Effects of tamoxifen alone and in combination with risperidone on hyperlocomotion, hippocampal structure and bone in ketamine-induced model of psychosis in rats

Abstract

Background and aim of the work: Protein kinase C activation with subsequent increase in oxidative stress (OXS) and reduction in brain derived neurotrophic factor (BDNF) are implicated in the pathophysiology of psychotic disorders and in osteoporosis. Accordingly PKC inhibitors such as tamoxifen could be a novel approach to psychotic illness and may reduce progression of osteoporosis. Since current antipsychotics such as risperidone have inconsistent effects on OXS and BDNF, combination with tamoxifen could be beneficial. Accordingly in this work, tamoxifen was used to investigate the impact of changes in OXS and BDNF on behavioral, hippocampus structural changes in a ketamine induced model of psychosis in rats. The impact of tamoxifen on the antipsychotic effects of risperidone and on its bone damaging effects was also determined. Ketamine was chosen, because it is a valid model of psychosis. Hippocampus was chosen, since hippocampal overactivity is known to correlate with the severity of symptoms in psychosis. Hippocampal overactivity contributes to hyperdopaminergic state in ventral tegmental area and increase in DA release in nucleus accumbens, these are responsible for positive symptoms of schizophrenia and hyperlocomotion in rodents. Hyperlocomotion is considered a corelate of positive symptoms of psychotic illness in rodents and is considered primary outcome to assess manic-like behavior. Methods: Rats were divided into seven groups (ten rats each (1) non-ketamine control and (2) ketamine treated groups (a ketamine control, b risperidone/ketamine, c tamoxifen/ketamine, d Risp/Tamox/ketamine risperidone, tamoxifen/risperidone) to test if TAM exhibited behavioral changes or potentiated those of risperidone); (e clomiphene/ketamine and f clomiphene/risperidone/ketamine) to verify that estrogen receptor modulators do not exhibit behavioral changes or potentiates those of risperidone. In addition, thus, the effects of tamoxifen are not due to estrogen effects but rather due to protein kinase c inhibition. Drugs were given for 4 weeks and ketamine was given daily in the last week. Effects of drugs on ketamine-induced hyperlocomotion (open field test) and hippocampus and bone biochemical (MDA, GSH, BDNF) and histological changes (Nissel granules, GFAP positive astrocytes in hippocampus were determined). Electron microscopy scanning of the femur bone was done. Histomorphometric parameters measuring the: 1. Trabecular bone thickness and 2. The trabecular bone volume percentage. Results: Tamoxifen reduced hyperlocomotion, and improved hippocampus structure in ketamine-treated rats, by reducing OXS (reduced malondialdehyde and increased glutathione) and increasing BDNF. These effects might be related to (PKC) inhibition, rather than estrogen modulation, since the anti-estrogenic drug clomiphene had no effect on hyperlocomotion. Tamoxifen enhanced the beneficial effects of risperidone on hippocampal OXS and BDNF, augmenting its effectiveness on hyperlocomotion and hippocampal structure. It also reduced risperidone-induced OXS and the associated bone damage. Conclusions: PKC inhibitors, particularly tamoxifen, might be potential adjuncts to antipsychotics, by reducing OXS and increasing BDNF increasing their effectiveness while reducing their bone damaging effects.