Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids (original) (raw)
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Nandrolone Decanoate Enhances Hypothalamic Biogenic Amines in Rats
Medicine & Science in Sports & Exercise, 2003
Purpose: To identify possible mechanisms for an anabolic-androgenic steroid induced increase in aggressive behavior and work capacity, the levels of some biogenic amines considered to be closely related to a systemic hyper-adrenergic state were measured in selected regions of the brain. Methods: Wistar male rats were divided randomly into five groups: nontreated (control), oil-vehicle-treated (vehicle) or one of three (therapeutic dose and 10-or 100-fold higher dose) anabolic-androgenic steroid-treated (steroid-1, -2, -3) groups. Rats in the steroid and vehicle groups were given a single dose of nandrolone decanoate or oil vehicle, respectively, one week before tissue sampling. The levels of norepinephrine (NE) and its metabolite, 4-hydroxy-3-methoxyphenylglycol (MHPG), serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were measured in the cerebral cortex, hypothalamus and cerebellum by high-performance liquid chromatography. Immunostaining for c-fos was performed as a confirmation of increased neural activity. Results: The levels of NE and MHPG were increased by~2-and~7-fold in the hypothalamus of the steroid-2 compared with the control and vehicle groups. The levels of 5-HT and 5-HIAA were~40 and~50% higher in the steroid-2 compared with the control and vehicle groups. A significantly higher number of c-fos expressing neurons were observed in the periventricular region of the steroid-2 than the control and vehicle groups, indicating enhanced neuronal activity after nandrolone decanoate treatment. Conclusions: The present results, combined with previously reported findings of physical performance enhancement after anabolic-androgenic steroid treatment, are consistent with the interpretation that elevated levels of adrenergic and serotonergic amines in the hypothalamus could contribute to aggressive behaviors as well as improved physical performance.
Brain Research Bulletin, 2006
Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) released from nerve terminals in the brain are primarily removed from the synaptic cleft by a reuptake mechanism. In part, the homeostasis is maintained by monoamine oxidase (MAO) deamination achieved primarily intracellularly. The present study's aim was to examine the effect of the acute administration of the MAO inhibitors, moclobemide (a MAO-A inhibitor) and deprenyl (a MAO-B inhibitor), on 5-HT synthesis rates, measured in discrete regions of the rat brain by an autoradiographic method, using ␣-[ 14 C]methyl-l-tryptophan as a tracer. MAO inhibitors have different effects on 5-HT synthesis rates in the cell bodies and areas of the nerve terminals. Moclobemide (10 mg/kg, i.p. 30 min before the tracer injection) and deprenyl (3 mg/kg, i.p. 2 h before the tracer injection) decreased the 5-HT synthesis rates in the dorsal (−18% and −22%) and median (−22% and −33%) raphe, respectively. Moclobemide also significantly decreased 5-HT synthesis in the entire nerve terminal areas investigated. The reductions were between 23% (cingulate cortex) and 50% (locus coeruleus). Deprenyl did not significantly affect 5-HT synthesis in the nerve terminals. The present results suggest that MAO-A, and to a lesser extent, MAO-B, are involved in the regulation of 5-HT synthesis in the rat brain. The mechanism(s) of MAO inhibitors' action on 5-HT synthesis in the raphe nuclei are probably related to an increase in the extraneuronal 5-HT concentration and also to the interaction between the serotonergic and catecholaminergic neurons. The reduction of 5-HT synthesis in the raphe nuclei likely occurs by an action of extracellular 5-HT via the dendritic autoreceptors with a possible contribution from the action of extracellular DA and NE. In the terminal regions, the most likely mechanism is via the presynaptic autoreceptors through which elevated extraneuronal 5-HT acts on synthesis control. However, there is also a possibility that the elevation in intraneuronal 5-HT directly inhibits its synthesis, especially following deprenyl treatment. A great influence of moclobemide on 5-HT synthesis could be related to its antidepressant action.
