Anxiolytic-like Effect of Testosterone in Male Rats: GABAC Receptors Are Not Involved

Document Type: Original Article

Authors

1 Physiology and Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran

3 Department of Biology, Tarbiat Moallem University, Tehran, Iran

Abstract

Objective(s)
The effect of testosterone on anxiety-like behaviors has been the subject of some studies. There is evidence that testosterone modulates anxiety via GABA (gama aminobutyric acid) and GABAergic system. The involvement of GABAC receptors in those effects of testosterone on anxiety-like behaviors of the rats was investigated in the present study.
Materials and Methods
A group of rats received subcutaneous injections of testosterone (5, 10 and 20 mg/kg). Two groups of rats received intracerebroventricular injections of either CACA (GABAC agonist, 0.125 pg/rat) or TPMPA (GABAC antagonist, 3 microg/rat) following administration of testosterone (5, 10 and 20 mg/kg). After the injections, the rats were submitted to the elevated plus-maze test of anxiety.
Results
The rats received testosterone alone, showed a decreased in anxiety-like behaviors (P< 0.01). Administration of either CACA or TPMPA did not modify animals’ behavior compared to the rats received testosterone alone.
Conclusion
The results of the present study showed that administration of testosterone induces anxiolytic-like behaviors in the rats and GABAC receptors possibly are not involved in the anxiolytic effect of testosterone.

Keywords


1.Women and anxiety disorders: implications for diagnosis and treatment. Proceedings of a conference. CNS Spectr 2004; 9:1-16.

2.Aikey JL, Nyby JG, Anmuth DM, James PJ. Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Horm Behav 2002; 42:448-460.

3.Bing O, Heilig M, Kakoulidis P, Sundblad C, Wiklund L, Eriksson E. High doses of testosterone increase anticonflict behaviour in rat. Eur Neuropsychopharmacol 1998; 8:321-323.

4.Frye CA, Edinger KL. Testosterone's metabolism in the hippocampus may mediate its anti-anxiety effects in male rats. Pharmacol Biochem Behav 2004; 78:473-481.

5.Bitran D, Kellogg CK, Hilvers RJ. Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat. Horm Behav 1993; 27:568-583.

6.Fernandez-Guasti A, Martinez-Mota L. Orchidectomy sensitizes male rats to the action of diazepam on burying behavior latency: role of testosterone. Pharmacol Biochem Behav 2003; 75:473-479.

7.Rocha VM, Calil CM, Ferreira R, Moura MJ, Marcondes FK. Influence of anabolic steroid on anxiety levels in sedentary male rats. Stress 2007; 10:326-331.

8.Ambar G, Chiavegatto S. Anabolic-androgenic steroid treatment induces behavioral disinhibition and down regulation of serotonin receptor messenger RNA in the prefrontal cortex and amygdala of male mice. Genes Brain Behav 2009; 8:161-173.

9.Cunningham GR, Tindall DJ, Means AR. Differences in steroid specificity for rat androgen binding protein and the cytoplasmic receptor. Steroids 1979; 33:261-276.

10.Rupprecht R. The neuropsychopharmacological potential of neuroactive steroids. J Psychiatr Res 1997; 31:297-314.

11.Roselli CE, Horton LE, Resko JA. Time-course and steroid specificity of aromatase induction in rat hypothalamus-preoptic area. Biol Reprod 1987; 37:628-633.

12.Bormann J. The 'ABC' of GABA receptors. Trends Pharmacol Sci 2000; 21:16-19.

13.Chebib M, Johnston GA. GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology. J Med Chem 2000; 43:1427-1447.

14.Li S, Zhang Y, Liu H, Yan Y, Li Y. Identification and expression of GABAC receptor in rat testis and spermatozoa. Acta Biochim Biophys Sin (Shanghai) 2008; 40:761-767.

15.Amikishieva AV. Testosterone and behavior: involvement of the hormone in psychotropic effects of baclofen. Bull Exp Biol Med 2007; 143:259-263.

16.Li W, Jin X, Covey DF, Steinbach JH. Neuroactive steroids and human recombinant rho1 GABAC receptors. J Pharmacol Exp Ther 2007; 323:236-247.

17.Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. Academic Press: San Diego; 1998.

18.Rodgers RJ, Johnson NJT. Factor analysis of spatiotemporal and ethological measures in the murine elevated plus- maze test of anxiety. Pharmacol Biochem Behav 1995; 52:297-303.

19.Agren G, Thiblin I, Tirassa P, Lundeberg T, Stenfors C. Behavioural anxiolytic effects of low-dose anabolic androgenic steroid treatment in rats. Physiol Behav 1999; 66:503-509.

20.Frye CA, Edinger K, Sumida K. Androgen administration to aged male mice increases anti-anxiety behavior and enhances cognitive performance. Neuropsychopharmacology 2008; 33:1049-1061.

21.Rivera-Arce JC, Morales-Crespo L, Vargas-Pinto N, Velazquez KT, Jorge JC. Central effects of the anabolic steroid 17alpha methyltestosterone in female anxiety. Pharmacol Biochem Behav 2006; 84:275-281.

22.Edinger KL, Frye CA. Intrahippocampal administration of an androgen receptor antagonist, flutamide, can increase anxiety-like behavior in intact and DHT-replaced male rats. Horm Behav 2006; 50:216-222. 

23.Frick KM, Burlingame LA, Arters JA, Berger-Sweeney J. Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience 2000; 95:293-307.

24.Johnston AL, File SE. Sex differences in animal tests of anxiety. Physiol Behav 1991; 49:245-250.

25.Hameed A, Brothwood T, Bouloux P. Delivery of testosterone replacement therapy. Curr Opin Investig Drugs 2003; 4:1213-1219.

26.Howell S, Shalet S. Testosterone deficiency and replacement. Horm Res 2001; 1:86-92.

27.Barreto-Estrada JL, Barreto J, Fortis-Santiago Y, Rivera-Ramos I, Fortis-Santiago A, Jorge JC. Modulation of affect after chronic exposure to the anabolic steroid 17alpha-methyltestosterone in adult mice. Behav Neurosci 2004; 118:1071-1079.

28.Reddy DS, Jian K. The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther 2010; 334:1031-1041.

29.Chebib M, Hinton T, Schmid KL, Brinkworth D, Qian H, Matos S, et al. Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory. J Pharmacol Exp Ther 2009; 328:448-457.

30.Roohbakhsh A, Mahmoodi Delfan K, Rostami P, Hajizadeh Moghaddam A. The Effect of Intracerebroventricular Injection of GABAC Selective Agonist and Antagonist on Anxiety-like Behaviors in Male Rats. J Rafsanjan Unive Med Sci 2008; 7:13-20.

31.Arnaud C, Gauthier P, Gottesmann C. Study of a GABAC receptor antagonist on sleep-waking behavior in rats. Psychopharmacology (Berl) 2001; 154:415-419.

32.Chebib M, Hinton T, Schmid KL, Brinkworth D, Qian H, Matos S, et al. Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory. J Pharmacol Exp Ther 2009; 328:448¬457.