Abstract
Preliminary evidence suggests that testosterone (T) may have anxiety-reducing and cognitive-enhancing properties in animals and people. Performance in a number of affective and cognitive behavioral tasks was examined in intact, T-depleted, and T-depleted and T-replaced male rats. Rats that were gonadally intact (n = 33), gonadectomized (GDX; n = 30), or GDX with silastic capsules of T implanted (n = 28) were tested through a battery of affective tasks (horizontal crossing, open field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive burying) and in the inhibitory avoidance task for cognitive performance. An additional 6 rats per group had plasma androgen concentrations measured and were determined to be physiological for intact rats, supraphysiological for T-implanted rats, and near the nadir for GDX rats. Testosterone implants produced analgesia as shown by the increased tailflick latencies of the GDX rats with silastic capsules of T implanted, relative to intact or GDX rats. Testosterone also produced anxiolysis. Intact rats spent more time interacting with a conspecific and less time burying an electrified prod than did the GDX or T-implanted rats. Intact rats or GDX rats with T implants also spent more time on the open arms of the elevated plus-maze than did GDX rats. Testosterone also enhanced cognitive performance in the inhibitory avoidance task. Intact rats had longer crossover latencies in the inhibitory avoidance task relative to GDX rats; GDX rats with T implants had longer crossover latencies relative to GDX or intact rats. Together, these data demonstrate that endogenous T or administration of T produced analgesia and enhanced affect and cognitive performance of adult male rats.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Astur, R. S., Ortiz, M. L., & Sutherland, R. J. (1998). A characterization of performance by men and women in a virtual Morris water task: A large and reliable sex difference. Behavioural Brain Research, 93, 185–190.
Bardo, M. T., & Valone, M. J. (1994). Morphine-conditioned analgesia using a taste cue dissociation of taste aversion and analgesia. Psychopharmacology, 114, 269–274.
Beatty, W. W. (1984). Hormonal organization of sex differences in play fighting and spatial behavior. Progress in Brain Research, 61, 315–330.
Bitran, D., Kellogg, C. K., & Hilvers, R. J. (1993). Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat. Hormones & Behavior, 27, 568–583.
Boissy, A., & Bouissou, M. F. (1994). Effects of androgen treatment on behavioral and physiological responses of heifers to fear-eliciting situations. Hormones & Behavior, 28, 66–83.
Bradley, D. R., & Wygant, C. R. (1998). Male and female differences in anxiety about statistics are not reflected in performance. Psychological Reports, 82, 245–246.
Brudzynski, S. M., & Krol, S. (1997). Analysis of locomotor activity in the rat: Parallelism index, a new measure of locomotor exploratory pattern. Physiology & Behavior, 62, 635–642.
Cheeta, S., Irvine, E. E., Kenny, P. J., & File, S. E. (2001). The dorsal raphe nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology, 155, 78–85.
Christiansen, K., & Knussmann, R. (1987). Sex hormones and cognitive functioning in men. Neuropsychobiology, 18, 27–36.
Cunningham, G. R., Tindall, D. J., & Means, A. R. (1979). Differences in steroid specif icity for rat androgen binding protein and the cytoplasmic receptor. Steroids, 33, 261–276.
D'Amour, F. E., & Smith, D. L. (1941). A method for determining loss of pain sensation. Journal of Pharmacology & Experimental Therapeutics, 72, 74–79.
Davis, S. (2001). Testosterone deficiency in women. Journal of Reproductive Medicine, 46, 291–296.
Dawson, J. L. (1972). Effects of sex hormones on cognitive style in rats and men. Behavior Genetics, 2, 21–42.
Dunn, R., Copeland, P., Reed, T., & Frye, C. A. (1998). Anti-anxiety effects of nitric oxide inhibitors. Neuropharmacology, 37, 899–904.
Farr, S. A., Banks, W. A., & Morley, J. E. (2000). Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus. Brain Research, 864, 263–269.
File, S. E, Pellow, S., & Braestrup, C. (1985). Effects of the betacarboline, FG 7142, in the social interaction test of anxiety and the holeboard: Correlations between behaviour and plasma concentrations. Pharmacology, Biochemistry & Behavior, 22, 941–944.
Flood, J. F., Farr, S. A., Kaiser, F. E., La Regina, M., & Morley, J. E. (1995). Age-related decrease of plasma testosterone in SAMP8 mice: Replacement improves age-related impairment of learning and memory. Physiology & Behavior, 57, 669–673.
Flood, J. F., Morley, J. E., & Roberts, E. (1992). Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proceedings of the National Academy of Sciences, 89, 1567–1571.
