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Ethanol exposure during development reduces resident aggression and
testosterone in rats
Joaquin N. Lugo Jr. a^ , Melissa D. Marino b, Justin T. Gass a^ ,
Marlene A. Wilson b^ , Sandra J. Kelly a,b,*
a (^) Department of Psychology, University of South Carolina, Columbia, SC 29208, USA b (^) Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA
Received 2 March 2005; received in revised form 15 July 2005; accepted 21 October 2005
Abstract
Ethanol exposure during development has been shown to alter social behaviors in people, but the range of deficits is not clear. Using an animal model of Fetal Alcohol Spectrum Disorders, inter-male aggression and testosterone levels were examined in adult rats. Rats were exposed to ethanol during the entire prenatal period and from postnatal day 2 through 10. Ethanol was administered via intragastric intubation. Two other groups consisted of a nontreated control and an intubated control group that was exposed to the administration procedures but not ethanol. Both offensive and defensive aggression were examined in experimental residents and intruders under three different housing conditions for the resident males: (1) with another male, (2) with a pregnant female, and (3) with a female and litter fathered by the experimental animal. When housed with a female and litter, ethanol-exposed rats displayed reduced offensive aggression compared to control groups under the same condition. Defensive aggression in the non-experimental intruders was reduced in this same condition. There were no differences in duration of non-aggressive social behaviors among the groups in any of the housing conditions. Testosterone levels were reduced in ethanol-exposed rats compared to controls. In summary, ethanol exposure over the combined prenatal and postnatal periods reduces aggressive behavior in a condition where aggressive behavior is normally seen. This reduction may be related to lower testosterone levels. D 2005 Elsevier Inc. All rights reserved.
Keywords: Fetal alcohol syndrome; Aggression; Resident – intruder paradigm; Social behavior; Prenatal alcohol
Fetal Alcohol Spectrum Disorders (FASD) describes those individuals who manifest mild to severe disturbances of physical, behavioral, emotional, and/or social functioning due to in utero ethanol exposure. FASD individuals are found to commit high rate of crimes against others, engage in inappropriate sexual behavior, and are described as having a failure to consider the consequences of their actions [1,2]. Even though FASD individuals show high rates of crime, no direct measures of aggressive behaviors or testosterone in FAS individuals have been conducted. Animal models of FAS have examined the effect of different time periods of ethanol exposure on inter-male aggression. Ethanol exposure throughout the entire gestation
period in mice results in an increase in aggression [3 –6]; ethanol exposure from gestation day (GD) 6 to 19 increases offensive aggression in rats [7]. Ethanol exposure during the last four days of pregnancy and from postnatal day (PD) 1 to PD 4 increases aggression, while ethanol exposure confined to the period from PD 1 to 4 did not affect aggressive behavior in mice [8]. However, another study found that ethanol exposure from birth until PD 14 decreases aggression in mice [6]. These studies suggest that prenatal ethanol exposure may increase aggression, while postnatal ethanol exposure may decrease aggression. However, many of the early studies used ethanol administration procedures that were confounded by nutritional effects [4 –6,8] or resulted in minimal transfer of ethanol to the pup [6]. The effect of ethanol exposure during the entire gestation period and during early postnatal development (i.e. a period equivalent to all the trimesters in the human) on aggression has not been previously examined.
0031-9384/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2005.10.
- Corresponding author. Department of Psychology, University of South Carolina, Columbia, SC 29208, USA. Tel.: +1 803 777 7610; fax: +1 803 777
E-mail address: [email protected] (S.J. Kelly).
