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Changes in Brain Testosterone and Allopregnanolone Biosynthesis Elicit Aggressive Behavior

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Changes in Brain Testosterone and Allopregnanolone Biosynthesis Elicit Aggressive Behavior Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior Graziano Pinna*, Erminio Costa, and Alessandro Guidotti Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612 Contributed by Erminio Costa, December 23, 2004 In addition to an action on metabolism, anabolic͞androgenic ste- of testosterone results in the development of GABAergic trans- roids also increase sex drive and mental acuity. If abused, such mission down-regulation (8, 16). Hence, GABAergic transmis- steroids can cause irritability, impulsive aggression, and signs of sion may be an important mechanism underlying the action major depression [Pearson, H. (2004) Nature 431, 500–501], but the of AAS. mechanisms that produce these symptoms are unknown. The Several studies in mice unrelated to AAS have unequivocally present study investigates behavioral and neurochemical alter- shown that a GABAergic transmission impairment plays a ations occurring in association with protracted (3-week) adminis- pivotal role in the expression of aggressive behavior (18–20). For tration of testosterone propionate (TP) to socially isolated (SI) and example, the down-regulation of GABAA receptor signal trans- group-housed male and female mice. Male but not female SI mice duction (18–23) in socially isolated (SI) aggressive male mice is exhibit aggression that correlates with the down-regulation of associated with a down-regulation of 3␣-hydroxysteroid-5␣- brain neurosteroid biosynthesis. However, in female mice, long- pregnan-20-one (allopregnanolone, Allo) biosynthesis (19–21, term TP administration induces aggression associated with a de- 24). Allo acts as a potent (nM concentrations) positive allosteric crease of brain allopregnanolone (Allo) content and a decrease Ϸ ␣ modulator of signal transduction at several GABAA receptor ( 40%) of 5 -reductase type I mRNA expression. In spayed mice subtypes (25–27). treated with TP, restitution experiments with progesterone and Unlike SI male mice, SI female mice fail to develop aggression estrogen normalize brain Allo content and prevent aggression. or to express Allo down-regulation (19). Hence, these data Submicromolar doses of S-norfluoxetine (S-NFLX) that are insuffi- strongly implicate a lack of positive GABA receptor function NEUROSCIENCE cient to inhibit serotonin reuptake selectively increase brain Allo A modulation by 3␣,5␣-pregnane steroids and invite speculation content and abolish TP-induced aggression. Our results support the view that TP-induced aggressive behavior is the result of a TP- on the pivotal mechanism underlying mouse aggressive behavior. mediated neurosteroid biosynthesis down-regulation that can be The experiments to be reported were designed to answer the reversed by the S-NFLX-induced increase of brain Allo content. broad question: Is testosterone propionate (TP)-elicited aggres- sive behavior mediated by brain Allo content down-regulation? 5␣-reductase ͉ anabolic steroids ͉ neurosteroids ͉ social To answer this question, the following brain functions were isolation ͉ castration studied: (i) Allo levels; (ii) the expression of the mRNA encoding the rate-limiting step enzyme of pregnane steroid biosynthesis, i.e., 5␣-reductase type I (5␣-RI) (28); and (iii) aggressive he athletic performance-enhancing anabolic͞androgenic behavior in normal or spayed female mice treated or untreated steroids (AAS) are becoming a major public health concern T for 3 weeks with a daily TP dose of 0.5 mg͞kg s.c. worldwide (1, 2). Contrary to expectations, AAS abuse is not a problem restricted to elite athletes, but, because of their ability Methyltestosterone, oxandrolone, stanozolol, nandrolone, to enhance mental acuity, these agents are becoming part of the and a number of congeners of testosterone are among the most general recreational drug armamentarium. In fact, not only commonly abused AAS (7). However, the most extensively non-athlete adolescents of both sexes but also elderly subjects abused AAS is testosterone (2). Therefore, the present investi- abuse them (1–5). AAS abuse may increase the risk of cardio- gation is focused on the behavioral and neurochemical correlates vascular and hepatic disorders and prostate cancer, may upset of long-term TP administration. menstrual cycles (3, 6), and may elicit a wide range of psychiatric Materials and Methods symptoms (e.g., episodic mania, impulsive aggression, and major depression) in both males and females (reviewed in refs. 7 and Animals and Drug Treatment. Adult male and female Swiss– 8). If administered in large doses to female rodents, AAS Webster mice (Harlan Breeders, Indianapolis), 