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Influence of Early Postnatal Gonadal Hormones on Anxiety in Adult Male Rats
Physiology& Behavior,Vol.60, No. 6, pp. 1419-1423, 1996 CopyrightO 1996Eisevier +
Influenceof EarlyPostnatalGonadalHormones on Anxietyin AdultMale Rats ALDO B. LUCION,] HELENICE CHARCHAT, GABRIELA A. M. PEREIRA AND ALBERTO A. RASIA-FILHO Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil Received 15 August 1995 LUCION, A. B., H. CHARCHAT, G. A. M. PEREIRA AND A. A. RASIA-FILHO. Injiuence of early postnatal gonadal horrrrones on anxiety in adult male rats. PHYSIOL BEHAV 60(6) 1419– 1423, 1996.—Behavioral sex differences have been linked to the presence of testosterone secretion during a critical perinatal period. The present experiment tested whether or not castration at different ages (early postnatal period and adulthood) would alter performance in the plus maze, a behavioral test of anxiety. Intact adult male rats (n = 17) were compared to intact adult females (n = 17); adult castrated males (n = 7) to sham-operated adult male rats (n = 9); and newborn castrated males (n = 7) to sham-operated male offspring (n = 8). When adult, the subjects were left on an elevated plus maze for 5 min. Females made a higher percentage of entries onto the open arms and showed a greater number of scans over the edge of an open arm than males. There were no differences in the percentage of arm entries or time spent on the open arms when adult castrated males were compared to sham-operated rats. On the other hand, newborn castrated males showed a significantly higher number of open arm entries and spent a greater percentage of time on the open arms than sham-operated offspring. The results demonstrate that the absence of male gonadal hormones during the perinatal period decreases anxiety, as assessed in the elevated plus maze, leading to a behavioral pattern that resembles that of females. These data provide evidence for the organizational role of gonadal hormones in the development of behavioral inhibitory systems. Copyright O 1996 Elsevier Science Inc. Anxiety Sex differences Gonadal hormones
Elevated plus maze
Neonatal castration
Brain development
Testosterone
a
a ( ( a ( a
a
( a
( (
a
‘ Requests for reprints should be addressed to Aldo B. Lucion, Fisiologia, Biociencias, UFRGS, Sarmento Leite 500, Porto Alegre, RS 90050-170, Brazil. E-mail: ALUCION62VORTEX.UFRGS.BR
~FEMALE
70 60
* T
50 z ~ z g N
a
h
40 -
hill *
30 20 10 0ENTRIES
TIME
CLOSEO
TOTAL
1. Mean percentage (k SEM) of time spent on the open arms, percentage of entries onto the open arms, number of entries onto the closed arms, and total number of arm entries of intact adult male (MALE, n = 17) md adult female rats (FEMALE, n = 17) in the elevated phrs maze during a 5-rein test. * Significantly different from MALE, p <
StatisticalAnalysis
FIG.
(
X
(
X
+
+ A
0.05.
( RESULTS
a a a 1
Subjects
a a (p =
a
h
Apparatus 70
X
USHAM
GDX
DADULT
GDX
*
60 -
W a
50 WI x % 40 z ko 30 -
Procedure (n =
N
= =
* 20 10 -
= =
0-
(n =
ENTRIES
a 6h a
TIME
d CLOSED
~ TOTAL
FIG. 2. Mean percentage (~ SEM) of time spent on the open arms, percentage of entries onto the open arms, number of entries onto the closed arms, and total number of arm entries of adult sharn-gonadectomized rats (SHAM GDX, n = 9) and adult gonadectomized males (ADULT GDX, n = 7) in the elevated plus maze during a 5-tnin test. * Significantly different from adult p <0.05.
