Carbachol-induced inositol phosphate formation during rat cochlea development

The age related-intensity developmental pattern of the phosphoinositide breakdown, which leads to the formation of intracellular second messengers, was investigated in rat cochleas by measuring the accumulation of inositol phosphates induced by carbachol in the presence of LiCl. The accumulation of the phosphoinositide metabolites elicited by this muscarinic agonist is very low at post-natal day 1 and particularly large during the period between post-natal days 8 and 14 with a peak around day 12. In the 25-day-old rat cochlea, carbachol induced a 2-fold increase in inositol phosphates (IPs) accumulation, with respect to the basal control level. The apparent affinities of the carbachol-induced IPs responses are 49.6, 31.6 and 36.7 microM in cochleas of 12-, 16- and 25-day-old rats, respectively, thus suggesting that the specific developmental changes are rather due to a modification in the number of muscarinic cholinergic receptors than to alterations of the apparent affinity of carbachol for its receptors. This developmental pattern of carbachol-elicited IPs accumulation reveals a striking time coincidence with both the efferent synaptogenesis at the outer hair cells (OHCs) level and the period of increased sensitivity of OHCs to aminoglycoside toxicity. Phosphoinositide breakdown may, consequently, play a role in the maturation of OHCs and their efferent supply. In addition, the remaining IPs response measured at 25 post-natal days indicates that muscarinic agonist-mediated IPs metabolism also occurs in mature cochlea, and might be involved in the regulation of OHCs motility.