Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice

Abstract

Background Docosanyl ferulate (DF) is a behaviourally active GABAA receptor complex (GABAAR) agonist, recently isolated from the standardized methanolic extract of Withania somnifera Dunal (WSE) root. Previous studies have shown that WSE prevents both ethanol- and morphine-dependent acquisition and expression of conditioned place preference (CPP) and stimulation of dopamine release in the nucleus accumbens shell (AcbSh). Aims The study aimed at determining (a) whether DF contributes to WSE’s ability to affect the acquisition and expression of ethanol- and morphine-elicited CPP and, given that phosphorylation of extracellular signal-regulated kinase (pERK) in the AcbSh is involved in associative learning and motivated behaviours, (b) whether WSE and DF may affect ethanol- and morphine-induced ERKs phosphorylation in the AcbSh. Methods In adult male CD1 mice, DF’s effects on the acquisition and expression of ethanol- and morphine-elicited CPP were evaluated by a classical place conditioning paradigm, whereas the effects of WSE and DF on ethanol- and morphine-elicited pERK in the AcbSh were evaluated by immunohistochemistry. Results and conclusions The study shows that DF, differently from WSE, affects only the acquisition but not the expression of ethanol- and morphine-induced CPP. Moreover, the study shows that both WSE and DF can prevent ethanol- and morphine-elicited pERK expression in the AcbSh. Overall, these results highlight subtle but critical differences for the role of GABAARs in the mechanism by which WSE affects these ethanol- and morphine-dependent behavioural and molecular/cellular responses and support the suggestion of WSE and DF for the control of different components of drug addiction.

Alkaloids in Withania somnifera (L.) Dunal Root Extract Contribute to Its Anti-Inflammatory Activity

“…Most importantly, our results may suggest that new possible directions in the development of the therapeutic perspectives of WS extracts should take advantage from the use of alkaloid-enriched fractions, since a favorable efficacy/tolerability profile could be observed in vitro when WSA is compared to conventional WSE and WSW in RAW 264.7 macrophages. This finding is consistent with recent studies showing that WS components diverse from withanolides have relevant pharmacological activity, thus calling for future in vitro and in vivo studies on WS [29][30][31].…”

Withania somnifera influences MDMA-induced hyperthermic, cognitive, neurotoxic and neuroinflammatory effects in mice

“…Similar to what observed in morphine-treated mice, WSE administration reduced the motivation for alcohol drinking, the alcohol deprivation effect, and the reinstatement of alcohol-seeking behaviour evaluated with the operant self-administration paradigm [23]. Moreover, WSE impaired the acquisition and expression of alcohol-elicited place conditioning as well as the phosphorylation of the extracellular signal-regulated kinase in the shell of the nucleus accumbens of mice [9,24], and prevented both morphine-and alcohol-elicited mesolimbic increases in dopamine transmission in rats [7].…”

“…Interestingly, rodent studies from our group have previously demonstrated the efficacy of WSE in contrasting alterations associated not only with neurological disorders [1][2][3][4][5][6], but also with the exposure to addictive drugs, such as morphine and alcohol. Consistent with this, rodents treated with WSE displayed a reduction in the behavioral and neurochemical alterations induced by morphine or alcohol administration [7][8][9]. These findings indicate that WSE positively affects brain function and led us to hypothesize that it could also contrast the detrimental effects elicited in the brain by amphetamine-related drugs endowed with neurotoxic and neuroinflammatory properties.…”

“…PC/FWS1701003) was solubilized in saline and administered intraperitoneally (i.p.) in a volume of 10 ml/kg as described elsewhere [9,21,22,24]. MDMA was synthesized, solubilized, and administered by the i.p.…”

“…Solanaceae), commonly known as Ashwagandha, is a medicinal plant widely used in Ayurveda, the traditional medicine heavily practiced in India and Nepal, for the treatment of various pathological conditions. Over the last decades, several experimental studies have characterized the pharmacological properties of Withania somnifera (L.) Dunal root extract (WSE) in models of neurodegenerative diseases, such as Alzheimer's disease (AD) [1][2][3] and Parkinson's disease (PD) [4][5][6], but also in experimental animals exposed to drugs of abuse [7][8][9]. In addition, other experimental studies have demonstrated the efficacy of WSE in models of cancer, rheumatoid arthritis, stress and systemic inflammation [10][11][12][13][14].…”