OSHAM
GDx
~
iety (8,17),
NEONATAL GDX
70 -
a
60 -
m > %
z g
*
T
50 40 30 -
N
5
d
20 10 0TIME
ENTRIES
!lll
a
CLOSED
a
TOTAL
FIG. 3. Mean uercenta~e (t SEM) of time spent on the oPen WUM, percentage of ~ntries o~to the open arms, number of entries onto the closed arms, and total number of arm entries of sham-gonadectomized offspring (SHAM GDX, n = 8) and neonatal gonadectomized males (NEONATAL GDX, n = 7) in a plus maze during a 5-rein test. * Significantly different from neonatal SHAM GDX, p <0.05.
a
5 a a a a
a a
a
a a a &
t
p < a
a
a A
a a a
a
OMALE
~FEMALE
n9iAbI
25
1
*
*
u
w m x z
* z 5
5
5
0
0 SCAN
RISK
0 SCAN
RISK
4
RISK
FIG. 4. Mean (t SEM) number of scanning over the edge of an open arm (SCAN) and frequency of risk-assessment behavior (RISK) of intact adult males (MALE, n = 17); adult females (FEMALE, n = 17); adult sham-gonadectomized males (SHAM GDX, n = 7); adult gonadectomized mates (ADULT GDX, n = 9); neonatat sham-gonadectornized males (SHAM GDX, n = 7) and neonatal gonadectomized males (NEO GDX, n — 8) in the elevated plus maze test during a 5-rein test. * Significantly different from MALE or from neonatal SHAM GDX, p <0.05.
a
a ( 8)
a ( a a ( a ( a (
a a
( ( a
a
(
a
(
a 6 h
A. P.; Breedlove, S. M. Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Hortn. Behav. 19:469–498; 1985. 2. Becker, J. B. HorrnonaI influences on extrapyrarnidal sensorimotor function and hippocampal plasticity. In: Becker, J. B.; Breedlove,
The authors thank Dr. R. J. Blanchard (Department of Psychology, University of Hawaii, USA) for valuable advice and discussions on the design of this experiment. This study was supported by grants from the CNPq, FAPERGS, and FINEP.
S. M.; Crews, D., ed. Behavioral Endocrinology. Massachusetts: MIT Press; 1992:325–356. 3. Bemardi, M.; Genedani, S.; Tagliavini, S.; Bertolini, A. Effect of castration and testosterone in experimented models of depression in mice. Behav. Neurosci. 103:1148– 1150; 1989.
4. Blanchard, D. C.; Blanchard, R. J.; Rodgers, R. J. Risk assessment and animal models of anxiety. In: Olivier, B.; Mos, J.; Slangen, J. L., ed. Animal Models in Psychopharmacology. Basel:,Birkhauser; 1991:117– 134. 5. Blanchard, D. C.; Shepherd, J. K.; Carobrez, A. P.; Blanchard, R. J. Sex effects in defensive behavior: baseline differences and drug interactions. Neurosci. Biobehav. Rev. 15:461–468; 1991. 6. Blizard, D. A.; Lippman, H. R.; Chen, J. J. Sex differences in openfield behavior in the rat:the inductive and activational role of gonadal hormones. Physiol. Behav. 14:601-608; 1975. 7. Bradwejn, J.; Koszycki, D. The cholecystokinin hypothesis of anxiety and panic disorder. Ann. N.Y. Acad. Sci. 713:273–282; 1994. 8. Cruz, A. P. M.; Frei, F.; Graeff, F. G. Ethophmmacological analysis of rat behavior on the elevated plus-maze. Pharrnacol. Biochem. Behav. 49:171–176; 1994. 9. Dawson, G. R.; Tnckfebank, M. D. Use of the elevated plus maze in the search for novel anxiolytic drugs. Trends Pharmacol. Sci. 16:33–36; 1995. 10. Farabollini, F.; File, S. E.; Johnston, A. L.; Wilson, C. A. An analysis of sex differences in the open field and tests of exploration and anxiety. Br. J. Pharrnacol. 90:263P; 1987. 11. Frankfurt, M.; Siegel, R. A.; Sire, I.; Wuttke, W. Cholecystokinin and substance P concentration in discrete areas of the rat brain: sex differences. Brain Res. 358:53-58; 1985. 12. Giulian, D.; Pohorecky, L. A.; McEwen, B. S. Effects of gonadal steroids upon brain 5-hydroxytryptarnine levels in the neonatal rat. Endocrinology 93:1329–1335; 1973. 13. Gladue, B. A.; Clemens, L. C. Development of feminine sexual behavior in the rat: androgenic and temporal influences. Physiol. Behav. 29:263–267; 1982. 14. Gorski, R. A.; Harlan, R. E.; Jacobson, C. D.; Shryne, J. E.; Southam, A. M. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J. Comp. Nenrol. 193:529–539; 1980. 