Physiology & Behavior 87 (2006) 330 – 337
Prenatal ethanol exposure produces a feminizing effect on male sexual behavior, which is believed to result from de- creased testosterone levels [9]. Ethanol exposure from GD 12 to PD 10 decreases testosterone in male rats on PD 55 and PD 110 [10]. Ethanol exposure from GD 10 to 19 augments testosterone levels in male rats on GD 18 and 19 [11] and suppresses it during the early postnatal period [12]. Low levels of testosterone during development and/or during adulthood have been shown to result in low levels of offensive inter-male aggression in rats and mice [13– 16]. Thus, the ethanol-induced suppression of testosterone during both the early postnatal period and adulthood suggests that a decrease in inter-male aggression in adulthood should be observed in ethanol-exposed rats [13,16,17]. In the present study, rats were exposed to ethanol during a period that is equivalent to the three trimesters of human prenatal development [18]. This exposure period consists of GD 1 through 22 and PD 2 through 10. This exposure period reflects the drinking pattern of a mother likely to produce an offspring with FASD [19,20]; it has been shown that if a woman stops drinking prior to her third trimester (equivalent to the early postnatal period in the rat), the cognitive effects of the ethanol exposure on the offspring are ameliorated [19]. Furthermore, ethanol given during all three trimester equiva- lents in rats can have behavioral and neural effects that are not easily predicted from the effects of shorter periods of ethanol exposure [21,22], making it important to use the extended exposure period in order to enhance generalizability to the human condition. Because changes in testosterone can result in changes in aggressive behavior [13,15], it was hypothesized that ethanol exposure during the three-trimester equivalent period would decrease both offensive aggression and testos- terone levels in male Long– Evans rats tested as residents in the resident/intruder paradigm [23]. Three different housing con- ditions (which included housing with a male, with a pregnant female, and with a female and pups) for the rats were used because the different housing conditions result in different levels of aggression [15] thus increasing the possibility of detecting differences in aggression across groups and giving contextual specificity for any changes in aggression. In addition, it was hypothesized that the decrease in offensive aggression in the ethanol-exposed animals should also be reflected in a decrease in defensive behavior in the intruder males.
- Subjects and methods
1.1. Subjects
Animal facilities were accredited by the American Associ- ation of Laboratory Animal Care (AALAC), and all procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of South Carolina. All animals were housed in the animal colony of the Department of Psychology at the University of South Carolina. The colony was maintained at 22 - C with a 12 : 12 h light : dark cycle, which began at 0800 h. Female Long –Evans rats (Harlan)
were housed overnight with proven breeder Long – Evans males. Vaginal smears were conducted the following morning to check for the presence of sperm. The first day on which sperm was detected on the smear was designated gestational day (GD) 1. On GD 1, dams were individually housed in polypropylene cages with wood shavings and assigned to a treatment group. Three treatment groups were used in this study: ET (ethanol-treated), IC (intubated control), and NC (nontreated control).
1.2. Prenatal treatment
Ethanol administration to dams was performed from GD 1 through GD 22 in the latter half of the light cycle. ET dams were weighed daily and received daily intragastric intubations of ethanol (4.5 g/kg) in a volume of 20 ml/kg of distilled water from GD 1 to 22. Intubations consisted of insertion of a stainless steel gavage tube down the esophagus of the rat and injection of the ethanol dose directly into the stomach. The tube was dipped in corn oil to provide lubrication. ET dams also were given ad libitum access to water and rat chow. The rat chow was weighed daily to monitor food intake. An isocaloric maltose – dextrin solution in a volume of 20 ml/kg was administered to IC dams every day during gestation (GD 1– 22) through intragastric intubation. IC dams were pair-fed to an ET dam matched for gestational day and body weight on GD 1. The handling time for the intubation procedures was 2 to 5 min. The NC dams were weighed daily, but did not receive any other treatments. Three hours after intubations on GD 20, 10 Al of blood were collected from ET and IC dams via a nick to the tail. The blood samples from the ET dams were processed for determination of peak blood ethanol concentra- tions (BECs). No blood was taken from NC dams. The day of birth (GD 23) was designated postnatal day (PD) 1. Neither the dams nor the pups received any treatment on this day.