Forman, L. J., Tingle, V., Estilow, S., & Cater, J. (1989). The response to analgesia testing is affected by gonadal steroids in the rat. Life Sciences, 45, 447–454.
Frick, K. M., Burlingame, L. A., Arters, J. A., & Berger-Sweeney, J. (2000). Reference memory, anxiety and estrous cyclicity in C57BL/ 6NIA mice are affected by age and sex. Neuroscience, 95, 293–307.
Frye, C. A. (1995). Estrus-associated decrements in a water maze task are limited to acquisition. Physiology & Behavior, 57, 5–14.
Frye, C. A. (2001). Estradiol tends to improve inhibitory avoidance performance in adrenalectomized male rats and reduces pyknotic cells in the dentate gyrus of adrenalectomized male and female rats. Brain Research, 889, 358–363.
Frye, C. A., & Duncan, J. E. (1994). Progesterone metabolites, effective at the GABAA receptor complex, attenuate pain sensitivity in rats. Brain Research, 643, 194–203.
Frye, C. A., & Duncan, J. E. (1995). Estradiol benzoate potentiates neuroactive steroids' effects on pain sensitivity. Pharmacology, Biochemistry & Behavior, 53, 27–32.
Frye, C. A., Duncan, J. E., Basham, M., & Erskine, M. S. (1996). Behavioral effects of 3a-androstanediol. II: Hypothalamic and preoptic area actions via a GABAergic mechanism. Behavioral Brain Research, 79, 119–130.
Frye, C. A., & Lacey, E. H. (2001). Posttraining androgens' enhancement of cognitive performance is temporally distinct from androgens' increases in affective behavior. Cognitive, Affective, & Behavioral Neuroscience, 2, 172–182
Frye, C. A., & McCormick, C. M. (2000). The neurosteroid, 3α-androstanediol, prevents inhibitory avoidance deficits and pyknotic cells in the granule layer of the dentate gyrus induced by adrenalectomy in rats. Brain Research, 7, 166–170.
Frye, C. A., McCormick, C. M., Coopersmith, C., & Erskine, M. S. (1996). Effects of paced and non-paced mating stimulation on plasma progesterone, 3α-diol and corticosterone. Psychoneuroendocrinology, 21, 431–439.
Frye, C. A., Park, D., Tanaka, M., Rosellini, R, & Svare, B. (2001). The testosterone metabolite and neurosteroid 3α-androstanediol may mediate the effects of testosterone on conditioned place preference. Psychoneuroendocrinology, 26, 731–750.
Frye, C. A., Petralia, S. M., & Rhodes, M. E. (2000). Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP. Pharmacology, Biochemistry & Behavior, 67, 1–10.
Frye, C. A., & Reed, T. A. (1998). Androgenic neurosteroids: Anti-seizure effects in an animal model of epilepsy. Psychoneuroendocrinology, 23, 385–399.
Frye, C. A., Van Keuren, K. R., & Erskine, M. S. (1996). Behavioral effects of 3α-androstanediol. I: Modulation of sexual receptivity and promotion of GABA-stimulated chloride flux. Behavioural Brain Research, 79, 109–118.
Frye, C. A., Van Keuren, K. R., Rao, P. N., & Erskine, M. S. (1996a). Analgesic effects of the neurosteroid 3α-androstanediol. Brain Research, 709, 1–9.
Frye, C. A., Van Keuren, K. R., Rao, P. N., & Erskine, M. S. (1996b). Progesterone and 3α-androstanediol conjugated to bovine serum albumin affects estrous behavior when applied to the MBH and POA. Behavioral Neuroscience, 110, 603–612.
Gallagher, A. M., De Lisi, R., Holst, P. C., McGillicuddy-De Lisi, A. V., Morely, M., & Cahalan, C. (2000). Gender differences in advanced mathematical problem solving. Journal of Experimental Child Psychology, 75, 165–190.
Gallo, M. A., & Smith, S. S. (1993). Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: A possible rat model of PMS anxiety. Pharmacology, Biochemistry & Behavior, 46, 897–904.
Gaulin, S. J. C., & Fitzgerald, R. W. (1989). Sexual selection for spatial-learning ability. Animal Behaviour, 37, 322–331.
Ge, J., Barnes, N. M., Costall, B., & Naylor, R. J. (1997). Effect of aversive stimulation on 5-hydroxytryptamine and dopamine metabolism in the rat brain. Pharmacology, Biochemistry & Behavior, 58, 775–783.
Gee, K. W. (1988). Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore. Molecular Neurobiology, 2, 291–317.
Gonzalez, M. I., Farabollini, F., Albonetti, E., & Wilson, C. A. (1994). Interactions between 5-hydroxytryptamine (5-HT) and testosterone in the control of sexual and nonsexual behavior in male and female rats. Pharmacology, Biochemistry & Behavior, 47, 591–601.