15. Greenstein, B. Steroid hormone receptors in the brain. In: Lightman, S. L.; Everitt, B. J., ed. Neuroendocnnology. London: Blackwell; 1986:32–48. 16. Hansen, S. Hypothalamic control of motivation:tbe medial preoptic area and masculine sexual behavior of the rat. Scand. J. Psychol. 1:121–126; 1982. 17. Johnston, A. L.; File, S. E. Sex differences in animal tests of anxiety. Physiol. Behav. 49:245–249; 1991. 18. Joseph, R.; Hess, S.; Birecree, E. Effects of hormone manipulations and exploration on sex differences in maze learning. Behav. Biol. 24:364–377; 1978. 19. Kellogg, C. K.; Primus, R. J.; Bitran, D. Sexually dimorphic influence of prenatal exposure to diazepam on behavioral responses to environmental challenge and on gama-aminobutyric acid (GABA)stimulated chloride uptake in the brain. J. Pharmacol. Exp. Tber. 256:259-265; 1991. 20. Kelly, D. Sexual differentiation of the nervous system. In: Kandel, E.; Schwartz, J. H.; Jessell, T. M., ed. Principles of Neural Sciences. New York: Elsevier; 1991:959–973. 21. Lucion, A. B.; de Almeida, R. M. M. Role of the intruder in the aggressive behaviour of colonies of wild rats (Rams rwrvegicus). In: Olivier, B.; Mos, J.; Slangen, J. L., ed. Animal Models in Psychopharmacology. Base]: Birkhauser; 1991:347–356. 22. MacLusky, N. J.; Naftolin, F. Sexual differentiation of the central nervous system. Science 211: 1294– 1303; 1981. 23. Majewska, M. D. Steroid regulation of the GABAA receptor: ligand binding, chloride transport and behaviour. In: Chadwick, D.; Widdows, K., eds. Steroids and Neuronal Activity. CIBA Foundation Symposium 153. Chichester:John Wiley & Sons; 1990:83–106. 24. Malsbury, C. W.; McKay, K. Neurotropbic effects of testosterone
25. 26.
27. 28.
29. 30.
31. 32.
33. 34. 35. 36.
37. 38.
39. 40.
41. 42. 43.
on the medial nucleus of the amygdala in adult male rats. J. Neuroendocrinol. 6:57–69; 1994. Matsumoto, A. Sex steroid induction of synaptic reorganization in adult nenroendocrine brain. Rev. Neurosci. 3:287–306; 1992. McEwen, B. S. Endocrine effects on the brain and their relationship to behavior. In: Siegel, G. J.; Agranoff, B. W.; Alber, R. W.; Molinoff, P. B., eds. Basic Neurochemistry. New York: Raven Press; 1994:1003-1023. McEwen, B. S. How do sex and stress hormones affect nerve cells? Am. N.Y. Acad. Sci. 743:1– 18; 1994. McEwen, B. S.; Coirini, H.; Westlind-Danielsson, A.; Frankfurt, M.; Gould, E.; Schumacher, M.; Wooley, C. Steroid hormones as mediators of neural plasticity. J. Steroid Biochem. Mol. Biol. 39:223– 232; 1991. Nishizuka, M.; Arai, Y. Sexual dimorphism in synaptic organization in the amygdala and its dependence on neonatal hormone environment. Brain Res. 212:31 –38; 1981. Olivier, B.; Mos, J.; Tulp, M. Tb. M.; van der Peel, A. M. Animal models of anxiety and aggression in the study of serotonergic agents. In: Langer, S. Z.; Brnnello, N.; Mendlewiczf, J., eds. Serotonin receptor subtypes: pharmacological significance and clinical implications. Basel: Karger; 1992:80–88. Pellow, S.; Chopin, P.; File, S. E.; Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods 14:149–167; 1985. Rasia-Filho, A. A.; Peres, T. M. S.; Cubilla-Gutierrez, F. H.; Lucion, A. B. Effect of estradiol implanted in the corticomedial amygdala on the sexual behavior of castrated male rats. Braz. J. Med. Biol. Res. 24:1041–1049; 1991. Rodgers, R. J.; Cole, J. C. Influence of sociaf isolation, gender, strain, and prior novelty on plus-maze behaviour in mice. Phys. Behav. 54:729-736; 1993. Roselli, C. E. Sex differences in androgen receptors and aromatase activity in microdissected regions of the rat brain. Endocrinology 128:1310–1316; 1991. Segama, A. C.; McEwen, B. S. Estrogen increases spine density in ventromedial hypothalamic neurons of peripubertal rats. Neuroendocrinology 54:365-372; 1991. Shepherd, J. K.; Flores, T.; Rodgers, R. J.; Blanchard, R. J.; Blanchard, D. C. The anxiety ldefense test battery: influence of gender and ritansenn treatment on antipredator defensive behavior. Physiol. Behav. 