1.3. Postnatal treatment
Litters were culled to 10 pups (5 male, 5 female) whenever possible. On PD 2 through PD 10, pups from all groups were removed from the nest one at a time and weighed, marked with nontoxic marker for identification, and intubated (ET and IC groups). All pup intubations were performed using PE 10 Intramedic tubing dipped in corn oil for lubrication and conducted in the latter half of the light cycle. ET pups received a 3.0 g/kg dose of ethanol in a volume of 27.8 ml/kg milk [24]. Two hours after the ethanol administration, ET pups were intubated a second time with the milk solution only (27.8 ml/ kg) to compensate for any reduction in milk intake due to intoxication. The milk solution was formulated to simulate dam’s milk [24]. The IC pups received the same procedure (two intubations) as the ET pups with PE 10 Intramedic tubing dipped in corn oil, but no solutions were administered. The postnatal procedure duration was approximately 2 min for each pup, and every effort was made to reduce the time of separation between the pup and the dam. The NC pups were weighed and handled only once daily in the latter half of the light cycle from
Dam body weights on GD 1 through GD 22 were analyzed using a repeated measures analysis of variance (ANOVA). Only a main effect of gestational day [ F(21, 1029) = 295.0; P < .001] was found indicating a normal increase in weight due to pregnancy for all groups. Body weights of the dams on GD 1, 5, 10, 15, 20 and 22 are shown in Table 1. A repeated measures ANOVA on the body weights on PD 2 through 10 of those animals tested in the current study indicated significant main effects of group [ F(2, 49) = 24.9; P < .001] and day [ F(8, 292) = 1907; P < .001) and a signifi- cant interaction of group and day [ F(8, 392) = 1907; P < .001]. In general, ET animals weighed less than the IC and NC animals (Tukey’s HSD test: Ps < 0.05) and all animals gained weight from PD 2 through 10. Further analyses of simple main effects followed by Tukey’s HSD tests indicated that the ET animals weighed significantly less that the IC and NC animals, which did not differ from each other, on PD 2 through PD 10 [ Ps < .05]. A repeated measures ANOVA on the body weights on PD 21, 30, 60 and 90 of those animals tested in the current study revealed a significant main effect of postnatal day [ F(3, 147) = 3377; P < .001] (indicating weight gain) but no effect of or interaction with group. Body weight data of the offspring on PD 2, 10, 21, 30, 60 and 90 are depicted in Table 2.
2.2. Blood ethanol concentrations
Average BECs and standard error of the means (SEMs) of the dams and pups were 310 T 21 and 265 T 23 mg/dl, respectively. There was no significant difference between dam and pup BECs.
2.3. Aggression tests
The resident experimental males exposed to ethanol showed reduced offensive aggression when housed with a female and pups and did not show changes in non-aggressive social behavior compared to the control males (see Fig. 1). A repeated measures ANOVA on the offensive behaviors of the resident experimental males across housing conditions indicated an interaction between housing condition and group [ F(4, 98) = 4.9; P < .01]. Analyses of simple main effects on each condition
indicated a significant effect of group only when the testing was done on experimental animals housed with a female and her pups [ F(2, 49) = 5.8; P < .01]. This effect was due to the ET males exhibiting less offensive aggression than either the IC or NC males (Tukey’s HSD; Ps < 0.05). The IC and NC males did not differ from each other. A repeated measures ANOVA on non-aggressive social behavior of the resident experimental males across housing conditions revealed no significant effects (see Table 3). There was not enough defensive aggression by the resident experimental males to yield a valid analysis; this data is shown in Table 3. Biting, which was a behavior that was included in the category of offensive aggression, was examined separately. None of the 16 ET animals in any of the housing conditions engaged in biting. In contrast within the IC group of 19 animals, there were 3, 2, and 1 animal(s) which ended an aggression test session by biting when housed with a male, with a pregnant female, or with a female and pups, respectively. With the NC group of 17 animals, there were 2, 3 and 6 animals which ended an aggression test session by biting when housed with a male, with a pregnant female or with a female and pups, respectively. It is clear that the reduction in offensive aggression by the ET group could not result from a shorter period of observation that would result from a quick latency to a bite (since there were no bites by members of this group). The complete lack of biting in the ET group is consistent with our finding of lower levels of offensive aggression generally. The pattern of findings in the intruder males reflected that seen in the resident males except that the reduction was observed in defensive aggression. A repeated measuresANOVA on the defensive aggressive behaviors of the intruder males across housing conditions indicated an interaction between housing condition and group [ F(4, 98) = 3.80; P < .05]. Analy- ses of simple main effects on each condition indicated a significant effect of group only when the testing was done on intruders tested with an experimental animal housed with a female and her pups [ F(2, 49) = 4.76; P < .05]. Intruders tested
Table 1 Mean body weights of dams (g) and SEMs
Group Gestational day 1 5 10 15 20 22
ET 263.0 T 1.1 271.1 T1.3 285.1 T1.3 307.1 T1.1 358.0 T 3.3 364.9 T 1. IC 258.7 T 1.0 261.7 T 0.8 272.0 T 0.8 288.8 T 0.7 328.4 T 1.0 346.7 T 1. NC 255.8 T 0.8 257.6 T 0.9 267.9 T 0.7 288.1 T 0.7 329.7 T 1.0 350.1 T1.
