Volume versus wiring transmission in the brain: a new theoretical frame for neuropsychopharmacology.

A volume transmission mode of communication in brain was implicit already in the early work of Golgi, who postulated the existence of electrical signals in the extracellular fluid (ECF) based on Volta's "wet conductor" made by solutions. The term volume transmission is taken from the term volume conduction describing the flow of ionic currents in the ECF as a basis for the electrocorticogram. The slow VT mode includes also chemical signals and is opposed to the fast synaptic (wiring) transmission. Every neuron may function in a dual mode, the synaptic and the volume transmission mode, when considering the autocrine and synaptic classes of communication. The paracrine- and neuroendocrine-like classes only involve the VT mode in the latter case including the CSF as a route. The chemical signals for VT are the neuropeptides, but also the classical transmitters, the monoamines, acetylcholine, GABA, and glutamate can participate, when they operate via slow, high affinity G protein coupled receptors. Ions such as K+, Ca++, and H+ also function as VT signals. The hypothesis is also introduced that CO2 can act as a multifacit long-distance VT and WT regulator besides being part of the CO2/HCO3 buffer. CO2 via regulating NMDA receptor sensitivity can also regulate NO formation, which represents a paracrine and fast VT signal. The therapy of CNS disorders is also discussed in the frame of the wiring and VT concept. Two therapeutical approaches can therefore be developed, one based on increasing WT and one based on increasing VT. In contrast to the WT therapy, which must preserve the electrotemporal code, the VT therapy can operate also with postsynaptic agonists. Therefore, a therapeutic effect with such a drug indicates that the deficiency in the communication process operates via VT. In view of the lack of very effective negative feedbacks in VT vs. WT, VT therapy may produce less tolerance and drug dependency.