Gupta, D., Rager, K., Zarzycki, & Eichner, M. (1975). Levels of luteinizing hormone, follicle-stimulating hormone, testosterone, and dihydrotestosterone in the circulation of sexually maturing intact male rats and after orchidectomy and experimental bilateral cryptorchidism. Journal of Endocrinology, 66, 183–193.
Holson, R. R., Ali, S. F., Scallet, A. C., Slikker, W., & Paule, M.G. (1989). Benzodiazepine-like behavioral effects following withdrawal from chronic delta-9-tetrahydrocaanabinol administration in rats. Neurotoxicology, 10, 605–619.
Isgor, C., & Sengelaub, D. R. (1998). Prenatal gonadal steroids affect spatial behavior, CA1 and CA3 pyramidal cell morphology in rats. Hormones & Behavior, 34, 183–198.
Janowsky, J. S., Chavez, B., & Orwoll, E. (2000). Sex steroids modify working memory. Journal of Cognitive Neuroscience, 12, 407–414.
Janowsky, J. S., Oviatt, S. K., & Orwoll, E. S. (1994). Testosterone influences spatial cognition in older men. Behavioral Neuroscience, 108, 325–332.
Johnson, U. (1997). Coping strategies among long-term injured competitive athletes. A study of 81 men and women in team and individual sports. Scandinavian Journal of Medicine & Science in Sports, 7, 367–372.
Johnston, A. L., & File, S. E. (1991). Sex differences in animal tests of anxiety. Physiology & Behavior, 49, 245–250.
Kritzer, M. F., McLaughlin, P. J., Smirlis, T., & Robinson, J. K. (2001). Gonadectomy impairs T-maze acquisition in adult male rats. Hormones & Behavior, 39, 167–174.
Lambadjieva, N. D. (1998). Influence of testosterone on some behavioral reactions of male immature rats. Methods & Findings in Experimental & Clinical Pharmacology, 20, 673–677.
Linn, M. C., & Petersen, A. C. (1985). Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Development, 56, 1479–1498.
Lund, B. C., Bever-Stille, K. A., & Perry, P. J. (1999). Testosterone and andropause: The feasibility of testosterone replacement therapy in elderly men. Pharmacotherapy, 19, 951–956.
McCarthy, M. M., Felzenberg, E., Robbins, A., Pfaff, D. W., & Schwartz-Giblin, S. (1995). Infusions of diazepam and allopregnanolone into the midbrain central gray facilitate open-field behavior and sexual receptivity in female rats. Hormones & Behavior, 29, 279–295.
McCleary, R., & Zucker, E. L. (1991). Higher trait- and state-anxiety in female law students than male law students. Psychological Reports, 68, 1075–1078.
McGee, M. G. (1979). Human spatial abilities: Psychometric studies and environmental, genetic, hormonal, and neurological influences. Psychological Bulletin, 86, 889–918.
Moger, W. H. (1977). Serum 5α-androstane-3α,17β-diol, androsterone, and testosterone concentrations in the male rat. Influence of age and gonadotropin secretion. Endocrinology, 100, 1027–1032.
Molina, N., Bedran-de-Castro, M. T., & Bedran-de-Castro, J. C. (1994). Sex-related differences in the analgesic response to the rat tail immersion test. Brazilian Journal of Medical & Biological Research, 27, 1669–1672.
Morley, J. E. (2000). Andropause, testosterone therapy, and quality of life in aging men. Cleveland Clinic Journal of Medicine, 67, 880–882.
Morley, J. E., Kaiser F. E., Sih, R., Hajjar, R., & Perry, H. M., III. (1997). Testosterone and frailty. Clinics in Geriatric Medicine, 13, 685–695.
Morley, K. C., & McGregor, I. S. (2000). (+/-)-3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) increases social interaction in rats. European Journal of Pharmacology, 408, 41–49.
O'Connell, A., Earley, B., & Leonard, B. E. (1994). Phencyclidine prevents spatial navigation and passive avoidance deficits in ibotenate lesioned rats. Neuropharmacology, 33, 1095–1101.
Pellow, S., Chopin, P., File, S. E., & Briley, M. (1985). Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods, 14, 149–167.
Pellow, S., & File, S. E. (1986). Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: A novel test of anxiety in the rat. Pharmacology, Biochemistry & Behavior, 24, 525–529.
Postma, A., Meyer, G., Tuiten, A., van Honk, J., Kessels, R. P., & Thijssen, J. (2000). Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology, 25, 563–575.
