Issues involved in the transmission of chemical signals through the brain extracellular space

Two classes of substances exist within the extracellular space: energetic and informational. Examples of the former are glucose, dissolved oxygen and CO2 while the latter include excitatory amino acids, cathecholamines and opiates. The simple ions Na+ and Cl- are generally associated with energetic processes while extracellular K+ and Ca2+ tend to be informational in function. Local release of an informational substance brings about a concentration gradient that causes the substance to be dispersed in the extracellular space by diffusion. This process is modified relative to a free aqueous medium by the constraints of volume fraction, tortuosity and uptake. Volume fraction is defined simply as the fraction of a brain region that is extracellular. If a given quantity of substance is released into a region with a reduced volume fraction then the substance will reach a higher concentration than it would in a free medium. Tortuosity is related to the increase in the path length of the random walk of a diffusing particle due to the necessity to navigate around cellular obstructions. Tortuosity manifests itself as a decrease in the diffusion coefficient. Uptake represents the movement of a substance from the extracellular space to the intracellular. Since initially a concentration gradient exists in this direction and all membranes have some permeability some concentration-dependent uptake always occurs. In addition there exist specific carrier-mediated uptake processes for some substances such as amino acids or catecholamines. In some regions the dispersal process can be dominated by uptake rather than diffusion. While volume fraction, tortuosity and uptake have all been demonstrated by a technique based on the use of radiolabels and other methods, these classical techniques have limited spatial and temporal resolution. The advent of methods based on micro-injection of substances by iontophoresis or pressure and subsequent detection with ion-selective microelectrodes (ISMs) or voltammetric microsensors (VMs) has opened a new window onto the dynamic local behavior of the extracellular space. In the last decade our laboratory and others have studied the migration of the test substances tetramethylammonium, tetraethylammonium, AsF6- and alpha naphthalene sulfonate, the endogenous ions K+ and Ca2+, the epileptogenic agent penicillin and the neurotransmitter dopamine. These studies have been carried out on the cerebellum and some other regions in a variety of species that include rat, turtle, skate and an intervertebrate, the cuttlefish.(ABSTRACT TRUNCATED AT 400 WORDS)