22–25 g of body promote the onset of male behavior by remodeling synaptic links weight, maintained under a 12-h dark͞light cycle, and food and in specific CNS circuits (reviewed in ref. 9). Episodes of irrita- water ad libitum, were used for all experiments. Animals were bility and aggressive behavior, commonly referred to as steroid group housed (GH) (five to six per 24 ϫ 17 ϫ 12-cm cage) or SI rage (colloquially called ‘‘roid rage’’), are among the side effects in a cage of the same size for a period of 3 weeks, during which frequently expressed by AAS users (10, 11). These episodes can they were subjected to daily s.c. injections of TP, estradiol, escalate to extreme violence, including murder attempts (7). progesterone, or vehicle. Treatment was discontinued 24 h AAS abuse may lead to dependence, and drug discontinuation preceding our behavioral and biochemical studies (19). Neuro- can cause severe withdrawal symptoms that may lead to suicide steroids were measured in the olfactory bulbs (OB) because of attempts (12, 13). the importance of this brain region in aggressive behavior (29), Despite the social impact caused by the high incidence of AAS abuse, the neuronal mechanisms underlying this drug-induced syndrome are not understood. Abbreviations: S-NFLX, S-norfluoxetine; SI, social isolation; SI, socially isolated; GH, group The symptoms of such behavioral disorders strongly suggest a housed; ORX, orchiectomized; Allo, allopregnanolone; TP, testosterone propionate; AAS, anabolic͞androgenic steroids; 5␣-RI, 5␣-reductase type I; OB, olfactory bulbs; HFBA, hep- modification of neuronal events mediated by GABAergic trans- tafluorobutyric acid anhydride. ␮ mission (8, 13–17). Although M concentrations of testosterone *To whom correspondence should be addressed at: Psychiatric Institute, Department of can directly exert a positive allosteric modulation of the action Psychiatry, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612. E-mail: of GABA at different recombinant GABAA receptors (16), it [email protected]. has also been shown that protracted daily exposure to large doses © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0409643102 PNAS ͉ February 8, 2005 ͉ vol. 102 ͉ no. 6 ͉ 2135–2140 Downloaded by guest on September 24, 2021 and because this area expresses the highest levels of neuro- were derivatized with heptafluorobutyric acid anhydride steroids in the rodent brain (23, 28). (HFBA) and subjected to GC-mass fragmentography analysis. Ovariectomy (dorsal route), orchiectomy, or olfactory bulbec- Mass fragmentography analysis of derivatized progesterone tomy were performed under nembutal anesthesia. Vehicle or and Allo was performed in the standard electron impact (EI) tested drugs were prepared in sesame oil and given s.c., as 0.1 ml mode. Testosterone was analyzed in the negative ion chemical per 10 g of body weight. S-norfluoxetine (S-NFLX) was admin- ionization mode (NICI) by using methane as the reaction gas. istered to SI mice i.p., 30 min before behavioral test. The detection limit for progesterone, Allo, and testosterone Because estrous cycle stage was deemed an important variable was Ϸ10 fmol; the standard curve was linear between 5 and 105 in most of the behavioral and biochemical tests, vaginal smears fmol. For progesterone, Allo, or testosterone quantification, the were conducted in mice at the time of testing. m͞z ion-monitoring mode was 510 for HFBA-progesterone, 518 S-NFLX was a generous gift from Eli Lilly. Testosterone, for HFBA-D-progsterone, 496 for HFBA-Allo, 500 for HFBA- estradiol, and progesterone were from Sigma. TP was from D-Allo, 660 for HFBA-testosterone, and 663 for HFBA-D- Steraloids (Newport, RI). testosterone. Resident–Intruder Test. Aggressive behavior in SI mice. To test the Quantitative RT-PCR Analyses of 5␣-RI mRNAs. The 5␣-RI mRNAs aggressive behavior of SI mice, an intruder mouse of the same were quantified with competitive RT-PCR as described by gender as the SI resident male (male͞male resident–intruder) Dong et al., (28). Primers for 5␣-RI mRNA quantification were (19, 20) or male bulbectomized intruder for SI resident female as follows: reverse 308–331 (5Ј-ACCATGACTCATTGCTC- (female͞male resident–intruder) (30) was placed in the resident CCTGCTT-3Ј) and forward 1–24 (5Ј-CATCATCAGTGG- home cage, and resident–intruder interactions were videotaped TACCTCGAGAAG-3Ј). Templates for 5␣-RI internal stan- for 10 min. Olfactory bulbectomized males were used as intrud- dards contained a restriction endonucleases site XbaI, which ers because they elicit aggressive behavior in SI female mice that on digestion generated fragments of 135 and 182 bp (28). Each received 3 weeks of TP treatment (30). The aggressive behavior primer pair annealed to a single RNA template on multiple of resident SI mice was characterized by
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