Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine PKC412 (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-l-y1) methylamine (TCB-2) increased locomotor activity. By
contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link
between 5-HT2A activation and hallucinogenesis. (C) 2013 Elsevier Ltd. All rights reserved.”
“Purpose: Atypical antipsychotics have neuroprotective effects, which may be one of the mechanisms for their success in the treatment of schizophrenia. Growing evidence suggest that brain-derived neurotrophic factor (BDNF) is abnormally regulated in patients with schizophrenia, and its expression can be up-regulated during by atypical antipsychotics. Selleck VX-809 Atypical antipsychotic drugs may positively regulate transcription of the BDNF gene, but the molecular mechanism of atypical antipsychotic drug action on BDNF gene activity has not been investigated. The aim of the present study was to explore the possible involvement of some intracellular signaling pathways in olanzapine action on BDNF promoter activity.
Methods: We examined the effects of olanzapine on BDNF gene promoter activity in SH-SY5Y cells transfected
with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in glycogen synthase kinase-3 beta (GSK-3 beta) and cAMP response element (CRE) binding protein (CREB) phosphorylation were measured by Western blot analysis.
Results: Olanzapine treatment (10-100 mu M) increased basal BDNF gene promoter activity in a dose-dependent manner and increased protein levels at high dose, and inhibitors of protein kinase A (PKA), H-89 (10 mu M), phosphatidylinositol 3-kinase (PI3K), wortmannin (0.01 mu M), PKC (protein kinase C), GF109203 (10 mu M), calcium/calmodulin kinase II (CaMKII), and KN-93 (20 mu M) partially attenuated the stimulatory effect of olanzapine on BDNF promoter activity.