The probability of synaptic transmitter release is regulated by presynaptic receptors responding to transmitter released from the same terminal or from terminals (synaptosome) is the simplest system in which the presynaptic modulation can be studies. This preparation is a good model to investigate the second messenger pathways coupled to the major presynaptic receptors that control glutamate release. In the glutamatergic terminals from the cerebral cortex, a β-adrenegic heteroreceptor, positively coupled to adenylyl cyclase, produces cAMP and activities the cAMP-dependent kinase with the result of an increased excitability that facilitates the release of glutamate. The glutamatergic nerve endings also have metabotropic glumtamate receptors (mGluRs) some of which facilitate, while other inhibit glutamate release. Facilitatory autoreceptors stimulate phospholipase C to generate diacylglycerol and activate protein kinase C which, in turn, inhibit K^+- channel activity with the subsequent enhancement of the action potentials. In contrast, the inhibitory autoreceptors sensitive to L-2-amino-4-phosphonobutyric acid inhibit Ca²⁺ channels with the subsequent decrease in release. The facilitatory and inhibitory autoreceptors and the pathways linked to them coexist in the same glutamatergic terminal mediating a complex interaction that may be relevant in synaptic plasticity.