The endogenous rhythmic activity of isolated pacemaker neurones of Aplysia californica appears to be controlled by the operation of a substrate cycle. The recycling of fructose-6-phosphate is mediated by two membrane-bound enzymes: phosphofructokinase (PFK) and fructose-1,6-diphosphatase (FDPase). Allosteric effectors which promote the PFK-FDPase system either increase the regular beating activity or induce bursting discharges, while inhibitory effectors reduce pacemaker activity. Associated with the PFK-FDPase cycle are slow oscillations in membrane potential, the postulate being that changes in amplitude and time period of the waves are brought about by the cyclic fluctuations of H+ ions and ATP in the immediate vicinity of the membrane. Other enzyme reactions which affect the concentrations of gluconeogenic substrates or PFK effectors can modulate the oscillatory driving input, a good example being the neurogenic amino acid glutamate. Modifiers of FDPase and PFK are equally effective in changing pacemaker activity within the intact neuronal network and, hence, the rhythmic body function connected to this network. This has been demonstrated with pacemaker neurones governing cardiovascular activity in Apylsia, blood pressure or heart beat in the cat, and respiration or thermoregulation in the rabbit. Nature appears to have achieved a functional differentiation between different pacemaker neurones by altering their response to at least one or two of the PFK and FDPase effectors. New periodicities can be entrained by current stimuli on the pre-existing rhythms of isolated Aplysia pacemaker neurones. Stimulus-induced resetting of the discharges is in fact accompanied by a redistribution between two kinetically distinct forms of PRK, and modifiers of this enzyme can stabilize the new periodicities or facilitate the conditioning effect of a stimulus. Memory facilitation and consolidation under PFK modifiers could also be demonstrated in avoidance and discrimination learning trials with honey bees and rats, which are consistent with the metabolic nature of the slow-wave rhythmicity in vertebrate microneurones thought to be the site of memory storage.

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