Journal of Neurochemistry, 1972
The injection of 50 pg of 5,6-dihydroxytryptamine (5,6-HT) into a lateral ventricle of the rat depleted the spinal cord and various regions of the brain of indoleamines (presumably 5-HT) and 5-hydroxyindole acetic acid. The concentrations of 5-HT were measured by two different methods: the formation of a fluorescent derivative with ophthalaldehyde, and the native fluorescence in hydrochloric acid. When the results of both methods were compared on the pons and medulla 4 days after injecting 5,6-HT, the loss in indoteamine appeared to be greater when o-phthalaldehyde was used. This suggests that the two methods may be measuring different compounds. According to both methods, the loss of 5-HT persisted fDr several days after the injection of 5,6-HT, but by 2 months 5-HT concentrations (measured only by the native fluorescence procedure), had recovered to near-normal values. The depletion of 5-HT was most pronounced in regions adjacent to the ventricular system and in the spinal cord. Initially, caudate and septum were more aflected on the side of the injection, and later showed some permanent atrophy. The injection of up to 50 pg of 5,6-HT did not lead to any significant loss of noradrenaline or dopamine from the brain, or to any reduction in the activity of the enzyme tyrosine hydroxylase. The drug was a potent inhibitor of the uptake of [3H]5-HT by brain slices, but was less effective in inhibiting catecholamine uptake systems. These observations suggest a preferential action on tryptaminergic neurones. Larger doses of 5,6-HT caused a loss of catecholamines and tyrosine hydroxylase from the brain, and were severely toxic.
Journal of Neural Transmission, 1990
Brain regional 5-hydroxytryptamine (5-HT) and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations tended to be slightly higher in female rats than in males but differences were substantial only in the hippocampus where female values were 34% and 36% higher respectively. These findings were consistent with the synthesis rates of 5-HT as this was 53% greater in the female than in the male hippocampi. Other regions did not show significant sex differences. The 5-HTIA agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 mg/kg sc) caused comparable decreases of 5-HT synthesis rate in both sexes and in all regions studied except the hippocampus where the percentage decrease was twice as large in the females (-64%) as in the males (-32%) so that the sex difference in 5-HT synthesis in this region largely disappeared. The results are discussed in relation to sex differences in behaviour and hippocampal function.
Journal of Neuroendocrinology, 1992
We investigated the effect of central serotonin (5-hydroxytryptamine, 5-HT) administration on hypothalamic tuberoinfundibular dopamine neurons and related changes in neuronal activity to circulating prolactin (PRL) levels. Ovariectomized rats were treated with either vehicle or 5-HT through a lateral ventricular cannula in one of two dose paradigms: 1) a bolus of 20pg, with tissues taken at 30 min, or 2) the same bolus immediately followed by 20 pgl30 rnin via a syringe pump for 120 min, and tissues taken at 120 min. Blood samples were taken throughout experiments and plasma PRL determined by radioimmunoassay. Under both paradigms, NSD 1015, a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor (25 mglkg intraarterially) was injected 10 rnin before decapitation and brain excision followed by stalk-median eminence dissection. The rate of DOPA accumulation, determined by measuring DOPA levels in the stalk-median eminence by high-performance liquid chromatography with electrochemical detection was used as a measure of tyrosine hydroxylase (TH) catalytic activity. Stalk-median eminence DOPA accumulation in control rats was 29.9k4.2 and 28.8f4.4 nglmg protein (30 and 120 min experiments, respectively). DOPA accumulation in 5-HTtreated rats was significantly reduced (P<0.05) after 30 rnin to 17.8k1.2 nglmg protein, but it was similar (21.7k3.9) to controls after 120 min of 5-HT infusion. 5-HT levels in the stalk-median eminence of rats treated with 5-HT were 13-to 17-fold greater than controls (16.9 to 18.5 nglmg protein). Plasma PRL levels in both groups increased -10-fold after 5-HT treatment with a peak at 5 rnin, returning to baseline by 120 min. TH mRNA levels were determined by in situ hybridization in a second group of rats which were treated with the 20 pg bolus and subsequent 120 rnin infusion of 5-HT. TH mRNA signal levels in the arcuate nucleus of control rats averaged 144k21 grainslcell. After: treatment with 5-HT, TH mRNA levels in the arcuate nucleus were significantly lower (P<O.OOOl) with 6 9 k 14 grainslcell. In a third group of rats, the effects of the 30 rnin 5-HT treatment on TH catalytic activity and circulating PRL levels was challenged with two 5-HT2 receptor antagonists, LY53857 (5 mglkg intraperitoneally) or ketanserin (10 mglkg intraperitoneally). Neither the 5-HT-induced decrease in TH catalytic activity nor the increase in PRL was altered by pretreatment (120 min) with 5-HT2 antagonists. These data suggest that central 5-HT is capable of decreasing TH activity and TH mRNA levels in the tuberoinfundibular dopamine neurons and that the decrease in dopaminergic neuronal activity may contribute to the 5-HT-induced PRL rise. The changes in TH catalytic activity and PRL after intracerebroventricular administration of 5-HT do not appear to be mediated by 5-HT2 receptors.
