Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor

Abstract

High doses of anabolic androgenic steroid are associated with changes in personality, e.g. increased aggression and irritability, behavioural changes that may be linked to structural changes in the hippocampus. In this in vivo study we demonstrate acute effects of a single injection of 19-nortestosterone on proteins that play a major role in molecular plasticity at synaptic connections. The steroid rapidly and transiently decreased total and phosphorylated NMDA receptor GluN2B subunit levels and phosphorylated extracellular signal-regulated kinase 1 in rat hippocampal synaptoneurosomes. Pretreatment with the androgen receptor antagonist flutamide prevented these effects suggesting an androgen receptor mediated mode of action. However, flutamide alone stimulated the phosphorylation of both extracellular signal-regulated kinase 1 and 2. EphrinB2 and phosphorylated translation initiation factor 4E, two proteins that act on synaptic plasticity through NMDA receptor and/or mitogen-activated protein kinase pathways, were not affected by any of the treatment regimens. This study demonstrates rapid in vivo effects of an anabolic androgenic steroid on two key elements in hippocampal synaptic plasticity.

Neural Androgen Receptor Deletion Impairs the Temporal Processing of Objects and Hippocampal CA1-Dependent Mechanisms

“…We found that the deficits of NMDAR activation occurred principally at the postsynaptic level, since the magnitude of the NMDAR-mediated field excitatory postsynaptic potentials were decreased whereas activation of presynaptic fiber volleys was not affected. The normal levels of protein for NMDAR subunits in the CA1 of AR NesCre males strongly suggest that the impaired activation of NMDAR is rather due to changes in the functional or pharmacological properties of the receptor, as reported for anabolic androgens [ 55 ]. It is important to note that neural AR deletion had differential effects on the expression of NMDAR-dependent synaptic plasticity depending on the strength of the presynaptic activation.…”

The Buzz about Anabolic Androgenic Steroids: Electrophysiological Effects in Excitable Tissues

“…Given the broad range of actions that endogenous androgens have on ion channel function in electrically excitable tissue (33), it is likely that these synthetic steroids also alter neuronal function via effects on voltage-gated channels and intracellular ion homeostasis in the CNS. Assessment of how AAS modify expression of these other receptors and channels and how they influence their function via phosphorylation (96, 126) or direct allosteric modulation remain critical questions that need to be addressed to fully understand the neural and behavioral consequences of both licit and illicit use of AAS.…”

Rapid Modulation of Aromatase Activity in the Vertebrate Brain

“…For example, the acute elevation of steroid hormones in vitro triggers the activation of numerous intracellular signaling pathways, including the modulation of intracellular calcium concentrations and the phosphorylation of a variety of proteins such as the mitogen-activated protein kinase (MAPK) and cAMP response element binding protein (CREB) 1–6. Importantly, these fast changes induced by steroid hormones at the molecular levels were also shown to rapidly modulate neuronal activation in various brain regions, and, in some cases, were shown to acutely affect behavior 7–12. In particular, one of these steroid hormones, 17β-estradiol (E2), has been the focus of an extensive research, and our lab, amongst others, has shown that the specific activation of estrogen receptors leads to rapid modulation of behavior, including motivation to approach and copulate with a female 13,14.…”

“…[1][2][3][4][5][6] Importantly, these fast changes induced by steroid hormones at the molecular levels were also shown to rapidly modulate neuronal activation in various brain regions, and, in some cases, were shown to acutely affect behavior. [7][8][9][10][11][12] In particular, one of these steroid hormones, 17β-estradiol (E2), has been the focus of an extensive research, and our lab, amongst others, has shown that the specific activation of estrogen receptors leads to rapid modulation of behavior, including motivation to approach and copulate with a female. 13,14 While the rapid effects of steroid hormones have received a lot of attention, there remain numerous questions concerning how this rapid change in steroid concentration can occur.…”