Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors

Abstract

Ethanol and caffeine are frequently consumed in combination and have opposite effects on the adenosine system: ethanol metabolism leads to an increase in adenosine levels, while caffeine is a non-selective adenosine A1/A2A receptor antagonist. These receptors are highly expressed in striatum and olfactory tubercle, brain areas involved in exploration and social interaction in rodents. Ethanol modulates social interaction processes, but the role of adenosine in social behavior is still poorly understood. The present work was undertaken to study the impact of ethanol, caffeine and their combination on social behavior, and to explore the involvement of A1 and A2A receptors on those actions. Male CD1 mice were evaluated in a social interaction three-chamber paradigm, for preference of conspecific vs. object, and also for long-term recognition memory of familiar vs. novel conspecific. Ethanol showed a biphasic effect, with low doses (0.25 g/kg) increasing social contact and higher doses (1.0–1.5 g/kg) reducing social interaction. However, no dose changed social preference; mice always spent more time sniffing the conspecific than the object, independently of the ethanol dose. Ethanol, even at doses that did not change social exploration, produced amnestic effects on social recognition the following day. Caffeine reduced social contact (15.0–60.0 mg/kg), and even blocked social preference at higher doses (30.0–60.0 mg/kg). The A1 antagonist Cyclopentyltheophylline (CPT; 3–9 mg/kg) did not modify social contact or preference on its own, and the A2A antagonist MSX-3 (1.5–6 mg/kg) increased social interaction at all doses. Ethanol at intermediate doses (0.5–1.0 g/kg) was able to reverse the reduction in social exploration induced by caffeine (15.0–30.0 mg/kg). Although there was no interaction between ethanol and CPT or MSX-3 on social exploration in the first day, MSX-3 blocked the amnestic effects of ethanol observed on the following day. Thus, ethanol impairs the formation of social memories, and A2A adenosine antagonists can prevent the amnestic effects of ethanol, so that animals can recognize familiar conspecifics. On the other hand, ethanol can counteract the social withdrawal induced by caffeine, a non-selective adenosine A1/A2A receptor antagonist. These results show the complex set of interactions between ethanol and caffeine, some of which could be the result of the opposing effects they have in modulating the adenosine system.

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

“…All drugs and vehicle (saline) solutions were administered intraperitoneally. Doses and times were selected based on previous experiments (Acquas et al, 2010; Hilbert et al, 2013; Ibba et al, 2009; López-Cruz et al, 2016; Rosas et al, 2017; SanMiguel et al, 2019; Spina et al, 2015).…”

“…For instance, in mice, low doses of caffeine (5-10 mg/kg) increase ethanol consumption, but higher doses (20 mg/kg) reduce intake (SanMiguel et al, 2019). In contrast, although low doses of caffeine are able to improve memory acquisition and retention in different learning models (Angelucci et al, 2002;Dash et al, 2004;Spinetta et al, 2008), caffeine in a wide range of doses (5-40 mg/kg) does not reverse the learning deficits caused by low doses of ethanol (1.0-1.4 g/kg) in a plus-maze discriminative avoidance task (Gulick and Gould, 2009) or in social recognition task (López-Cruz et al, 2016).…”

Genomic signatures of recent convergent transitions to social life in spiders

“…Genes involved in neurotransmitter secretion and neurotransmitter receptor transport stand out as interesting candidates influencing the evolution of spider social behavior because many genes annotated with these functions experienced significant shifts in evolutionary rates in social spiders and have also previously been implicated in the regulation of social behaviors in other animals (SI Appendix, Table S6). For example, the gene adenosine A 2A receptor ( adora2a ), which experienced relaxed selection in social spiders, regulates glutamate and dopamine release and influences motivation for social interactions in mice (63, 64), and variation in adora2a has been associated with mood and anxiety disorders in humans (65, 66). The gene dystrophin, isoforms A/C/F/G/H ( dys ), which experienced accelerated evolution in social spiders, affects social behavior, communication, and synaptic plasticity in mice (67, 68), and mutations in dys are associated with autism and intellectual disability in humans (68).…”

Caffeine Potentiates Ethanol-Induced Neurotoxicity Through mTOR/p70S6K/4E-BP1 Inhibition in SH-SY5Y Cells

“…Since blood alcohol levels at higher than 100 mg/dL can suppress human brain activity 45 and caffeine is a brain stimulant, the popular opinion is that caffeine can antagonize or at least reduce the neuropsychiatric and motor deficits induced by alcohol intoxication. 25,26 However, only some animal experiments supported the benefits of caffeine on neuronal functions. In a rat model of ischemic stroke, a combination of low-dose ethanol and caffeine protected the brain from damage only when treated immediately before or for 2 hours after focal stroke 28 but not for chronic daily oral ethanol plus caffeine prior to ischemia.…”

“…[21][22][23] Caffeine and ethanol act on the adenosinergic system in distinct ways resulting in opposing physiological effects. 24 Some studies suggested that caffeine antagonized the cognitive and behavioral effects caused by ethanol intoxication, 25,26 while neuroprotective effects of caffeine on ethanol-induced neuronal cell death have also been reported. Previous studies in rats showed that low doses of ethanol, which singularly aggravates cerebral ischemia, reduced ischemic damage when applied with caffeine, 27,28 while another study in a rat model of alcoholism showed that the simultaneous ingestion of ethanol and caffeine reversed ethanol-induced neuronal and glial cell death in the cerebellar tissue.…”