Evidence for homeostatic adjustments of rat somatosensory cortical neuronsto changes in extracellular acetylcholine concentrations produced by iontophoretic administration of acetylcholine and by systemic diisopropylfluorophosphate treatment

We describe the responses of single units in the awake (24 cells) or uretha ne-anesthetized (37 cells) rat somatosensory cortex during repeated iontoph oretic pulses (1.0 s, 85 nA) of acetylcholine, both before and after system ic treatment with the irreversible acetylcholinesterase inhibitor diisoprop ylfluorophosphate (i.p., 0.3-0.5 LD50). The time-course of the response to acetylcholine pulses differed among cortical neurons but was characteristic for a given cell. Different time-courses included monophasic excitatory or inhibitory responses, biphasic (excitatory-inhibitory, inhibitory-excitato ry, excitatory-excitatory, and inhibitory-inhibitory), and triphasic (excit atory-excitatory-inhibitory, inhibitory-inhibitory-excitatory, and inhibito ry-excitatory-inhibitory) responses. Although the sign and time-course of t he individual responses remained consistent, their magnitude fluctuated acr oss time; most cells exhibited either an initial increase or decrease in re sponse magnitude followed by oscillations in magnitude that diminished with time, gradually approaching the original size. The time-course of the char acteristic response to an acetylcholine pulse appeared to determine directi on and rate of change in response magnitude with successive pulses of acety lcholine. Diisopropylfluorophosphate treatment, given Ih after beginning re peated acetylcholine pulses, often resulted in a gradual increase in sponta neous activity to a slightly higher but stable level. Superimposed on this change in background activity, the oscillations in the response amplitude r eappeared and then subsided in a pattern similar to the decay seen prior to diisopropylfluorophosphate treatment. Our results suggest that dynamic, homeostatic mechanisms control neuronal e xcitability by adjusting the balance between excitatory and inhibitory infl uences within the cortical circuitry and that these mechanisms are engaged by prolonged increases in extracellular acetylcholine levels caused by repe ated pulses of acetylcholine and by acetylcholinesterase inhibition. Howeve r, this ability of neurons in the cortical neuronal network to rapidly adju st to changes in extracellular levels of acetylcholine questions the potent ial efficacy of therapeutic treatments designed to increase ambient levels of acetylcholine as a treatment for Alzheimer's disease or to enhance mecha nisms of learning and memory. (C) 1999 IBRO. Published by Elsevier Science Ltd.