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THE NEUROPHARMACOLOGISTS DILEMMA GEORGE B. KOELLE* According to current estimates, the human central nervous system (CNS) contains approximately 17 billion neurons, and at least an equal number of glial cells. The magnitude of this figure is difficult for the ordinary mind to grasp. More difficult is the task of the neuropharmacologist who attempts to determine the effects of drugs and to identify putative neurohumoral transmitters at specific central synaptic sites. To illustrate the extent of the impediments involved, an analogy is offered . The figure indicated above is at present being proclaimed on hundreds of signboards across the nation as the number of hamburgers that have been purveyed to date by a national chain. If the volume of a hamburger, including the roll, is estimated as 24 cubic inches (4 inches x 4 inches x 1.5 inches), the total volume of this output would be 236 million cubic feet. The original outside dimensions of the elliptical Colosseum were 630 feet x 513 feet x 160 feet, representing a volume slightly in excess of 40 million cubic feet. Therefore, it would require six Colosseums, with all inside structures removed, to encompass the entire production of this massive culinary enterprise. Now, let each neuron of the CNS be represented by a hamburger, with the investing roll serving as the equivalent of the glial sheath. You are faced with half a dozen contiguous Colosseums, representing six arbitrary divisions of the CNS, all packed with these succulent morsels. Your task is to insert a fire hose, filled with catsup, into one of the stadia and apply the condiment to the meat of a single predetermined hamburger at the center of the mass. This is tantamount to the microiontophoretic application of a drug or putative transmitter to a known central neuron. Alternatively, you must insert an empty fire hose to the immediate vicinity of the identical hamburger, extract a bit ofitsjuice by the application of negative pressure, remove the sample, and identify it by determining its reaction with bovine and perhaps other appropriate antisera. The neuropharmacologist faces an equivalent challenge when *Department of Pharmacology, Medical School, University of Pennsylvania, Philadelphia , Pennsylvania 19174. 402 I George B. Koelle · Neuropharmacologist's Dilemma he attempts to isolate and identify the central neurotransmitter at a specific site. Is it surprising that progress has not been more rapid in ascertaining the sites and mechanisms of action of drugs that affect millions of synapses simultaneously in producing complex effects, including the modification of behavior itself? IDENTITY CRISIS II* A dingy pale green Euglenoid Went flagellating through the void In a mood of dark despair; Uncertainty he could not bear. "I've seen so little light of late, I've no phytyl chlorophyllate. My plastids hardly work at all; Am I then plant or animal?" A nasty mess we must agree; Is he close kin to man or pea? Men kill and tear the Earth apart, Peas are good, but not too smart. In such a touchy situation No taxonomic arbitration Can do the trick; it seems, in sum, We must define a new Kingdom. John R. Pringle IDENTITY CRISIS I appeared in Perspect. Biol. Med., 18:331, 1975. Perspectives in Biology and Medicine · Spring 1976 | 403 ...

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