Table 2 Mean body weights of the experimental animals (g) and SEMs
Group PD 2 PD 10 PD 21 PD 30 PD 60 PD 90
ET 6.3 T 0.3 18.4 T 0.6 48.2 T 1.2 93.5 T 1.9 310.0 T 1.3 431.6 T 1. IC 7.1 T 0.2 20.2 T 0.3 47.8 T 0.6 107.8 T 5.4 324.4 T 1.0 452.5 T 1. NC 7.4 T 0.2 20.8 T 0.5 46.3 T 0.9 94.6 T 0.6 320.0 T 1.6 435.3 T 1.
0
10
20
30
40
50
60
70
80
Housed with Male Housed with Pregnant Dam
Housed with Dam and Pups
Duration (sec)
NC IC ET
Fig. 1. Duration of offensive aggression in resident experimental males across housing conditions. The star indicates a significant difference between the ET group and the control groups in that condition. Error bars represent standard error of the mean (SEM).
with ET males exhibited less defensive aggression than intruders tested with either the IC or NC males (Tukey’s HSD; Ps < .05), which did not differ from each other (see Fig. 2). A repeated measures ANOVA on non-aggressive social behaviors of the intruder males across housing conditions revealed no significant effects (see Table 3). There was not enough offensive aggression by the intruder males to yield a valid analysis and none of the intruder animals exhibited any biting in any test session. These data are shown in Table 3.
2.4. Pain sensitivity
An ANOVA on the average tail flick latencies revealed no significant effect of group. Average tail flick latencies and SEMs for the ET, IC and NC groups were 2.74 T 0.21, 2.16 T 0.23, and 3.02 T 0.35, respectively.
2.5. Testosterone levels
A univariate ANOVA on the testosterone levels indicated a main effect of group [ F(2, 49) = 21.2; P < .05]. The testosterone
levels in the ET animals were significantly lower than those in the IC and NC animals (Tukey’s HSD; Ps < .05) (see Fig. 3). The correlation of testosterone levels to offensive aggression is 0.25, which is a small but significant ( P < 0.05) relationship.
- Discussion
The results confirm the original hypotheses. This study found that ethanol exposure during a period equivalent to three trimesters of human development reduced offensive aggression in a resident/intruder paradigm and reduced testosterone levels in male rats compared to both controls groups. A non- experimental intruder tested with ethanol-exposed males showed a concomitant decrease in defensive behavior compared to both control groups. Non-aggressive social behaviors and pain sensitivity did not differ among groups. The reduction of inter-male aggression by ethanol exposure compared to both control groups has to our knowledge only been found in mice [6]. The reduction of aggression may critically depend upon the exposure period; Yanai and Ginsburg [6] found a decrease in aggression following postnatal exposure, whereas studies using prenatal exposure periods found an increase in aggression [4 –7]. Administration of ethanol during a combined prenatal and postnatal period
Table 3 Social behavior other than aggression, defensive aggression by the resident animals, and offensive aggression by the intruder animals
Duration of social behaviors other than aggression (mean T SEM (s))
Resident animals showing defensive aggression or Intruder animals showing offensive aggression (%) Housing with Housing with Male Pregnant female
Female and pups
Male Pregnant female
Female and pups Resident groups ET 12.5 T 2.5 19.4 T 3.6 17.8 T 2.4 25.0 18.7 0. IC 14.7 T 4.6 13.6 T 1.6 15.2 T 2.2 15.8 5.3 5. NC 11.9 T 2.1 16.9 T 2.8 21.4 T 3.2 23.5 23.5 23.
Intruder groups ET 9.7 T 1.9 6.9 T 1.4 4.1 T1.0 25.0 25.0 6. IC 6.9 T 1.5 5.6 T 1.3 11.0 T 4.8 21.0 26.3 5. NC 9.6 T 2.6 6.6 T 1.6 5.1 T1.1 23.5 35.3 29.
0
10
20
30
40
50
60
70
80
Housed with Male Housed with Pregnant Dam
Housed with Dam and Pups
Duration (sec)
NC IC ET
Fig. 2. Duration of defensive aggression in intruder males across housing conditions. The group and housing condition of the intruder male is determined by the status of the resident experimental animal. The star indicates a significant difference between the ET group and the control groups in that condition. Error bars represent SEM.
1.
1.
1.
1.
1.
2.
2.
2.
2.
2.
NC IC ET
Plasma Testosterone (ng/ml)
Fig. 3. Plasma testosterone levels in experimental animals. The star indicates a significant difference between the ET group and the control groups. Error bars represent SEM.
animal models of FASD are needed to more fully delineate the nature of the social abnormalities induced by ethanol exposure during development.
