IntroductionDue to the heterogeneity of psychiatric illnesses and overlapping mechanisms, patients with psychosis are differentially responsive to pharmaceutical drugs. In addition to having therapeutic effects for schizophrenia and bipolar disorder, antipsychotics and mood stabilizers have many clinical applications and are used unconventionally due to their direct and indirect effects on neurotransmitters. Synapsins, a family of neuronal phosphoproteins, play a key regulatory role in neurotransmitter release at synapses. In this study, we investigated the effects of mood stabilizers, lithium, and valproic acid on synapsin gene expression in the rat brain.MethodsIntraperitoneal injections of saline, lithium, and valproic acid were administered to male Sprague Dawley rats twice daily for 14 d, corresponding to their treatment group. Following decapitation and brain tissue isolation, mRNA was extracted from various brain regions including the hippocampus, striatum, prefrontal cortex, and frontal cortex.ResultsBiochemical analysis revealed that lithium significantly increased gene expression of synapsin I in the striatum, synapsin IIa in the hippocampus and prefrontal cortex, and synapsin IIb in the hippocampus and striatum. Valproic acid significantly increased synapsin IIa in the hippocampus and prefrontal cortex, as well as synapsin IIb in the hippocampus and striatum.ConclusionThese significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics and provide deeper insight on the involvement of synaptic proteins in treating neuropsychiatric illnesses.

Background Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Procedure Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein‐1 (AP‐1) inhibitor for 24–72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT‐qPCR. Results In vitro studies showed lithium‐treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP‐1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium‐treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Conclusion Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP‐1 transcription factor.

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Background: Bipolar disorder (BD) is a recurrent chronic psychiatric disorder. Evidence indicates that many individuals with BD exhibit high serum levels of inflammation and oxidative stress markers, which are further associated with mood symptoms and cognitive dysfunction. Due to the crosstalk between the periphery and central nervous system in BD, the disruption of the blood-brain barrier (BBB) has been proposed as a key mechanism of the pathophysiology of the disorder. This study aimed to investigate claudin-5 expression – a major protein of the BBB – in the brain of an animal model of mania induced by d-amphetamine (AMPH) and evaluate the effects of treatment with lithium. Results: AMPH-injected animals exhibited increased overall activity in the open field test. In the serum, TBARS levels were augmented in the lithium-treated groups, regardless of AMPH injection, while TNFα was not detected. In the brain, TBARS and TNFα did not differ between groups but were positively and strongly correlated in the ST of AMPH-injected rats. Contrary to the primary hypothesis, AMPH and lithium injections did not affect brain claudin-5 protein levels.Conclusions: This is one of the first attempts to investigate the effects of AMPH on BBB integrity. Although no evidence of BBB disruption was found in the current study, our results provide evidence and rationale for future research to elucidate the importance of such alteration in BD.