolescent vs. adult AAS exposure on the relationship between aggression and anxiety during AAS exposure and withdrawal. In these studies pubertal and adult male hamsters were repeatedly administered a mixture of AAS that mimics a 'heavy use' regimen in humans (Pope & Katz, 1988, 1994), although recent surveys indicate that these doses (i.e., 5mg/kg/day, which corresponds to ~20× the therapeutic dose of testosterone) are more moderate by today’s standards where recommendations and examples can exceed this amount up to fivefold; ranging between 35–100× the therapeutic dose of testosterone (i.e., upwards toward 3000mg/week) (see http://www.Steroidtips.com and www.steroid.com/steroid_cycles.php for examples). The behavioral data confirm our previous findings that show that moderate dose AAS exposure significantly increases aggressive responding in adolescents during AAS exposure but not during AAS withdrawal, while increasing anxiety-like responding in adolescents during AAS withdrawal but not AAS exposure (Ricci et al., 2012, 2013). By comparison, unlike that observed following adolescent exposure, repeated administration of AAS to adult animals did not affect offensive aggressive behaviors during AAS exposure or AAS withdrawal, but had an anxiolytic effect during AAS withdrawal.

The severity of AAS abuse has been shown to correlate with adverse behavioral effects in humans, with higher doses and longer use times correlating with both aggression and anxiety (Pagonis, Angelopoulos, Koukoulis, Hadjichristodoulou, et al., 2006; Pagonis, Angelopoulos, Koukoulis, & Hadjichristodoulou, 2006; Payne, 1974a; Pope & Katz, 1987, 1988, 1994; Su et al., 1993). For instance, in adults the prolonged use of high dose AAS (i.e., upwards of 100× the therapeutic dose of testosterone – typically equivalent to near 3000 mg/week) has been correlated with increased aggressive behavior (Isacsson & Bergman, 1993; Kouri et al., 1995; Kreuz & Rose, 1972; Pope & Katz, 1988, 1994; Pope et al., 2000; Strauss, Wright, & Finerman, 1983; Strauss, 1987; Su et al., 1993). Similarly, in adolescent teenagers, aggression correlates with testosterone level (Archer, 1991; Johnson et al., 1989; Johnson, 1990; Mattsson et al., 1980; Scerbo & Kolko, 1994; Schaal, Tremblay, Soussignan, & Susman, 1996) where high levels of testosterone as well as AAS use are associated with provoked aggression and violence in adolescent males (Beaver et al., 2008; Dabbs, Frady, Carr, & Besch, 1987; Dabbs et al., 1991; Mattsson et al., 1980; Olweus et al., 1980; Olweus, 1987; Scerbo & Kolko, 1994; Schalling, 1987). Interestingly, there are also reports of increased aggression in adolescents administered lower (e.g., physiologic) levels of AAS (Finkelstein et al., 1997), suggesting that adolescent users may have a greater sensitivity to the aggression-provoking effects of testosterone. Like aggression, an increased incidence of anxiety-related disorders is correlated with prolonged, high dose AAS use (Bahrke et al., 1990; Daly et al., 2003; Johnson, 1990; Pagonis, Angelopoulos, Koukoulis, Hadjichristodoulou, et al., 2006; Pagonis, Angelopoulos, Koukoulis, & Hadjichristodoulou, 2006; Pope & Katz, 1988, 1994), particularly during withdrawal (Bahrke et al., 1990; Brower, 2002; Corrigan, 1996; Lindqvist et al., 2007; Malone et al., 1995; Malone & Dimeff, 1992; Perry et al., 1990), although it is unclear whether the level of maturity during the exposure or withdrawal periods contributes to the development and expression of this behavioral phenotype or whether young users have a greater sensitivity to the anxiety-provoking effects of testosterone.