Acknowledgements
The authors would like to acknowledge the technical assistance of Melissa K. Reese, Eric Heape, and Kris Ford. J. N. Lugo, Jr. was funded by a predoctoral fellowship AA from NIH. The research was funded by NIH grants RO AA11566 to S.J.K and RO1 MH63344 to M.A.W.
References
[1] Streissguth AP, Barr AM, Kogan FL, Bookstein FL. Understanding the occurrence of secondary disabilities in clients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE), Final report to the Centers for Disease Control and Prevention (CDC). Seattle’ University of Washington, Fetal Alcohol and Drug Unit, Tech. Rept.; 1996. [2] Streissguth AP, O’Malley K. Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders. Semin Clin Neuropsy- chiatry 2000;5:177 – 90. [3] Albert DJ, Chew GL. The septal forebrain and the inhibitory modulation of attack and defense in the rat. A review. Behav Neural Biol 1980; 30:357 – 88. [4] Elis J, Krxiak M. Effect of alcohol administration during pregnancy on social behaviour of offspring of mice. Act Nerv Super 1975;17:281 – 2. [5] Krxiak M, Elis J, Po¨ schlova´ N, Maxek K. Increased aggressiveness and lower brain serotonin levels in offspring of mice given alcohol during gestation. J Stud Alcohol 1977;38:1696 – 704. [6] Yanai J, Ginsburg BE. A developmental study of ethanol effects on behavioural and physical development in mice. Alcohol, Clin Exp Res 1977;1:325 – 33. [7] Royalty J. Effects of prenatal ethanol exposure on juvenile play-fighting and postpubertal aggression in rats. Psychol Rep 1990;66:551 – 60. [8] Brain PF, Ajarem JS, Petkov VV. The utility of ethological assessments of murin agonistic interactions in behavioural teratology: the fetal alcohol syndrome. In: Olivier B, Mos J, Brain F, editors. Ethopharmacology of agonistic behaviour in animals and humans. Boston’ Martinus Nijhoff Publishers, 1987. p. 110 – 21. [9] Ward IL, Ward OB, Winn RJ, Bielawski D. Male and female sexual behavior potential of male rats prenatally exposed to the influence of alcohol, stress, or both factors. Behav Neurosci 1994;108:1188 – 95. [10] Udani M, Parker S, Gavaler J, VanThiel DH. Effects of in utero exposure to alcohol upon male rats. Alcohol, Clin Exp Res 1985;9:355 – 259. [11] Ward IL, Ward OB, Affuso JD, Long III WD, French JA, Hendricks SE. Fetal testosterone surge: specific modulations induced in male rats by maternal stress and/or alcohol consumption. Horm Behav 2003;43: 531 – 9. [12] Ward OB, Ward IL, Denning JH, French JA, Hendricks SE. Postparturi- tional testosterone surge in male offspring of rats stressed and/or fed ethanol during late pregnancy. Horm Behav 2002;41:229 – 35. [13] Albert DJ, Walsh ML, Gorzalka BB, Siemens Y, Louie H. Testosterone removal in rats results in a decrease in social aggression and loss of social dominance. Physiol Behav 1986;36:407. [14] Debold JF, Miczek KA. Sexual dimorphism in the hormonal control of aggressive behavior in rats. Pharmacol Biochem Behav 1981;14: 89 – 93. [15] Miczek KA, Debold JF, Thompsonk ML. Pharmacological, hormonal, and behavioral manipulations in analysis of aggressive behavior. Prog Clin Biol Res 1984;167:1 – 26. [16] vom Saal FS, Svare B, Gandelman R. Time of neonatal androgens exposure influences length of testosterone treatment required to induce aggressiveness in adult male and female mice. Behav Biol 1976;17: 391 – 7.