51:277–285; 1992. Shepherd, J. K.; Rodgers, R. J.; Blanchwd, R. J.; Magee, L. K.; Blanchard, D. C. Ondansetron, gender and antipredator defensive behaviour. J. Psychopharmacol. 7:72-81; 1993. Shinoda, K.; Nagano, M.; Osawa, Y. Neuronal aromatase expression in preoptic, striatal, and amygdaloid regions during late prenatal and early postnatal development in the rat. J. Comp. Neurol. 343:113– 129; 1994. Silveira, M. C.; Sander, G.; Graeff, F. G. Induction of Fos immunoreactivity in the brain by exposure to the elevated plus-maze. Behav. Brain Res. 56:115-118; 1993. Steenberger, H. S.; Heinsbroek, R. P. W.; van Hest, A.; van de Poll, N. E. Sex-dependent effects of inescapable shock administration on shuttlebox-escape performance and elevated plus-maze behavior. Physiol. Behav. 48:571–576; 1990. Williams, C. L.; Barnett, A. L.; Meek, W. H. Organizational effects of early gonadal secretions on sexuaf differentiation in spatial memBehav. Neurosci. 104:84-97; 1990. Woolley, C. S.; McEwen, B. S. Role of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J. Comp. Neurol. 336:293–306; 1993. Zimmerberg, B.; Farley, M. J. Sex differences in anxiety behavior in rats:role of gonadal hormones. Physiol. Behav. 54:11 19– 1124; 1993.
Influenceof EarlyPostnatalGonadalHormones on Anxietyin AdultMale Rats ALDO B. LUCION,] HELENICE CHARCHAT, GABRIELA A. M. PEREIRA AND ALBERTO A. RASIA-FILHO Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil Received 15 August 1995 LUCION, A. B., H. CHARCHAT, G. A. M. PEREIRA AND A. A. RASIA-FILHO. Injiuence of early postnatal gonadal horrrrones on anxiety in adult male rats. PHYSIOL BEHAV 60(6) 1419– 1423, 1996.—Behavioral sex differences have been linked to the presence of testosterone secretion during a critical perinatal period. The present experiment tested whether or not castration at different ages (early postnatal period and adulthood) would alter performance in the plus maze, a behavioral test of anxiety. Intact adult male rats (n = 17) were compared to intact adult females (n = 17); adult castrated males (n = 7) to sham-operated adult male rats (n = 9); and newborn castrated males (n = 7) to sham-operated male offspring (n = 8). When adult, the subjects were left on an elevated plus maze for 5 min. Females made a higher percentage of entries onto the open arms and showed a greater number of scans over the edge of an open arm than males. There were no differences in the percentage of arm entries or time spent on the open arms when adult castrated males were compared to sham-operated rats. On the other hand, newborn castrated males showed a significantly higher number of open arm entries and spent a greater percentage of time on the open arms than sham-operated offspring. The results demonstrate that the absence of male gonadal hormones during the perinatal period decreases anxiety, as assessed in the elevated plus maze, leading to a behavioral pattern that resembles that of females. These data provide evidence for the organizational role of gonadal hormones in the development of behavioral inhibitory systems. Copyright O 1996 Elsevier Science Inc. Anxiety Sex differences Gonadal hormones
Elevated plus maze
Neonatal castration
Brain development
Testosterone
a
a ( ( a ( a
a
( a
( (
a
‘ Requests for reprints should be addressed to Aldo B. Lucion, Fisiologia, Biociencias, UFRGS, Sarmento Leite 500, Porto Alegre, RS 90050-170, Brazil. E-mail: ALUCION62VORTEX.UFRGS.BR
~FEMALE
70 60
* T
50 z ~ z g N
a
h
40 -
hill *
30 20 10 0ENTRIES
TIME
CLOSEO
TOTAL
1. Mean percentage (k SEM) of time spent on the open arms, percentage of entries onto the open arms, number of entries onto the closed arms, and total number of arm entries of intact adult male (MALE, n = 17) md adult female rats (FEMALE, n = 17) in the elevated phrs maze during a 5-rein test. * Significantly different from MALE, p <
StatisticalAnalysis
FIG.