Rodriguez, M., Sosa, J., Hernandez, G., & Mas, M. (1984). Pineal indols and testosterone affect exploratory activity of male rats. Experientia, 40, 397–398.
Romero, M. T., Cooper, M. L., Komisaruk, B. R., & Bodnar, R. J. (1988). Gender-specific and gonadectomy-specific effects upon swim analgesia: Role of steroid replacement therapy. Physiology & Behavior, 44, 257–265.
Roselli, C. E. (1991). Sex differences in androgen receptors and aromatase activity in microdissected regions of the rat brain. Endocrinology, 128, 1310–1315.
Rosellini, R. A., Svare, B. B., Rhodes, M. E., & Frye, C. A. (2001). The testosterone metabolite and neurosteroid 3α-androstanediol may mediate the effects of testosterone on conditioned place preference. Brain Research Reviews, 37, 162–171.
Silverman, I., Kastuk, D., Choi, J., & Phillips, K. (1999). Testosterone levels and spatial ability in men. Psychoneuroendocrinology, 24, 813–822.
Smythe, J. W., McCormick, C. M., Rochford, J., & Meaney, M. J. (1994). The interaction between prenatal stress and neonatal handling on nociceptive response latencies in male and female rats. Physiology & Behavior, 55, 971–974.
Sternbach, H. (1998). Age-associated testosterone decline in men: Clinical issues for psychiatry. American Journal of Psychiatry, 155, 1310–1318.
Stewart, J., Skvarenina, A., & Pottier, J. (1975). Effects of neonatal androgens on open-field behavior and maze learning in the prepubescent and adult rat. Physiology & Behavior, 14, 291–295.
Stumpf, W., & Sar, M. (1976). Steroid hormone target sites in the brain: The differential distribution of estrogen, progestin, androgen and glucocorticosteroid. Journal of Steroid Biochemistry, 7, 1163–1170.
Svensson, A. I., Soderpalm, B., & Engel, J. A. (2000). Gonadectomy enhances shock-induced behavioral inhibition in adult male rats: Implications for impulsive behavior. Pharmacology, Biochemistry & Behavior, 65, 731–736.
Treit, D. (1985). The inhibitory effect of diazepam on defensive burying: Anxiolytic vs. analgesic effects. Pharmacology, Biochemistry & Behavior, 22, 47–52.
Treit, D., Pinel, J. P., & Fibiger, H. C. (1981). Conditioned defensive burying: A new paradigm for the study of anxiolytic agents. Pharmacology, Biochemistry & Behavior, 15, 619–626.
Vandenheede, M., & Bouissou, M. F. (1993). Effect of androgen treatment on fear reactions in ewes. Hormones & Behavior, 27, 435–448.
Vazquez-Pereyra, F., Rivas-Arancibia, S., Loaeza-Del Castillo, A., & Schneider-Rivas, S. (1995). Modulation of short term and long term memory by steroid sexual hormones. Life Sciences, 56, PL255-PL260.
Venault, P., Chapouthier, G., de Carvalho, L. P., Simian, J., Morre, M., Dodd, R. H., & Rossier, J. (1986). Benzodiazpine impairs and beta-carboline enhances performance in learning and memory tasks. Nature, 321, 864–866.
Verhoeven, G., Heyns, W., & De Moor, P. (1975). Testosterone receptors in the prostate and other tissues. Vitamins & Hormones, 33, 265–281.
Warren, S. G., & Juraska, J. M. (1997). Spatial and nonspatial learning across the rat estrous cycle. Behavioral Neuroscience, 111, 259–266.
Williams, C. L., Barnett, A., & Meck, W. H. (1991). Organizational effects of early gonadal secretions on sexual differentiation in spatial memory. Behavioral Neuroscience, 104, 84–97.
Williams, C. L., & Meck, W. H. (1991). The organizational effects of gonadal steroids on sexually dimorphic spatial ability. Psychoneuroendocrinology, 16, 155–176.
Zangrossi, H., & File, S. E. (1992). Behavioral consequences in animal tests of anxiety and exploration of exposure to cat odor. Brain Research Bulletin, 29, 381–388.
Author information
Authors and Affiliations
Corresponding author
Additional information
This research was supported by grants from the National Science Foundation (98-96263). We appreciate the assistance of Madeline Rhodes, Alicia Walf, Zoe Orecki, and Shannon Jeddi in the implementation of the studies and in the preparation of the manuscript.
Rights and permissions
About this article
Cite this article
Frye, C.A., Seliga, A.M. Testosterone increases analgesia, anxiolysis, and cognitive performance of male rats. Cognitive, Affective, & Behavioral Neuroscience 1, 371–381 (2001). https://doi.org/10.3758/CABN.1.4.371
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.3758/CABN.1.4.371