In laboratory studies using adolescent and adult male rats and hamsters, chronic AAS exposure has consistently been shown to produce elevated levels of aggression during the AAS exposure period (Farrell & McGinnis, 2004; Lumia et al., 1994; McGinnis, Lumia, Breuer, et al., 2002; McGinnis, Lumia, & Possidente, 2002; Melloni & Ricci, 2010). This elevated level of aggression has been shown to be both maintained (Farrell & McGinnis, 2004) or reduced (Grimes & Melloni, 2006; Grimes, Ricci, & Melloni, 2006) during AAS withdrawal. The findings here and in our previous reports that show that adolescent AAS exposure significantly increases aggressive responding during AAS exposure, but not during AAS withdrawal, are to some extent similar to data from several of these studies (Farrell & McGinnis, 2004; McGinnis, Lumia, Breuer, et al., 2002; McGinnis, Lumia, & Possidente, 2002). In these studies, intact adolescent and adult rats were treated with AAS for greater than 9 weeks and then tested for aggressive behavior at the end of the AAS exposure period and/or following short-term (i.e., 3–5 weeks) or long-term (i.e., 9–12 and/or 15–17 weeks) AAS withdrawal (Farrell & McGinnis, 2004; McGinnis, Lumia, Breuer et al., 2002; McGinnis, Lumia, & Possidente, 2002). In these studies, immediate and lasting increases in aggressive behavior were observed after the cessation of AAS treatment. Contrary to our findings, in adolescent AAS-treated animals, heightened aggression has been observed during AAS withdrawal (although only in animals physically provoked to fight) (Farrell & McGinnis, 2004). No effect of adolescent AAS exposure was observed on aggression during withdrawal in animals without prior provocation, suggesting that an external physical stimulus is necessary to activate the aggressive response during AAS withdrawal in rats. Further, unlike rats, moderate dose AAS administration during adulthood (i.e., 5mg/kg/day × 30 days) did not affect aggression during the exposure or withdrawal period in hamsters.

Alongside AAS studies, it is interesting to note that testosterone levels correlate positively with dominant behaviors through development, both of which stabilize during early adulthood (Vomachka and Greenwald, 1979; Whitsett, 1975; Menard et al., 2003). In contrast, aggression levels are the same in the absence or presence of exogenous testosterone in castrated adult hamsters (Romeo, Schulz, Nelson, Menard, & Sisk, 2003), and similarly, the present findings show that AAS exposure and withdrawal produced no observable changes in offensive aggressive responding in adults when compared with their vehicle-treated counterparts. Although these findings contrast some early evidence that testosterone enhances aggressive behavior in adult rodents (e.g., Grelk, Papson, Cole, & Rowe, 1974; Payne & Swanson, 1972; Payne, 1974b), differences between our findings and these results are likely due to a range of methodological inconsistencies such as treatment regimen (i.e., acute vs. chronic administration), age of treatment, testing conditions, and behavioral observations (i.e., dominance, offensive, defensive or submissive) (see Albers, Huhman, & Meisel, 2002 for review). Relatedly, across species, studies that examined the effects of AAS-withdrawal in adult rats have reported that aggression increased following short-term withdrawal, but only in animals administered moderate doses of AAS for a considerably extended period of time (5mg/kg/day × 12 weeks) (McGinnis, Lumia, Breuer et al., 2002; McGinnis, Lumia, & Possidente, 2002), i.e., three times longer than that administered in the current set of studies. Taken together, data generated from other researchers as well as those presented in this report indicate that AAS may have differential lasting effects on aggressive behavior that depend upon age of exposure, length of treatment, and dose of AAS.