(
X
(
X
+
+ A
0.05.
( RESULTS
a a a 1
Subjects
a a (p =
a
h
Apparatus 70
X
USHAM
GDX
DADULT
GDX
*
60 -
W a
50 WI x % 40 z ko 30 -
Procedure (n =
N
= =
* 20 10 -
= =
0-
(n =
ENTRIES
a 6h a
TIME
d CLOSED
~ TOTAL
FIG. 2. Mean percentage (~ SEM) of time spent on the open arms, percentage of entries onto the open arms, number of entries onto the closed arms, and total number of arm entries of adult sharn-gonadectomized rats (SHAM GDX, n = 9) and adult gonadectomized males (ADULT GDX, n = 7) in the elevated plus maze during a 5-tnin test. * Significantly different from adult p <0.05.
OSHAM
GDx
~
iety (8,17),
NEONATAL GDX
70 -
a
60 -
m > %
z g
*
T
50 40 30 -
N
5
d
20 10 0TIME
ENTRIES
!lll
a
CLOSED
a
TOTAL
FIG. 3. Mean uercenta~e (t SEM) of time spent on the oPen WUM, percentage of ~ntries o~to the open arms, number of entries onto the closed arms, and total number of arm entries of sham-gonadectomized offspring (SHAM GDX, n = 8) and neonatal gonadectomized males (NEONATAL GDX, n = 7) in a plus maze during a 5-rein test. * Significantly different from neonatal SHAM GDX, p <0.05.
a
5 a a a a
a a
a
a a a &
t
p < a
a
a A
a a a
a
OMALE
~FEMALE
n9iAbI
25
1
*
*
u
w m x z
* z 5
5
5
0
0 SCAN
RISK
0 SCAN
RISK
4
RISK
FIG. 4. Mean (t SEM) number of scanning over the edge of an open arm (SCAN) and frequency of risk-assessment behavior (RISK) of intact adult males (MALE, n = 17); adult females (FEMALE, n = 17); adult sham-gonadectomized males (SHAM GDX, n = 7); adult gonadectomized mates (ADULT GDX, n = 9); neonatat sham-gonadectornized males (SHAM GDX, n = 7) and neonatal gonadectomized males (NEO GDX, n — 8) in the elevated plus maze test during a 5-rein test. * Significantly different from MALE or from neonatal SHAM GDX, p <0.05.
a
a ( 8)
a ( a a ( a ( a (
a a
( ( a
a
(
a
(
a 6 h
A. P.; Breedlove, S. M. Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Hortn. Behav. 19:469–498; 1985. 2. Becker, J. B. HorrnonaI influences on extrapyrarnidal sensorimotor function and hippocampal plasticity. In: Becker, J. B.; Breedlove,
The authors thank Dr. R. J. Blanchard (Department of Psychology, University of Hawaii, USA) for valuable advice and discussions on the design of this experiment. This study was supported by grants from the CNPq, FAPERGS, and FINEP.
S. M.; Crews, D., ed. Behavioral Endocrinology. Massachusetts: MIT Press; 1992:325–356. 3. Bemardi, M.; Genedani, S.; Tagliavini, S.; Bertolini, A. Effect of castration and testosterone in experimented models of depression in mice. Behav. Neurosci. 103:1148– 1150; 1989.
