• Energy Research
• US close

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.

BackgroundCaffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)‐related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD‐1 mice.MethodsAcute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol‐induced (1.5 to 3.5 g/kg) changes in open‐field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor‐dependent phosphorylation markers were assessed: extracellular signal‐regulated kinase (pERK), and dopamine‐and cAMP‐regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP‐32‐Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol‐sensitized (1.5 g/kg) mice.ResultsAcute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol ‐induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol‐induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol‐sensitized mice in an ethanol‐free state resulted in blunted stimulant effects compared with those seen in ethanol‐naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP‐32(Thr75) immunoreactivity.ConclusionsThe present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol‐sensitized animals.

Abstract The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde's psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol's central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol.

Morphine- and ethanol-induced stimulation of neuronal firing of ventral tegmental area (VTA) dopaminergic neurons and of dopamine (DA) transmission in the shell of the nucleus accumbens (AcbSh) represents a crucial electrophysiological and neurochemical response underlying the ability of these compounds to elicit motivated behaviors and trigger a cascade of plasticity-related biochemical events. Previous studies indicate that the standardized methanolic extract of Withania somnifera roots (WSE) prevents morphine- and ethanol-elicited conditioned place preference and oral ethanol self-administration. Aim of the present research was to investigate whether WSE may also interfere with the ability of morphine and ethanol to stimulate VTA dopaminergic neurons and thus AcbSh DA transmission as assessed in male Sprague-Dawley rats by means of patch-clamp recordings in mesencephalic slices and in vivo brain microdialysis, respectively. Morphine and ethanol significantly stimulated spontaneous firing rate of VTA neurons and DA transmission in the AcbSh. WSE, at concentrations (200-400 μg/ml) that significantly reduce spontaneous neuronal firing of VTA DA neurons via a GABAA- but not GABAB-mediated mechanism, suppressed the stimulatory actions of both morphine and ethanol. Moreover, in vivo administration of WSE at a dose (75 mg/kg) that fails to affect basal DA transmission, significantly prevented both morphine- and ethanol-elicited increases of DA in the AcbSh. Overall, these results highlight the ability of WSE to interfere with morphine- and ethanol-mediated central effects and suggest a mechanistic interpretation of the efficacy of this extract to prevent the motivational properties of these compounds.

Background: Clinical and experimental studies support the therapeutic potential of Withania somnifera ( WS) (L.) Dunal on anxiety disorders. This potential is attributable to components present in different plant extracts; however, the individual compound(s) endowed with specific anxiolytic effects and potential modulatory activity of the GABAA receptor complex (GABAAR) have remained unidentified until the recent isolation from a WS methanolic root extract of some GABAAR-active compounds, including the long alkyl-chain ferulic acid ester, docosanyl ferulate (DF). Aims: This study was designed to assess whether DF (0.05, 0.25 and 2 mg/kg), similarly to diazepam (2 mg/kg), may exert anxiolytic effects, whether these effects may be significantly blocked by the benzodiazepine antagonist flumazenil (10 mg/kg) and whether DF may lack some of the benzodiazepines’ typical motor, cognitive and motivational side effects. Methods: The behavioural paradigms Elevated Plus Maze, Static Rods, Novel Object Recognition, Place Conditioning and potentiation of ethanol-induced Loss of Righting Reflex were applied on male CD-1 mice. Results: Similarly to diazepam, DF exerts anxiolytic effects that are blocked by flumazenil. Moreover, at the full anxiolytic dose of 2 mg/kg, DF lacks typical benzodiazepine-like side effects on motor and cognitive performances and on place conditioning. Moreover, DF fails to potentiate ethanol’s (3 g/kg) depressant activity at the ethanol-induced Loss of Righting Reflex paradigm. Conclusions: These data point to DF as an effective benzodiazepine-like anxiolytic compound that, in light of its lack of motor, mnemonic and motivational side effects, could be a suitable candidate for the treatment of anxiety disorders.