Caffeine is the most widely consumed psychoactive substance. It is estimated that caffeine consumption from all sources averages approximately 70 mg/person/day worldwide and -220 mg/day/person in the US and Canada. Moderate consumption of caffeine produces overall psychostimulant effects (reducing fatigue, enhancing performance) in humans with little risk of harmful side effects. Caffeine is known to act at a multitude of molecular targets. Therefore, depending on dose, caffeine can produce many different effects in the intact organism. Presently, caffeine is believed to exert its effects primarily by blocking brain adenosine, particularly AI and A2A receptors. However, the evidence is circumstantial and the possible contribution of other molecular targets, particularly in the untoward effects of higher doses, remains to be determined. The overall goal of the proposed studies is to conclusively assess the contribution of the AI and A2A receptors and of the central versus peripheral Aj/AaA receptors to caffeine's psychostimulant and cardiovascular effects in mature and developing animals. This proposal is built on our successful development of two novel adenosine receptor knockout models: the congenic Ai-A2A receptor double knockout and a conditional, tissue-specific A2A receptor knockout mouse. With these novel knockout models coupled with molecular, neurochemical and pharmacological analyses, we will test the hypotheses that: (1) forebrain A2A receptors are essential for the psychostimulant properties of caffeine, and combined blockade of AI and A2A receptors mediate most effects of caffeine in adult animals; (2) both AI and A2A receptors contribute to the cardiovascular response to acute caffeine, and (3) the short and long-term effects of caffeine on immature animals are distinct from effects in adults and are mediated by different molecular targets. The information derived from these studies will provide the clearest assessment yet of the role of subtypes of adenosine receptors in mediating caffeine's psychostimulant effect. This will also shed light on the long-term effects of perinatal caffeine exposure, which may have significant public health relevance. This knowledge will significantly enhance our understanding of caffeine's psychostimulant action, and provide a neurobiological basis for guidelines for healthy usage of caffeine as a stimulant to improve human performance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048995-03
Application #
7271838
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Mitler, Merrill
Project Start
2005-08-15
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$302,982
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Wei, Catherine J; Augusto, Elisabete; Gomes, Catarina A et al. (2014) Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol Psychiatry 75:855-63
Shen, Hai-Ying; Canas, Paula M; Garcia-Sanz, Patricia et al. (2013) Adenosine A?A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8:e80902
Wei, Catherine J; Singer, Philipp; Coelho, Joana et al. (2011) Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning. Learn Mem 18:459-74
Lazarus, Michael; Shen, Hai-Ying; Cherasse, Yoan et al. (2011) Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J Neurosci 31:10067-75
Xu, M H; Gong, Y S; Su, M S et al. (2011) Absence of the adenosine A2A receptor confers pulmonary arterial hypertension and increased pulmonary vascular remodeling in mice. J Vasc Res 48:171-83
Boison, D; Chen, J-F; Fredholm, B B (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071-82
Zhou, Xiangtian; Huang, Qinzhu; An, Jianhong et al. (2010) Genetic deletion of the adenosine A2A receptor confers postnatal development of relative myopia in mice. Invest Ophthalmol Vis Sci 51:4362-70
Yang, J N; Wang, Y; Garcia-Roves, P M et al. (2010) Adenosine A(3) receptors regulate heart rate, motor activity and body temperature. Acta Physiol (Oxf) 199:221-30
Dai, Shuang-Shuang; Zhou, Yuan-Guo; Li, Wei et al. (2010) Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci 30:5802-10
Chen, Jiang-Fan; Yu, Liqun; Shen, Hai-Ying et al. (2010) What knock-out animals tell us about the effects of caffeine. J Alzheimers Dis 20 Suppl 1:S17-24

Showing the most recent 10 out of 19 publications