The effect of sub-chronic nandrolone decanoate treatment on dopaminergic and serotonergic neuronal systems in the brains of rats.

Anabolic-androgenic steroids (AASs) are widely abused by adolescents, although persistent AAS use can cause several adverse physical and mental effects, including drug dependence. The first aim of the present study was to study the action of nandrolone decanoate on dopaminergic and serotonergic activities in the brains of rats. In order to evaluate the anabolic or toxic effects of the dosing regimens used, selected peripheral effects were monitored as well. Male Wistar rats were treated for 2 weeks. Injections containing nandrolone (5 and 20 mg/kg, i.m.) or vehicle were given once daily, 5 days a week. The levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were assayed from dissected brain regions 3 days after the last injection. Blood was collected for chemical assays before, after 1 week treatment and at decapitation. Both doses of nandrolone significantly increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of DA in the cerebral cortex, and the higher dose of nandrolone increased the concentrations of 5-HT in the cerebral cortex compared with the vehicle. In addition, after nandrolone treatment, the levels of hemoglobin and erythrocytes increased, and reticulocyte levels decreased. The results suggest that nandrolone at supraphysiological doses, high enough to induce erythropoiesis, induces changes in the dopaminergic and serotonergic neuronal system in the brains of rats. These phenomena may account to some of the observed central stimulatory properties that have been reported following AAS abuse.

Pharmacokinetics and tissue distribution of the stereoisomers of 4-methylaminorex in the rat.

4-Methylaminorex, a potential psychostimulant drug of abuse, exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R, which were shown previously to possess stereospecific effects. This study characterized their pharmacokinetic and tissue distribution profiles, and metabolic turnover to norephedrine and norpseudoephedrine, in male Wistar rats. The rats received each isomer intravenously, intraperitoneally, or orally, followed by blood sample collection via cannula (pharmacokinetic study), or tissue sample collection at predetermined time points (tissue distribution study). The samples were analyzed for cis- and trans-isomers, and when appropriate for norephedrine and norpseudoephedrine, with gas chromatography/mass spectrometry. Trans-4S,5S-, cis-4R,5S-, and cis-4S,5R-isomers behaved comparably kinetically (volume of distribution 1.7-2.3 l/kg, distribution half-life 3.8-7.0 min, elimination half-life 35-42 min, and bioavailability 32-57% intraperitoneally or 4-16% orally), whereas trans-4R,5R-isomer differed from the others, with a longer elimination half-life (118-169 min) and higher bioavailability (100% intraperitoneally or 83% orally). The highest isomer concentrations were observed in the kidney followed most frequently by the liver, brain, muscle, and last by fat and blood. The elimination half-lives of the stereoisomers from the tissues were generally similar to those in blood. No pharmacologically significant amounts of norephedrine or norpseudoephedrine were detected in blood or the brain. In conclusion, differences between the stereoisomers of 4-methylaminorex in the pharmacokinetics and tissue distribution are described. However, these differences are not compatible with, and thus may not account for, the distinct behavioral and neurochemical effects of the stereoisomers demonstrated previously. Furthermore, metabolic turnover to norephedrine and norpseudoephedrine does not seem to contribute significantly to 4-methylaminorex pharmacology.

Acute neurochemical and behavioral effects of stereoisomers of 4-methylaminorex in relation to brain drug concentrations.

4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with high-performance liquid chromatography/electrochemical detection and for cis- and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S > cis-4S,5R approximately cis-4R,5S > trans-4R,5R, and for elevating 5-HT cis-4S,5R > trans-4S,5S approximately cis-4R,5S > trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.