Compared to aggression, there are little data from too few preclinical studies that adequately describe how AAS exposure and/or withdrawal affect anxiety across different stages of maturation. Two such studies related to these topics found that 17α-methyltestosterone did not alter anxiety-related behaviors after chronic administration in adults (Rojas-Ortiz, Rundle-González, Rivera-Ramos, & Jorge, 2006) or acute administration in adolescents (Ramos-Pratts, Rosa-González, Pérez-Acevedo, Cintrón-López, & Barreto-Estrada, 2013). In contrast, recent data from our laboratory show that hamsters chronically exposed to a mixture of AAS throughout adolescence have reduced levels of anxiety during AAS exposure and then heightened levels of anxious responding after a withdrawal period (Ricci et al., 2012, 2013). These data are consistent with studies showing rats chronically treated with nandrolone or testosterone propionate during adolescence exhibit increased levels of anxiety after a withdrawal (or washout) period from AAS (Olivares et al., 2014; Rainer et al., 2014). Behavioral reports using adult rodents indicate that acute exposure to AAS decreases anxiety (Aikey et al., 2002; Bitran et al., 1993; Melchior & Ritzmann, 1994), while chronic exposure has been shown to either enhance anxious responding (Ambar & Chiavegatto, 2009; Rocha et al., 2007) or have no effect (Rojas-Ortiz et al., 2006; Zotti et al., 2014). While several of these chronic studies fall in line with our current results showing that adult exposure to AAS does not alter anxious behavior, the differences between our results and other chronic studies may be due in large part to drug regimen and/or the behavioral data analyses used. For example, as an index of anxious behavior, Ambar et al. measured the time each animal spent in the open arms combined with time spent in the neutral area at the center of the elevated plus maze (EPM), while our measures only included the time animals spent in the open arms. In fact, similar to our results, Ambar et al. did not find any difference in open arm entries, an important measure of anxious behavior when using the EPM apparatus (Pellow et al., 1985). Rocha et al. used scoring criteria similar to our study, however they also used a different treatment regimen along with a single AAS (i.e., nandrolone) as apposed to a mixture of AAS used in our study. Specifically, Rocha et al. administered AAS twice per week limiting the circulating dose of nandrolone. This difference in regimen is also notable since similar studies using larger doses and daily injections of nandrolone showed increased numbers of entries- and time spent in the open arms of the EPM (Kouvelas et al., 2008), suggesting the dose-response of nandrolone for anxious behavior resembles an inverse sigmoidal curve which may or may not be similar to the effects of other AAS or AAS mixtures.

In summary, these studies provide data that indicate that moderate dose AAS exposure during adolescence and adulthood differentially modulates aggression and anxiety in hamsters. Specifically, these data show that moderate dose adolescent AAS exposure significantly increases aggressive responding during the adolescent AAS exposure period but not during AAS withdrawal while increasing anxiety-like responding during AAS withdrawal but not during the adolescent AAS exposure period. By comparison, unlike adolescent exposure, repeated adult exposure to moderate dose AAS does not influence offensive aggression during AAS exposure or AAS withdrawal, but appears to have a slight anxiolytic effect following cessation of administration. Together, these data suggest that the aggression and anxiety provoking influence of moderate doses of AAS are most likely to appear when the exposure period to AAS is early (e.g., during adolescence) thus representing a developmental phenomenon. This notion, in addition to our previous findings showing that the magnitude of adolescent AAS-facilitated aggressive responding has the ability to predict anxiety-like withdrawal (Ricci et al., 2012, 2013), further supports the notion of a common neuroanatomical locus modulating both aggression and anxiety. It is likely that the neurochemical signals (e.g., serotonin and GABA) that modulate aggression and anxiety are sensitive to neuroplastic changes during developmental exposure to AAS, and lose sensitivity beyond this critical period at a time when these systems have established functional maturity within brain regions that control the expression of aggression and anxiety.

HIGHLIGHTS.

  1. Anabolic steroids are anxiogenic during withdrawal in adolescents, but not adults

  2. Adult exposure to anabolic steroids may be anxiolytic over the long term

  3. Anabolic steroids do not alter aggression in adults during exposure or withdrawal

  4. In Adolescent-anabolic steroid withdrawal, aggression is low while anxiety is high

ACKNOWLEDGMENTS

The authors would also like to thank Jillian Joyce and Courtney Davis for their technical support in the completion of the experimental procedures. This study was supported by research grant (R01) DA10547 from NIH to R.H.M. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Footnotes

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