The medial prefrontal cortex (PFC) is thought to be the highest order association area in the mammalian cortex which is involved in cognitive functions. Especially, layer V pyramidal cells integrating afferent innervations from dopaminergic cell groups in the ventral tegmental area, glutamatergic inputs from the thalamus and neighbouring PFC pyramical cells, as well as GABAergic inputs from local interneurons are crucial for processing short-term working memory. These neurons are endowed with the NMDA- and AMPA-type excitatory amino acid receptors, described to be involved in the regulation of synaptic plasticity, the apparent basis of elementary learning processes. NMDA receptor currents were in fact regulated on the one hand by dopamine D1 receptors and on the other hand by ATP-sensitive receptors of the P2Y-type. P2Y4 receptors acted indirectly to potentiate NMDA receptor-currents by releasing vesicular glutamate from astrocytes, or attenuated these currents directly by stimulating P2Y1 receptors located at the PFC cells themselves. Long-term depression (LTD) induced in PFC pyramidal neurons could be blocked by P2Y1 receptors in a manner not depending on NMDA receptors but targeting voltage-sensitive dendritic Ca2+ channels. In vivo data also support the notion that P2Y1 receptors participate in the regulation of cognitive processes and addiction. For example, in a spatial delayed win-shift task, P2Y1 receptor-activation has been shown to deteriorate not the primary storage of information but its processing during and after a delay. Further, it is widely accepted that behavioural sensitization in animals provides a model for the intensification of drug craving believed to underlie addiction in humans. In fact, sensitization to amphetamine was interrupted by the blockade of P2Y1 receptors in the mesocortico-limbic dopaminergic system.