Effects of Drugs on the Central Nervous System

Abstract

The editors instructed me to be "fiercely selective" in the material that I was to include in this chapter. In one respect that is an easily followed in struction for a general physiologist who studies cell membranes and attempts to use pharmacology as a tool to help decipher the electrogenic phenomena of excitable cells. Electrophysiology is fortunate in having a theory which links electrogenesis with the permeability of the cell membrane to ions (25, 100). The dazzlingly quantitative application of this theory to account for the spike of the squid axon (101) is meeting with the stubborn complexities of living membranes (13,14,95,144,188,189). Nevertheless, some rela tively simple modifications of the ionic theory permit the latter to account, although only qualitatively at present, for the bulk of a large variety of electrophysiological and pharmacological phenomena (84,85,89,90).The situation appears to be quite different in pharmacology. The periodi cal literature seems to be styled after the biblical "begat" chapters and much of it is about equally innocent of theory. Even in the restricted field of neuro pharmacology the data are almost entirely based on various reactions of whole animals or of their individual organ systems. When theory is attempted it seems to regard as irrelevant the morphology and functional properties of individual neurons and effectors, and of their organization into the complex organ system of the neuraxis and its peripheral appendages.In another respect, however, this instruction must be disobeyed. The present reviewer arrived at his interest in neuropharmacology from an at tempt to use a relatively simple conceptual framework, gained from the study of peripheral junctions (78 to 80), to account for the actions of drugs on cells, including those of the central nervous system (77, 81). The studies on electrocortical phenomenon with Purpura and other colleagues (82, 148, 151, 152, 154 to 156) in which pharmacological tools were used extensively 1 The survey of the literature pertaining to this teview was concluded in July 1963.

The Action of Tetrodotoxin on Electrogenic Components of Squid Giant Axons

“…Spike electrogenesis is eliminated by tetrodotoxin in crayfish stretch receptor neurons (Loewenstein et al, 1963;Nakajima, 1964), and in the axons of Pacinian corpuscles (Loewenstein et al, 1963). However, the generator potentials of these receptors and of others (Grundfest, 1964) are not affected by the poison. Tetrodotoxin also does not block the response of the chemosensitive synaptic membrane to acetylcholine in the frog muscle endplate (Furukawa et al, 1959;Cheymol et al, 1962), or of the eel electroplaque (Higman and Bartels, 1962), nor does it inactivate the membrane of excitatory or inhibitory synapses of crayfish muscle fibers (Ozeki and Grundfest, 1965).…”

Cumulative and sensitisation effects of repeated applications of methomyl to the housefly, Musca domestica L. (Diptera: Muscidae)

“…The mode of action of none of these types of insecticides is satisfactorily understood, but carbamates, like organophosphates are generally assumed to kill both vertebrates and invertebrates by inhibiting cholinesterase in the nervous system (e.g. O'Brien, 1967), although doubt has been expressed as to the validity of the hypothesis (Koelle, 1962(Koelle, , 1963Chadwick, 1963;Grundfest, 1964). The lethal action of these insecticides in insects is thought to be due to inhibition of AChE-activity at the cholinergic synapses in the neuropile, but recent studies on the localisation of certain organophosphate and carbamate insecticides in the fly's central nervous system have shown this to be less tenable (Molloy, 1961;Brady, 1970;Booth & Metcalf, 1970).…”

Effects of glycine, β-alanine and diazepam upon morphine-tolerant-dependent mice

“…This effect cannot be ascribed to a 'glycine-like' action though an occupancy of glycine receptors. Pahnine has also been shown to be effective in depressing the crayfish neuromuscular junction (Dudel 1965) in which the inhibitory response is produced by means of the occupancy of GABA receptors (Curtis 1963 ;Grundfest 1964). Consequently, it is possible that its inhibitory action on morphine tolerance might be explained by its action on the GABA mechanisms.…”