Molecular Brain Research, 1999
Ž. Estrogen increases serotonin transporter SERT mRNA and binding sites in female rat brain. In order to determine whether changes in SERT are gender-and steroid-specific we have now carried out studies on adult male Wistar rats which were either intact or castrated Ž. Ž. Ž. under halothane anesthesia and injected with arachis oil, estradiol benzoate EB , testosterone propionate TP or the non-aromatizable Ž. Ž. androgen, 5a-dihydrotestosterone 5a-DHT. The number of SERT mRNA-expressing cells in the dorsal raphe DR nucleus was Ž. decreased by castration and increased by treatment for ; 32 h with EB or TP, but not 5a-DHT. Sex steroids had no effect on the number of SERT mRNA-expressing cells in the median raphe nucleus. The density of SERT sites, assessed by autoradiography of w 3 x H paroxetine binding, was significantly reduced in arcuate nucleus and median raphe after castration, and increased in arcuate, basolateral amygdala and ventromedial hypothalamic nucleus by treatment with EB or TP, but not 5a-DHT. Estradiol, but not testosterone or 5a-DHT reduced the density of SERT sites in midbrain central grey. These data show that testosterone as well as estrogen affects SERT expression in male brain, and that the action of testosterone probably depends upon its enzymatic conversion, by aromatase, to estradiol. Our findings may have implications for sex steroid control of mood and behavior, and the action of neurotoxic derivatives of amphetamine, such as 3,4-methylenedioxymethamphetamine, in the human.
British Journal of Pharmacology, 1992
1 Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidasetype B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2 Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400mgkg-1, i.p.), peaking at h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-' milacemide).
Feedback Control of Rat Brain 5-HYDROXYTRYPTAMINE Synthesis
Journal of Neurochemistry, 1971
The effect of increased levels of 5-hydroxytryptamine (5-HT) on the synthesis of [3H]5-HT from intrackternally injected tracer doses of 13H]tryptophan was studied in the rat brain stem. The ['HIS-HT which accumulated in the first 15 min after [3atryptophan injection was measured at various times after the acute intraperitoneal administration of the monoamine oxidase inhibitors Catron or Pargyline. The 5-HT levels reached two and three times control values respectively at 20 min and 180 min after monoamine oxidase inhibitor administration but [3H]5-HT accumulation was decreased (40 per cent) at 180 min when compared with 20 min. These data as well as those obtained after chronic treatment with monoamine oxidase inhibitors revealed that there is an inverse relationship between ['HIS-HT accumulation and the endogenous 5-HT level. Monoamine oxidase activity was undetectable during all the intervals in which [3H]5-HT accumulation was measured. No inhibition of ['HIS-HT accumulation was detected when [3H]5-hydroxytryptophan was injected instead of [3H]tryptophan. The results are consistent with a negative feedback of 5-HT synthesis at the rate-limiting tryptophan hydroxylation step. 10 ml of M-NaOH/KH2P0., pH 10.9. Endogenous Trp was determined by the method of UD-(1962) on a mixture of 1 ml Dowex eluate and 1 ml buffer. Dowex column eluates were taken for the estimation of [3H]Trp or [3a5-HTP radioactivities. In the experiments in which [3H]Trp was injected, the Dowex column eluates contained both amino acids. However, as [WIS-HTP was negligible when compared to [3H]Trp, the total radioactivities were considered as rH]Trp. Tritiated