4. Blanchard, D. C.; Blanchard, R. J.; Rodgers, R. J. Risk assessment and animal models of anxiety. In: Olivier, B.; Mos, J.; Slangen, J. L., ed. Animal Models in Psychopharmacology. Basel:,Birkhauser; 1991:117– 134. 5. Blanchard, D. C.; Shepherd, J. K.; Carobrez, A. P.; Blanchard, R. J. Sex effects in defensive behavior: baseline differences and drug interactions. Neurosci. Biobehav. Rev. 15:461–468; 1991. 6. Blizard, D. A.; Lippman, H. R.; Chen, J. J. Sex differences in openfield behavior in the rat:the inductive and activational role of gonadal hormones. Physiol. Behav. 14:601-608; 1975. 7. Bradwejn, J.; Koszycki, D. The cholecystokinin hypothesis of anxiety and panic disorder. Ann. N.Y. Acad. Sci. 713:273–282; 1994. 8. Cruz, A. P. M.; Frei, F.; Graeff, F. G. Ethophmmacological analysis of rat behavior on the elevated plus-maze. Pharrnacol. Biochem. Behav. 49:171–176; 1994. 9. Dawson, G. R.; Tnckfebank, M. D. Use of the elevated plus maze in the search for novel anxiolytic drugs. Trends Pharmacol. Sci. 16:33–36; 1995. 10. Farabollini, F.; File, S. E.; Johnston, A. L.; Wilson, C. A. An analysis of sex differences in the open field and tests of exploration and anxiety. Br. J. Pharrnacol. 90:263P; 1987. 11. Frankfurt, M.; Siegel, R. A.; Sire, I.; Wuttke, W. Cholecystokinin and substance P concentration in discrete areas of the rat brain: sex differences. Brain Res. 358:53-58; 1985. 12. Giulian, D.; Pohorecky, L. A.; McEwen, B. S. Effects of gonadal steroids upon brain 5-hydroxytryptarnine levels in the neonatal rat. Endocrinology 93:1329–1335; 1973. 13. Gladue, B. A.; Clemens, L. C. Development of feminine sexual behavior in the rat: androgenic and temporal influences. Physiol. Behav. 29:263–267; 1982. 14. Gorski, R. A.; Harlan, R. E.; Jacobson, C. D.; Shryne, J. E.; Southam, A. M. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J. Comp. Nenrol. 193:529–539; 1980. 15. Greenstein, B. Steroid hormone receptors in the brain. In: Lightman, S. L.; Everitt, B. J., ed. Neuroendocnnology. London: Blackwell; 1986:32–48. 16. Hansen, S. Hypothalamic control of motivation:tbe medial preoptic area and masculine sexual behavior of the rat. Scand. J. Psychol. 1:121–126; 1982. 17. Johnston, A. L.; File, S. E. Sex differences in animal tests of anxiety. Physiol. Behav. 49:245–249; 1991. 18. Joseph, R.; Hess, S.; Birecree, E. Effects of hormone manipulations and exploration on sex differences in maze learning. Behav. Biol. 24:364–377; 1978. 19. Kellogg, C. K.; Primus, R. J.; Bitran, D. Sexually dimorphic influence of prenatal exposure to diazepam on behavioral responses to environmental challenge and on gama-aminobutyric acid (GABA)stimulated chloride uptake in the brain. J. Pharmacol. Exp. Tber. 256:259-265; 1991. 20. Kelly, D. Sexual differentiation of the nervous system. In: Kandel, E.; Schwartz, J. H.; Jessell, T. M., ed. Principles of Neural Sciences. New York: Elsevier; 1991:959–973. 21. Lucion, A. B.; de Almeida, R. M. M. Role of the intruder in the aggressive behaviour of colonies of wild rats (Rams rwrvegicus). In: Olivier, B.; Mos, J.; Slangen, J. L., ed. Animal Models in Psychopharmacology. Base]: Birkhauser; 1991:347–356. 22. MacLusky, N. J.; Naftolin, F. Sexual differentiation of the central nervous system. Science 211: 1294– 1303; 1981. 23. Majewska, M. D. Steroid regulation of the GABAA receptor: ligand binding, chloride transport and behaviour. In: Chadwick, D.; Widdows, K., eds. Steroids and Neuronal Activity. CIBA Foundation Symposium 153. Chichester:John Wiley & Sons; 1990:83–106. 24. Malsbury, C. W.; McKay, K. Neurotropbic effects of testosterone
25. 26.
27. 28.
29. 30.
31. 32.
33. 34. 35. 36.
37. 38.
39. 40.
41. 42. 43.
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