Schematic representation of the main sources of volume transmission involving dopamine and nitric oxide signals in the central nervous system (Inspired by Zoli et al., ; Syková, ). (A) Synaptic transmission: Synaptic vesicular release followed by the diffusion of the transmitter outside the synaptic cleft at an effective concentration. Neurotransmitters can escape from the synaptic cleft (especially during repetitive stimulation and/or the massive release of a transmitter) and affect extrasynaptic receptors on glia or neurons or reach a neighboring synapse. These phenomena have been called “transmitter spillover” and “synaptic crosstalk.” This loss of synaptic independence means that transmitter release at one synapse can lead to the activation of receptors in nearby synapses. (B) Volume transmission: vesicular release from non-junctional varicosities, i.e. varicosities lacking pre-synaptic specializations and post-synaptic densities. Axons both in the central nervous system and in the autonomic nervous system form varicose (boutons-en-passant) branches that may release and uptake neurotransmitters. The transmitter release from varicosity without synaptic contact diffuses far away from the release site and activates remote receptors of high affinity. (C,D) Release of gaseous transmitters, e.g. nitric oxide release from neurons. The inside cell squares are representative of a local synthesis of the neurotransmitter, frequently by enzymatic regulated activity. Nitric oxide presumably operates within a 3-dimensional volume of tissue rather than, more conventionally, between immediately adjacent cellular partners (Kiss and Vizi, ). Glu, glutamate vesicles; NOS, nitric oxide synthase; NO, nitric oxide; NMDA, N-Methyl-d-Aspartate.