Modulatory effect of olanzapine on SMIM20/phoenixin, NPQ/spexin and NUCB2/nesfatin-1 gene expressions in the rat brainstem.

BACKGROUND: Phoenixin, spexin and nesfatin-1 belong to a family of newly discovered multifunctional neuropeptides that play regulatory roles in several brain structures and modulate the activity of important neural networks. However, little is known about their expression and action at the level of brainstem. The present work was, therefore, focused on gene expression of the aforementioned peptides in the brainstem of rats chronically treated with olanzapine, a second generation antipsychotic drug. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the brainstem excised. Total mRNA was isolated from homogenized samples of both structures and the RT-PCR method was used for estimation of related SMIM20/phoenixin, NPQ/spexin and NUCB2/nesfatin-1 gene expression. RESULTS: Long-term treatment with olanzapine is reflected in qualitatively different changes in expression of examined neuropeptides mRNA in the rat brainstem. Olanzapine significantly decreased NPQ/spexin mRNA expression, but increased SMIM20/phoenixin mRNA level in the rat brainstem; while NUCB2/nesfatin-1 mRNA expression remained unchanged. CONCLUSIONS: Olanzapine can affect novel peptidergic signaling in the rat brainstem. This may cautiously suggest the presence of an alternative mode of its action.

Olanzapine Increases Neural Chemorepulsant-Draxin Expression in the Adult Rat Hippocampus.

Draxin belongs to the family of inhibitory axon-guiding factors that regulate neuronal migration and axonal spreading in the developing brain. This glycoprotein has recently been considered to play an important role both in hippocampal differentiation and adult neurogenesis in the dentate gyrus. Given that it has been reported that antipsychotic drugs may affect neurite growth and neurogenesis, we have therefore investigated whether chronic treatment with olanzapine modulates draxin immunoreactivity in the adult rat hippocampus. After analysis of local fluorescence intensity, we found a significant increase of draxin immunoexpression both in the subgranular zone (SGZ) and granular zone of the rat hippocampus following long-term olanzapine administration. This study reveals, for the first time, the modulatory effect of the atypical antipsychotic medication olanzapine on expression of the novel chemorepulsive protein draxin in the context of adult neurogenesis regulation. Moreover, this is the first report dealing with pharmacological aspects of draxin signaling. An elevated draxin expression may indirectly support a recently formulated hypothesis that olanzapine may drive adult neurogenesis via paracrine draxin-related signaling. This action of draxin is a new element in the neurogenesis mechanism that may be part of the action of second-generation antipsychotics in the treatment of schizophrenia, indicating more detailed molecular studies are urgently required to fully investigate these potential novel mechanisms of neurogenesis.

Chlorpromazine affects the numbers of Sox-2, Musashi1 and DCX-expressing cells in the rat brain subventricular zone.

BACKGROUND: Adult neurogenesis observed both in the subventricular zone (SVZ) and hippocampus may be regulated and modulated by several endogenous factors, xenobiotics and medications. Classical and atypical antipsychotic drugs are able to affect neuronal and glial cell proliferation in the rat brain. The main purpose of this structural study was to determine whether chronic chlorpromazine treatment affects adult neurogenesis in the canonical sites of the rat brain. At present, the clinical application of chlorpromazine is rather limited; however, it may still represent an important model in basic neuropharmacological and toxicological studies. METHODS: The number of neural progenitors and immature neurons was enumerated using immunofluorescent detection of Sox2, Musashi1 and doublecortin (DCX) expression within SVZ. RESULTS: Chlorpromazine has a depressive effect on the early phase of adult neurogenesis in the rat subventricular zone (SVZ), as the mean number of Sox-2 immunoexpressing cells decreased following treatment. CONCLUSION: Collectively, these results may suggest that long-term treatment with chlorpromazine may decrease neurogenic stem/progenitor cell formation in the rat SVZ and may affect rostral migratory stream formation.