Effects of caffeine on ethanol-elicited place preference, place aversion and ERK phosphorylation in CD-1 mice

Abstract

Background: Epidemiological studies indicate a rise in the combined consumption of caffeinated and alcoholic beverages, which can lead to increased risk of alcoholic-beverage overconsumption. However, the effects of the combination of caffeine and ethanol in animal models related to aspects of drug addiction are still underexplored. Aims: To characterize the pharmacological interaction between caffeine and ethanol and establish if caffeine can affect the ability of ethanol (2 g/kg) to elicit conditioned place preference and conditioned place aversion, we administered caffeine (3 or 15 mg/kg) to male CD-1 mice before saline or ethanol. Moreover, we determined if these doses of caffeine could affect ethanol (2 g/kg) elicited extracellular signal-regulated kinase phosphorylation in brain areas, nucleus accumbens, bed nucleus of stria terminalis, central nucleus of the amygdala, and basolateral amygdala, previously associated with this type of associative learning. Results: In the place-conditioning paradigm, caffeine did not have an effect on its own, whereas ethanol elicited significant conditioned-place preference and conditioned-place aversion. Caffeine (15 mg/kg) significantly prevented the acquisition of ethanol-elicited conditioned-place preference and, at both doses, also prevented the acquisition of ethanol-elicited conditioned-place aversion. Moreover, both doses of caffeine also prevented ethanol-elicited extracellular signal-regulated kinase phosphorylation expression in all brain areas examined. Conclusions: The present data indicate a functional antagonistic action of caffeine and ethanol on associative learning and extracellular signal-regulated kinase phosphorylation after an acute interaction. These results could provide exciting grounds for further studies, also in a translational perspective, of their pharmacological interaction modulating other processes involved in drug consumption and addiction.

Impact of Caffeine on Ethanol‐Induced Stimulation and Sensitization: Changes in ERK and DARPP‐32 Phosphorylation in Nucleus Accumbens

“…Interestingly, in the present study using mice, EtOH (1.5 g/kg) significantly induced pERK, and this effect was counteracted by caffeine at both doses in both AcbC and AcbSh. These results are consistent with a recent paper from our laboratory in which caffeine (3 and 15 mg/kg) blocked EtOH (2.0 g/kg) induction of pERK in both subregions of Acb as well as 2 nuclei in the amygdala in this same strain of mice (Porru et al, 2020).…”

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

“…The results of the present study also confirm that both ethanol (Porru et al 2020(Porru et al , 2021Rosas et al 2017) and morphine (Rosas et al 2016;Valjent et al 2004) activate ERKs phosphorylation in the AcbSh of CD1 mice and show for the first time that both WSE (50 mg/kg) and DF (2 mg/ kg) are able to prevent these increases. The acute effects of WSE and DF in the prevention of either ethanol-or morphine-induced ERKs phosphorylation in the AcbSh was assessed, in distinct cohorts of animals, to better define the molecular mechanisms leading to WSE's and DF's prevention of the acquisition of ethanol-or morphine-elicited CPP.…”

“…Post-hoc analysis using the Newman-Keuls test confirmed that EtOH increases the number of AcbSh pERK-positive neurons (Ibba et al 2009;Porru et al 2020) and showed that pre-treatment with DF prevents this effect (p < 0.05). Figure 4B shows the effects of pre-treatment with vehicle (Veh) or DF (2 mg/kg) 30 min before the administration of vehicle (Veh) or morphine (MOR, 5 mg/kg) on the number of pERK-positive neurons in the AcbSh.…”

“…One-way ANOVA revealed that pre-conditioning preference times did not significantly differ between experimental groups (p > 0.05). Repeated measures three-way ANOVA with preference times (pre-and post-conditioning) as dependent factors, and with pre-treatment (Veh or DF) and treatment (Veh or EtOH) as independent factors, revealed significant effects of time [F (1,52) = 9.40, p < 0.005], pre-treatment [F (1,52) = 4.39, p < 0.05] and treatment [F (1,52) = 6.58, p < 0.05] confirming that EtOH stimulates a significant preference shift (Porru et al 2020;Spina et al 2015), indicating that DF on its own is devoid of conditioning properties (Maccioni et al 2021) and suggesting that it may significantly prevent the acquisition of CPP induced by EtOH (p < 0.05). Figure 1B shows the effects of treatment with vehicle (Veh) or DF (2 mg/kg) 30 min before the exposure to the two compartments for the post-conditioning test of mice conditioned with (pretreatment/treatment) Veh/Veh and Veh/EtOH.…”

“…Figure 3A shows the effects of pre-treatment with vehicle (Veh) or WSE (50 mg/kg) 30 min before the administration of vehicle (Veh) or ethanol (EtOH, 2 g/kg) (treatment) on the number of pERK-positive neurons (pERK expression) in the AcbSh. Two-way ANOVA with pre-treatment and treatment as categorical variables and pERK-positive cells counts as dependent variable revealed significant effects of pre-treatment [F (1, 24) = 7.86; p < 0.05) and treatment [F (1, 24) = 5.03; p < 0.05) confirming that ethanol increases the number of pERK-positive neurons (Ibba et al 2009;Porru et al 2020) and suggesting that pre-treatment with WSE may significantly prevent ethanol-induced ERK phosphorylation (p < 0.05). Figure 3B shows the effects of pre-treatment with vehicle (Veh) or WSE (50 mg/kg) 30 min before the administration of vehicle (Veh) or morphine (MOR, 5 mg/kg) (treatment) on the number of pERK-positive neurons in the AcbSh.…”