Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
153—Mood Disorders: Human Postmortem Studies
Sunday, November 10, 2013, 8:00 am - 12:00 noon
153.07: Up-regulation of the density of adenosine A1 and A2A receptors in the prefrontal cortex from postmortem tissue of suicide completers
Location: Halls B-H
*P. M. CANAS1, B. S. DA SILVA2, R. A. CUNHA3; 1Ctr. For Neurosci. and Cell Biol., Coimbra, Portugal; 2Natl. Inst. of Legal Med. and Forensic Sci. (INMLCF, I.P.), COIMBRA, Portugal; 3Ctr. For Neurosci. and Cell Biol. and Univ. of Coimbra, Coimbra, Portugal
Abstract Body: Chronic caffeine consumption attenuates the burden of repeated stress, the incidence of depression and suicide in humans and prevents phenotypic changes caused by chronic stress in rodents. Albeit the neurobiological basis of mood dysfunction is still ill defined, the involvement of pre-fronto-cortical circuits has been consistently reported, namely of Brodmann area 25 (BA25) in depression. The only known molecular target of caffeine in non-toxic doses is the antagonism of adenosine receptors and we have recently described an up-regulation of the adenosine neuromodulation system in the control of pre-frontal cortical function in animal models of attention deficit and hyperactivity disorders. Since 90% of suicide completers have clinical signs of depression, we now probed by Western blot analysis if there was also a modified density of adenosine A1 and A2A receptors (A1R, A2AR) in BA25 of suicide completers to justify targeting the adenosine neuromodulation system to manage mood dysfunction. We found an increase of the density of A1R (74.0±29.4%, n=6) and of A2AR (66.3±36.5%, n=6) in total extracts from BA25 of suicide completers compared to age-matched controls, using quality-validated (pH, RIN) postmortem fresh tissue samples. We next employed a subsynaptic fractionation, validated with adequate markers (syntaxin for presynaptic active zone; PSD-95 for postsynaptic density and synaptophysin for extra-synaptic zone), to determine if A2AR and A1R shared a common localization. We report that A2AR were predominantly located in nerve terminals outside of the active zone, although a minority was also located in the presynaptic active zone. In contrast, A1R were enriched in the active zone and in the postsynaptic density and in a lesser extent are located in the presynaptic active zone. These results show a different localization of adenosine receptors in the prefrontal cortex and confirm the up-regulation of adenosine receptors in the prefrontal cortex suicide completers, thus justifying the interest in targeting the adenosine neuromodulation system to manage mood disorders, namely depression.
Lay Language Summary: Our research indicates that the intake of caffeine can be helpful in preventing the occurrence of depression, as reported previously in retrospective studies. This information further validates the beneficial effects of caffeine already described in humans and in animal models for Parkinson's disease and Alzheimer’s disease. Additionally, in other animal models of brain disorders were also reported protective effects of caffeine namely: chronic stress, type 2 diabetes, attention deficit and hyperactivity disorder, early life convulsions, alcohol-induced amnesia and Machado-Joseph disease. Depression is the leading cause of disability in the working USA population. Often the outcome of the disease is impaired quality of life and a consequent increased suicide rate. Since currently used antidepressants have a limited efficacy, novel therapeutic strategies are required, a goal made difficult by our poor understanding of the neurobiological basis of depression. Hence, any attempt to better understand the cause and mechanisms of depression will help finding novel therapeutic strategies, and should be viewed as a socio-economical priority. Our results may explain why it was reported in the past, that chronic consumption of caffeine correlates inversely with the incidence of depression and with the risk of suicide. Chronic stress has being described a major risk factor for depression. Our group already confirmed that both caffeine and similar drugs that possess the same target prevented the behavioral modifications resulting from stress, in an animal model of chronic stress. The main target of caffeine is blocking adenosine receptors, especially adenosine A2A receptor. Our results show a different localization of adenosine receptors A1 and A2A in the prefrontal cortex and confirm the increase of adenosine receptors levels in the prefrontal cortex of suicide completers in a small study where we compared suicide completers and men with the same age that died from natural causes or car accidents. In the future we are planning to provide caffeine in the drinking water to an animal model of depression and to check if this constitutes a good anti-depressant strategy. This work justifies the interest in targeting the adenosine receptors to manage mood disorders, namely depression.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit