An update on the mechanisms of the psychostimulant effects of caffeine

Authors

  • Sergi Ferré

    1. National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA
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Address correspondence and reprint requests to Sergi Ferré, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Dr, Baltimore, MD 21224, USA.
E-mail: sferre@intra.nida.nih.gov

Abstract

There has been a long debate about the predominant involvement of the different adenosine receptor subtypes and the preferential role of pre- versus post-synaptic mechanisms in the psychostimulant effects of the adenosine receptor antagonist caffeine. Both striatal A1 and A2A receptors are involved in the motor-activating and probably reinforcing effects of caffeine, although they play a different role under conditions of acute or chronic caffeine administration. The present review emphasizes the key integrative role of adenosine and adenosine receptor heteromers in the computation of information at the level of the striatal spine module (SSM). This local module is mostly represented by the dendritic spine of the medium spiny neuron with its glutamatergic and dopaminergic synapses and astroglial processes that wrap the glutamatergic synapse. In the SSM, adenosine acts both pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A1 and A2A receptors among themselves and with D1 and D2 receptors, respectively. A critical aspect of the mechanisms of the psychostimulant effects of caffeine is its ability to release the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission by acting on different adenosine receptor heteromers localized in different elements of the SSM.

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