Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress

This abstract is technical and it may not be obvious what it is saying, but it is great news for coffee drinkers (and tea drinkers too). One of the neural circuits in our uses a neurotransmitter called glutamate. When too much of this activity happens it fries the neurons which is not a Good Thing. We like our neurons and want them to stay healthy. Some things have a protective effect, like NAC (N-Acetyl Cystine). Well, it turns out that another thing that protects your neurons from frying is caffeine!  

It is stress that causes your glutamate receptors to go nuts and start frying themselves. When that happens we get depressed (it is depressing to know you are frying neurons, isn’t it?). Drugs like lamotrigine, which is used for the depressed phase of bipolar disorder, also protect the neurons from getting fried by stress. 

It helps preserve your memory.

So, we have yet another reason to drink lots of coffee. Yay! I am going to go refill my coffee cup right now.

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress

Manuella P. Kastera,b,1, Nuno J. Machadoa,1, Henrique B. Silvaa,1, Ana Nunesa,1, Ana Paula Ardaisa,c, Magda Santanaa, Younis Baqid,e, Christa E. Müllerd, Ana Lúcia S. Rodriguesb, Lisiane O. Porciúnculac, Jiang Fan Chenf, Ângelo R. Toméa,g, Paula Agostinhoa,h, Paula M. Canasa, and Rodrigo A. Cunhaa,h,2Author AffiliationsEdited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved May 11, 2015 (received for review December 3, 2014)

Significant 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 A2A receptors (A2AR). CUS enhanced A2AR in synapses, and the selective elimination of neuronal A2AR abrogated CUS modifications. Moreover, A2AR blockade also afforded a therapeutic benefit, paving the way to consider A2AR blockers as a strategy to manage the negative impact of chronic stress on mood and memory.

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.chronic stress adenosine A2A receptor caffeine synaptic dysfunction mood dysfunction

Footnotes1M.P.K., N.J.M., H.B.S., and A.N. contributed equally to this work.2To whom correspondence should be addressed. Email: contributions: M.P.K., P.A., P.M.C., and R.A.C. designed research; A.L.S.R. provided important advice in planning experiments; M.P.K., N.J.M., H.B.S., A.N., A.P.A., M.S., Â.R.T., P.A., and P.M.C. performed research; Y.B., C.E.M., and J.F.C. contributed new reagents/analytic tools; M.P.K., N.J.M., H.B.S., A.N., A.P.A., A.L.S.R., L.O.P., Â.R.T., P.A., P.M.C., and R.A.C. analyzed data; and N.J.M. and R.A.C. wrote the paper.

Source: Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress

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