Antidepressant phenotype by inhibiting the phospholipase Cβ1 – Protein kinase Cγ pathway in the forced swim test

Abstract

a b s t r a c tAlthough great advances have recently been made in the study of signal transduction, the pathogenesis of affective disorders is still unknown. There is mounting evidence suggesting that elevated phosphoinositideeprotein kinase C (PIePKC) signal transduction pathway may be a pathophysiological feature of bipolar and major depressive disorders. The aim of the present study was to further investigated the phospholipase Ceprotein kinase C (PLCePKC) cascade by evaluating the effect produced by an acute blockade of this intracellular pathway at PLC and PKC level. Adult male mice were administered with pharmacological inhibitors of PLC or PKC and then subjected to the forced swim test (FST), an animal model which emulates the behavioural despair paradigm of depression. In this study we also tested the hypothesis that it might be possible to selectively modulate depressive behaviour by inhibiting the expression of specific PLC and PKC isoforms by means of specific antisense oligonucleotides (aODNs). Administration of the PLC inhibitors neomycin and U73122 as well as of the PKC inhibitors calphostin C and chelerytrine dose-dependently reduced the immobility time in the FST producing an antidepressant-like behaviour. Selective knockdown of the PLCb 1 and PKCg isoforms also induced an antidepressant phenotype. Conversely, the inhibition of the expression of PLCb 3 was unable to modify the immobility time values. The PLC and PKC modulators used, at the highest effective doses, altered neither locomotor activity nor motor coordination. We demonstrate that selective blockade of PLCb 1 ePKCg signalling pathway produces an antidepressant-like phenotype in mice.

Neurobehavioral phenotyping of Gαq knockout mice reveals impairments in motor functions and spatial working memory without changes in anxiety or behavioral despair

“…Additionally, we observed no significant differences in the forced swim test assessing depressive-like phenotypes. These results were unexpected as there is evidence in the literature suggesting that inhibiting the PLC—protein kinase C signaling transduction pathway or intracellular calcium release (which can be activated by G αq -coupled receptors) produces antidepressant effects in the forced swim test (Galeotti et al, 2006; Galeotti and Ghelardini, 2011). There is also evidence suggesting that chronic stress in rodent models alters transcript levels of Gnaq (Alfonso et al, 2006); another implication of alterations in G αq signaling in rodent models of depression.…”

Molecular and behavioral characterization of adolescent protein kinase C following high dose ethanol exposure

“…Blood samples were taken from the tail immediately after rats regained the righting reflex and analyzed using an AM5 Alcohol Analyzer (Analox Instruments, Lunenburg, MA). Notably, PDBu, CalC and AACOCF 3 do not elicit hypnotic effects in the absence of ethanol (Galeotti & Ghelardini 2011; Yeo et al 2004). With the exception of PDBu-treated adolescents, only 1–2 rats per group failed to lose their righting reflex.…”

Immune-enhancing effect of Danggwibohyeoltang, an extract fromAstragali RadixandAngelicae gigantis Radix,in vitroandin vivo

“…The FST is also a potent psychophysiological stressor that alters physiological endocrine and immune function. (26,27) In general, the swimming exercise is known to induce biochemical changes related to fatigue including Glc, TP, LDH, CK, and BUN levels in blood. (16) To demonstrate the antifatigue effect of DGBHT, we performed FST with ICR mice.…”