Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania

Abstract

Lithium (Li) is the main mood stabilizer and acts on multiple biochemical targets, leading to neuronal plasticity. Several clinical studies have shown that tamoxifen (TMX) - a protein kinase C (PKC) inhibitor - has been effective in treating acute mania. The present study aims to evaluate the effects of TMX on biochemical targets of Li, such as glycogen synthase kinase-3β (GSK-3β), PKC, PKA, CREB, BDNF and NGF, in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were treated with d-AMPH (2mg/kg, once a day) or saline (Sal; NaCl 0.9%, w/v), Li (47.5 mg/kg, intraperitoneally (i.p.), twice a day) or TMX (1 mg/kg i.p., twice a day) or Sal in protocols of reversion and prevention treatment. Locomotor behavior was assessed using the open-field task, and protein levels were measured by immunoblot. Li and TMX reversed and prevented d-AMPH-induced hyperactivity. Western blot showed that d-AMPH significantly increased GSK-3 and PKC levels, and decreased pGSK-3, PKA, NGF, BDNF and CREB levels in the structures analyzed. Li and TMX were able to prevent and reverse these changes induced by d-AMPH in most structures evaluated. The present study demonstrated that the PKC inhibitor modulates the alterations in the behavior, neurotrophic and apoptosis pathway induced by d-AMPH, reinforcing the need for more studies of PKC as a possible target for treatment of bipolar disorder.

cAMP Response Element-binding Protein (CREB) and Nuclear Factor κB Mediate the Tamoxifen-induced Up-regulation of Glutamate Transporter 1 (GLT-1) in Rat Astrocytes

“…In the rat hippocampus, TX regulates the expression of synaptophysin via CREB (51). TX-induced CREB activation is also involved in improving acute mania (52). Our finding shows that the NF-B pathway plays a critical role in TX-induced GLT-1 expression (Figs.…”

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

“…Increased PKC activity is observed in the PFC of rats submitted to AMPH administration [47,48]. AMPH-induced hyperlocomotion has been shown to be reversed [7] and prevented [49] by intraperitoneal administration of lithium or tamoxifen (TMX), a selective estrogen receptor modulator with PKC inhibitory activity [8,50]. Similarly, intraperitoneal administration of quercetin, a nonspecific PKC inhibitor, also prevented methylphenidate-induced hyperlocomotion [51].…”

“…The manic phenotype is usually induced in animal models by pharmacological (amphetamine [AMPH] and ouabain), environmental (paradoxical sleep deprivation [PSD]), and genetic (black Swiss mice) interventions [6]. These interventions induce behavioral changes that are analogous to manic symptoms, such as hyperlocomotion [7], insomnia, risk-taking behavior [8], and increased appetitive 50-kHz ultrasonic vocalizations (USV; a marker for euphoric mood and pressured speech) [9]. These models are tested for their face (animals mimicking manic symptoms), construct (correlation of similar pathophysiological alteration at molecular level), and predictive (amelioration of symptoms by currently accepted treatments of mania) validity to enhance our understanding of BD [10].…”

Contributions of animal models to the study of mood disorders

“…[117][118][119] Several studies have demonstrated that the chronic administration of AMPH decreases BDNF levels in the cerebral tissues of rats. [117][118][119] BDNF is a protein secreted by the brain responsible for regulating neural circuit development and function. The actions of BDNF are controlled by neural activity and its functions include neuronal differentiation, growth, and plasticity.…”

“…In addition, TMX as well as lithium increased levels of BDNF and Bcl-2, which are anti-apoptotic proteins. 118 The number of potential new drugs tested in animal models is growing, which helps further our knowledge of the pathophysiology of BD and supports the development of better drugs for the treatment of this disorder.…”