CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Role of adenosine A2A receptor on psychostimulant effect of caffeine


Caffeine is the most widely consumed psychostimulant substance, being self-administered throughout a wide range of conditions and present in numerous dietary products. Due to its widespread use and low abuse potential, caffeine is considered an atypical drug of abuse. The main mechanism of action of caffeine occurs via the blockade of adenosine A1 and A2A receptors. Adenosine is a modulator of CNS neurotransmission and its modulation of dopamine transmission through A2A receptors has been implicated in the motor stimulating effects of caffeine.

Some results

Our group examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity in neurologically intact and unilaterally 6-hydroxydopamine-(6-OHDA)-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor activity in intact rats and in turning behaviour in 6-OHDA-lesioned rats. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-OHDA-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects and induces neuroadaptive facilitatory changes in dopamine transmission.

Moreover, we have showed that the sensitized motor response to caffeine was associated with a decrease of adenosine A2A receptor and zif-268 mRNA levels in enkephalinergic neurons in the striatum and nucleus accumbens, whereas cross-sensitization to amphetamine was linked to a more pronounced increase of zif-268 mRNA levels, in the striatum, but not in the nucleus accumbens. Potentiation of amphetamine effects was not associated with modifications of amphetamine-induced dopamine release in nucleus accumbens in caffeine-pretreated rats compared with vehicle-pretreated rats. Results demonstrate that sensitization to caffeine and cross-sensitization to amphetamine are associated with post-synaptic neuroadaptive changes in selective neuronal populations of the striatum. Currently, to further characterize caffeine-mediated psychopharmacological effects, our research group is investigating whether acute caffeine exerted any influence on the emission and features of ultrasonic vocalizations, which are thought to correlate with changes involving emotional state, in male adult rats.


  • Simola N, Morelli M, Seeman P (2008) Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects. Synapse 62:394-7.
  • Simola N, Tronci E, Pinna A, Morelli M (2006) Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats. Amino Acids 31:359-63.
  • Tronci E, Simola N, Carta AR, De Luca MA, Morelli M (2006) Potentiation of amphetamine-mediated responses in caffeine-sensitized rats involves modifications in A2A receptors and zif-268 mRNAs in striatal neurons. J. Neurochem. 98:1078-89.
  • Cauli O, Pinna A, Morelli M (2005) Subchronic intermittent caffeine administration to unilaterally 6-hydroxydopamine-lesioned rats sensitizes turning behaviour in response to dopamine D(1) but not D(2) receptor agonists. Behav Pharmacol 16:621-6.
  • Cauli O, Pinna A, Valentini V, Morelli M (2003) Subchronic caffeine exposure induces sensitization to caffeine and cross-sensitization to amphetamine ipsilateral turning behavior independent from dopamine release. Neuropsychopharmacology 28:1752-9.


  • Prof. Philip Seeman, University of Toronto, Canada.


PI photo

Annalisa Pinna

Contact information

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email  +39 070 6758662

Participating staff

Micaela Morelli

Omar Cauli

Nicola Simola

Elisabetta Tronci