[17] Edwards DA. Early androgen stimulation and aggressive behavior in male and female mice. Physiol Behav 1969;4:333 – 8. [18] Bayer SA, Altman J, Russo RJ, Zhang X. Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology 1993;14:83 – 144. [19] Rosett H. The effects of alcohol on the fetus and offspring. In: Kalant OJ, editor. Alcohol and drug problems in women. Research advances in alcohol and drug problems. New York’ Plenum Press, 1980. p. 595 – 652. [20] Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980; 209:353 – 61. [21] Cronise K, Marino MD, Tran TD, Kelly SJ. Critical periods for the effects of alcohol exposure on learning in rats. Behav Neurosci 2001; 115:138 – 45. [22] Tran TD, Cronise K, Marino MD, Jenkins WJ, Kelly SJ. Critical periods for the effects of alcohol exposure on brain weight, body weight, activity, and investigation. Behav Brain Res 2000;116:99 – 110. [23] Miczek KA. A new test of aggression for aggression in rats without aversive stimulation: differential effects of d-amphetamine and cocaine. Psychopharmacology 1979;60:253 – 9. [24] West JR, Hamre KM, Pierce DR. Delay in brain growth induced by alcohol in artificially reared rat pups. Alcohol 1984;1:213 – 22. [25] Bonthius DJ, West JR. Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure. Alcohol, Clin Exp Res 1990;14:107 – 18. [26] Pierce DR, West JR. Blood alcohol concentration: a critical factor for producing fetal alcohol effects. Alcohol 1986;3:269 – 72. [27] Marino MD, Cronise K, Lugo Jr JN, Kelly SJ. Ultrasonic vocalizations and maternal – infant interactions in a rat model of Fetal Alcohol Syndrome. Dev Psychobiol 2002;41:341 – 51. [28] Brien JF, Clarke DW, Richardson BPJ. Disposition of ethanol in maternal blood, fetal blood and amniotic fluid of third-trimester pregnant ewes. Am J Obstet Gynecol 1985;152:583 – 90. [29] Dudek BC, Abbott ME. A biometrical genetic analysis of ethanol response in selectively bred long-sleep and short-sleep mice. Behav Genet 1984;14:1 – 19. [30] Kelly SJ, Franklin KB. Role of peripheral and central opioid activity in analgesia induced by restraint stress. Life Sci 1987;41:789 – 94. [31] Tran TD, Kelly SJ. Critical periods for ethanol-induced cell loss in the hippocampal formation. Neurotoxicol Teratol 2003;25:519 – 28. [32] Kelly SJ, Dillingham RR. Sexually dimorphic effects of perinatal alcohol exposure on social interactions and amygdala DNA and DOPAC concentrations. Neurotoxicol Teratol 1994;16:377 – 84. [33] Dalterio S, Bartke A, Blum K, Sweeney C. Marihuana and alcohol: perinatal effects on development of male reproductive functions in mice. Prog Biochem Pharmacol 1981;18:143 – 54. [34] Niikura S, Yokoyama O, Komatsu K, Yotsuyanagi S, Mizuno T, Namiki M. A causative factor of copulatory disorder in rats following social stress. J Urol 2002;168:843 – 9. [35] Nock BL, Leshner AI. Hormonal mediation of the effects of defeat on agonistic responding in mice. Physiol Behav 1976;17:111 – 9. [36] McGivern RF, Handa RJ, Raum WJ. Ethanol exposure during the last week of gestation in the rat: inhibition of the prenatal testosterone surge in males without long-term alterations in sex behavior. Neurotoxicol Teratol 1998;20:483 – 90. [37] Meyer LS, Riley EP. Social play in juvenile rats prenatally exposed to alcohol. Teratology 1986;34:1 – 7. [38] Dahlgren IL, Matuszczyk JV, Ha˚rd E. Sexual orientation in male rats prenatally exposed to ethanol. Neurotoxicol Teratol 1991;13:267 – 9. [39] Ha˚rd E, Dahlgren IL, Engel J, Larsson K, Liljequist S, Lindh A-S, Musi B. Development of sexual behavior in prenatally ethanol-exposed rats. Drug Alcohol Depend 1984;14:51 – 61. [40] Kruk MR, van der Lann CE, Mos J, van der Poel AM, Meelis W, Olivier B. Comparison of aggressive behavior induced by electrical stimulation in the hypothalamus of male and female rats. Prog Brain Res 1984;61:303 – 14. [41] Ward OB, Ward IL, Denning JH, Hendricks SE, French JA. Hormonal mechanisms underlying aberrant sexual differentiation in male rats
prenatally exposed to alcohol, stress or both. Arch Sex Behav 2002;31: 9 – 16. [42] Aikey JL, Nyby JG, Anmuth DM, James PJ. Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Hormones Behav 2002;42:448 – 60.
[43] Edinger KL, Frye CA. Testosterone’s analgesic, anxiolytic, and cognitive- enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus. Behav Neurosci 2004;118:1352 – 64. [44] King JA, De Oliveira WL, Patel N. Deficits in testosterone facilitate enhanced fear response. Psychoneuroendocrinology 2005;30:333 – 40.
