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New Perspectives of Nandrolone Decanoate for Central Nervous System Injury and Neuroprotection

Studies directed to AAS effects on the opioid peptide systems also included examining interactions between the steroids and the hypophysis–pituitary–adrenal axis. It was thus reported that chronic administration of nandrolone decanoate specifically reduces the levels of POMC gene transcript in arcuate nucleus in the hypothalamus (Lindblom et al., 2003). As earlier mentioned, the POMC translational products include the endogenous opioid β-endorphin. A study measuring the β-endorphin immunoreactivity (ir) in the brain of male rats exposed to AAS reported that administration of the steroids significantly reduced the number of ir-β-endorphin-containing neurons in the rostral area of the arcuate nucleus in hypothalamus, whereas AAS treatment did not affect the expression in the caudal or middle regions of the arcuate nucleus (Menard et al., 1995). In a later study, Harlan and coworkers studied the effect of AAS on the brain response to morphine and found that the steroid blunted the c-Fos response to this opioid (Harlan et al., 2000). They also found that chronic AAS increased the content of β-endorphin in the midline thalamus and suggested that the steroids may modulate the response to morphine through a regulatory mechanism including thalamostriatal neurons.

A study focused on effects of AAS on the endogenous dynorphin and enkephalin systems in the male rat brain was aimed to explore the steroid effects on the mesocorticolimbic reward system (Johansson et al., 2000a). These two peptide systems are known to have an important function in the regulation of brain reward mediated through dopaminergic pathways originating in ventral tegmental area and extending to nucleus accumbens and prefrontal cortex. While the enkephalins may stimulate the release of dopamine and induce euphoria, the dynorphins act in an opposite direction (Koob, and Nestler, 1997). In the experiment reported by Johansson and coworkers, male rats were exposed to chronic AAS with intramuscular injections of nandrolone decanoate and the levels of the opioid peptides were recorded by radioimmunoassay in two groups immediately after treatment and in two other groups following 3 weeks of recovery (Johansson et al., 2000a). It was found that chronic AAS enhanced the ir-activity of both dynorphin B and Met-enkephalin-Arg6-Phe7(MEAP) in certain brain areas, including hypothalamus, striatum, and periaqueductal gray (PAG), whereas in the nucleus accumbens, the steroid induced an imbalance between the levels of dynorphin and the enkephalin heptapeptide (Johansson et al., 2000a). A similar imbalance was also observed in the hypothalamus and PAG. It was also demonstrated that this imbalance remained after the whole period of recovery and as it was found to occur in brain areas involved in the regulation of aggression and defensive reactions, as well as in emotions and dependence (Johansson et al., 2000a).

In a subsequent study, a possible relationship between AAS and voluntary ethanol intake in experimental rats was investigated. Male Sprague–Dawley rats were chronically treated with AAS; first group of animals was given free access to alcohol 1 week after completed steroid treatment, and a second group was exposed to voluntary intake of alcohol 3 weeks after steroid treatment (Johansson et al., 2000b). A subsequent assessment of defensive behaviors and levels of dynorphin-ir and MEAP-ir were carried out. The results indicated that the AAS-treated rats appeared significantly more aggressive, and in behavioral tests, they showed lower fleeing and freezing reaction than control animals. It was further seen that treatment with the AAS enhanced voluntary alcohol intake, regardless, whether the free access to alcohol was presented 1 or 3 weeks after the treatment with AAS was completed. In animals receiving AAS decreased levels of ir-dynorphin B in the nucleus accumbens, declined concentrations of ir-MEAP in the PAG and higher levels of ir-MEAP in the hypothalamus were found. From these studies, it was suggested that the alteration seen in the activity of the dynorphin peptide may be involved in the rewarding effects of ethanol and thereby increasing intake, whereas that seen in the enkephalin heptapeptide (MEAP) in, for example, PAG was suggested to be associated with the control of the aggressive reaction (Johansson et al., 2000b). Consequently, steroids like nandrolone may interact with the endogenous opioids and thereby bring about a danger coefficient for defensive aggression and increased consumption of alcohol. This lodgment of behavioral symptoms is closely related to acts of crimes and violence, which are often seen in individuals abusing AAS (Klötz et al., 2007; Lundholm et al., 2010; Skårberg et al., 2010).n the Endogenous Opioid Peptides

In very early studies examining the effects of chronic AAS on the endogenous opioid systems, it was reported that high doses of these steroids affected the levels of β-endorphin in the male rat brain (Menard et al., 1995; Johansson et al., 1997). Following 2 weeks daily injections of nandrolone decanoate into male rats, the concentration of β-endorphin was significantly increased in the ventral tegmental area (see Fig. 3), an observation suggesting that AAS activate the mesocorticolimbic dopamine pathway associated with brain reward (Johansson et al., 1997). The effect of the steroids on the dopaminergic pathway was strengthened in a subsequent study, where chronic AAS was found to induce significant effects on the expression of the dopamine D1 and D2 receptor proteins as observed in studies applying receptor autoradiography (Kindlundh et al., 2001). Also, the expression of dopamine receptor gene transcripts was altered in the brain of male rats exposed to chronic steroids at high doses (Kindlundh et al., 2003). Alterations in the dopamine D1 and D2 receptors as well as the dopamine transporter following chronic AAS administration were visualized by positron emission tomography (PET) in the male rat brain (Kindlundh et al., 2002). Chronic treatment with the AAS nandrolone decanoate caused an upregulation of the binding potential of the dopamine transporter in the striatum as seen by both the PET technique and the autoradiography (Kindlundh et al., 2004).

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