ABSTRACT
Title
Chronic AAs treatment affects monoaminergic transmission in male rat brain
Authors
M. Zotti1, P. Tucci1, L. Trabace1 and V. Cuomo2
1Dept. of Biomedical Sciences, School of Medicine, University of Foggia, Italy
2 Dept. of Human Physiology and Pharmacology Vittorio Erspamer, University of Rome, La Sapienza, Italy
1Dept. of Biomedical Sciences, School of Medicine, University of Foggia, Italy
2 Dept. of Human Physiology and Pharmacology Vittorio Erspamer, University of Rome, La Sapienza, Italy
Abstract
Anabolic androgenic steroids (AAs) are widely abused by adolescents, although persistent AAs use can cause several adverse physical and mental effects, including drug dependence (Faigenbaum et al., 1998).
Changes in mood, euphoria, delusions, depression and violent behaviour are reported to be associated with the prolonged use of AAs (Lukas et al., 1996). This is supported by behavioural studies on animal models and psychiatric evaluation of human subjects. Alteration of dopamine function is indicated as a possible neurochemical basis for these behavioural effects. Additionally, cerebrospinal fluid levels of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindole acetic acid (5-HIAA), have been inversely correlated with aggression in young male AAs abuser (Brown et al., 1979). Moreover links between serotonin, androgens, depression and suicidal behaviours have been presented in literature (Pope and Katz, 2001); however, the effects of supratherapeutic doses of AAs on monoamine systems are not yet fully evaluated. The aim of the present study was to investigate the impact of chronic administration of nandrolone and stanozolol on dopamine and serotonin systems in the male rat brain. Wistar rats were treated for 4 weeks. Injections of nandrolone/stanozolol (5 mg/kg, s.c.), or vehicle (propylene glycol, 1 ml/kg) were given once daily. Twenty-four hours after the last injection, Dopamine (DA), 5-HT and their metabolite tissue levels were assayed from dissected brain regions primarily involved in drug dependence, aggressive behaviour and depressive symptoms. Our data showed that dopaminergic system was significantly affected by treatment with both AAs in the same pattern, with DA levels reduced in the hypothalamus and increased in the hippocampus. In prefrontal cortex, nandrolone had the ability to increase DA levels compared to control without affecting Homovanillic acid, 3,4-dihydroxyphenyl acetic acid (DOPAC) or metabolites/dopamine ratio, while chronic administration of stanozolol decreased DOPAC and DA levels. This effect might be due to altered dopamine synthesis or metabolism. No significant changes were observed in the amygdala or in the nucleus accumbens.Serotonergic system resulted dramatically affected in all brain areas investigated after chronic nandrolone or stanozolol exposure.Both AAs significantly and substantially depleted 5-HT and 5-HIAA in hippocampus of rats. Interestingly, in the other areas investigated, thereduction in 5-HT amount was accompanied by different effects on its metabolite. Indeed, stanozolol reduced 5HIAA content without altering the 5HIAA/5HT ratio; on the contrary, nandrolone produced an increase in this metabolite levels accompanied by an enhancement of 5-HT turn-over.Thus it can be speculated that the effects of these androgens on monoamines systems could be mediated by targeting different effectors involved in the synthesis process or in the metabolism. The results suggest that, in rats, administration of suprapharmacological doses of AAs affects dopaminergic and serotonergic systems. These alterations might underline some of the psychiatric/behavioural side effects reported in AAS abuser, providing a neurochemicalbasis for understanding the mechanism behind the effects of these compounds.
Faigenbaum et al. (1998). Pediatrics 101, E6.
Lukas et al. (1996), Annu. Rev. Pharmacol. Toxicol. 36, 333– 357.
Brown et al. (1979). Psychiatry Res. 1, 131–139.
Pope and Katz. (2001). Arch. Gen. Psychiatry. 51,375-382.
Changes in mood, euphoria, delusions, depression and violent behaviour are reported to be associated with the prolonged use of AAs (Lukas et al., 1996). This is supported by behavioural studies on animal models and psychiatric evaluation of human subjects. Alteration of dopamine function is indicated as a possible neurochemical basis for these behavioural effects. Additionally, cerebrospinal fluid levels of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindole acetic acid (5-HIAA), have been inversely correlated with aggression in young male AAs abuser (Brown et al., 1979). Moreover links between serotonin, androgens, depression and suicidal behaviours have been presented in literature (Pope and Katz, 2001); however, the effects of supratherapeutic doses of AAs on monoamine systems are not yet fully evaluated. The aim of the present study was to investigate the impact of chronic administration of nandrolone and stanozolol on dopamine and serotonin systems in the male rat brain. Wistar rats were treated for 4 weeks. Injections of nandrolone/stanozolol (5 mg/kg, s.c.), or vehicle (propylene glycol, 1 ml/kg) were given once daily. Twenty-four hours after the last injection, Dopamine (DA), 5-HT and their metabolite tissue levels were assayed from dissected brain regions primarily involved in drug dependence, aggressive behaviour and depressive symptoms. Our data showed that dopaminergic system was significantly affected by treatment with both AAs in the same pattern, with DA levels reduced in the hypothalamus and increased in the hippocampus. In prefrontal cortex, nandrolone had the ability to increase DA levels compared to control without affecting Homovanillic acid, 3,4-dihydroxyphenyl acetic acid (DOPAC) or metabolites/dopamine ratio, while chronic administration of stanozolol decreased DOPAC and DA levels. This effect might be due to altered dopamine synthesis or metabolism. No significant changes were observed in the amygdala or in the nucleus accumbens.Serotonergic system resulted dramatically affected in all brain areas investigated after chronic nandrolone or stanozolol exposure.Both AAs significantly and substantially depleted 5-HT and 5-HIAA in hippocampus of rats. Interestingly, in the other areas investigated, thereduction in 5-HT amount was accompanied by different effects on its metabolite. Indeed, stanozolol reduced 5HIAA content without altering the 5HIAA/5HT ratio; on the contrary, nandrolone produced an increase in this metabolite levels accompanied by an enhancement of 5-HT turn-over.Thus it can be speculated that the effects of these androgens on monoamines systems could be mediated by targeting different effectors involved in the synthesis process or in the metabolism. The results suggest that, in rats, administration of suprapharmacological doses of AAs affects dopaminergic and serotonergic systems. These alterations might underline some of the psychiatric/behavioural side effects reported in AAS abuser, providing a neurochemicalbasis for understanding the mechanism behind the effects of these compounds.
Faigenbaum et al. (1998). Pediatrics 101, E6.
Lukas et al. (1996), Annu. Rev. Pharmacol. Toxicol. 36, 333– 357.
Brown et al. (1979). Psychiatry Res. 1, 131–139.
Pope and Katz. (2001). Arch. Gen. Psychiatry. 51,375-382.