Significance: Epidemiological studies show that individuals exposed to repeated stress, a major trigger of depression, increase their caffeine intake, which correlates inversely with the incidence of depression. However, the mechanism underlying this protective effect is unknown. We used an animal model of chronic unpredictable stress (CUS) to show that caffeine prevents the maladaptive changes caused by CUS in a manner mimicked by the selective blockade of adenosine A _2A receptors (A _2A R). CUS enhanced A _2A R in synapses, and the selective elimination of neuronal A _2A R abrogated CUS modifications. Moreover, A _2A R blockade also afforded a therapeutic benefit, paving the way to consider A _2A R blockers as a strategy to manage the negative impact of chronic stress on mood and memory.

Many plants, including some of the commonly consumed herbs and spices in our daily food, can be safely and effectively used to prevent and/or treat some health concerns. For example, caffeine the active ingredient found in coffee beans (Coffea), shows biological activity in the treatment of the central nervous system (CNS) disorders, indole-3-carbinol and 3,3'-diindolylmethane are both broccoli (Brassica oleracea) derived phytochemicals with potential anti-cancer activity, and resveratrol, isolated from grape (Vitis vinifera), is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects. Date palm fruits possess high nutritional and therapeutic value with significant antioxidant, antibacterial, antifungal and anti-proliferative properties. This review focuses on the date fruits extracts and their benefits in individual health promoting conditions and highlights their application as useful to the nutraceutical and pharmaceutical industries in the development of natural compound-based products.

Mesolimbic dopamine (DA) is involved in behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. In the present study, the effects of several drug treatments were assessed using a progressive ratio (PROG)/chow feeding concurrent choice task. With this task, rats can lever press on a PROG schedule reinforced by a preferred high-carbohydrate food pellet, or alternatively approach and consume the less-preferred but concurrently available laboratory chow. Rats pass through each ratio level 15 times, after which the ratio requirement is incremented by one additional response. The DA D₂ antagonist haloperidol (0.025–0.1 mg/kg) reduced number of lever presses and highest ratio achieved but did not reduce chow intake. In contrast, the adenosine A_2A antagonist MSX-3 increased lever presses and highest ratio achieved, but decreased chow consumption. The cannabinoid CB1 inverse agonist and putative appetite suppressant AM251 decreased lever presses, highest ratio achieved, and chow intake; this effect was similar to that produced by pre-feeding. Furthermore, DA-related signal transduction activity (pDARPP-32(Thr34) expression) was greater in nucleus accumbens core of high responders (rats with high lever pressing output) compared to low responders. Thus, the effects of DA antagonism differed greatly from those produced by pre-feeding or reduced CB1 transmission, and it appears unlikely that haloperidol reduces PROG responding because of a general reduction in primary food motivation or the unconditioned reinforcing properties of food. Furthermore, accumbens core signal transduction activity is related to individual differences in work output.

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A_2A receptor (A_2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A_2AR in age-related conditions. We report, for the first time, a significant overexpression of A_2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A_2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca²⁺ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A_2AR blockade. This A_2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Consumption of certain substances during pregnancy can interfere with brain development, leading to deleterious long-term neurological and cognitive impairments in offspring. To test whether modulators of adenosine receptors affect neural development, we exposed mouse dams to a subtype-selective adenosine type 2A receptor (A_2AR) antagonist or to caffeine, a naturally occurring adenosine receptor antagonist, during pregnancy and lactation. We observed delayed migration and insertion of γ-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the first postnatal week in offspring of dams treated with the A_2AR antagonist or caffeine. This was associated with increased neuronal network excitability and increased susceptibility to seizures in response to a seizure-inducing agent. Adult offspring of mouse dams exposed to A_2AR antagonists during pregnancy and lactation displayed loss of hippocampal GABA neurons and some cognitive deficits. These results demonstrate that exposure to A_2AR antagonists including caffeine during pregnancy and lactation in rodents may have adverse effects on the neural development of their offspring.