Increased polyphosphoinositide responsiveness in the cerebral cortex induced by cholinergic denervation.
Lesion of the nucleus basalis in the basal forebrain of the rat results in the degeneration of the large cholinergic neurones which innervate the cortex. Parameters of cholinergic function, namely, acetylcholinesterase activity, muscarinic acetylcholine receptor number, and the depolarisation-induced release of acetylcholine, fall in ipsilateral cortex subsequent to lesion. These deficits are likely to reflect the loss of the presynaptic input to the cortex. A reversal in these deficits is seen 1 month after lesion, and a full recovery is seen after 150 days. This is thought to be due to a process of "spared axon sprouting" followed by the reestablishment of synapses. To examine the integrity of the cortical muscarinic receptor response following denervation, an assay of the polyphosphoinositide response was carried out. Cortical tissue slices, prelabelled with [3H]inositol, were incubated for 40 min with carbachol in the presence of Li+; the accumulation of [3H]inositol monophosphate ([3H]IP1) was used as an index of this response. A 92% increase in the carbachol-stimulated production of [3H]IP1 was seen 5 days after lesion compared to normal cortex. Sham-operated animals showed no change in [3H]IP1 accumulation at this time point. Dose-response experiments showed that this increase was due to an increase in the maximal response to carbachol after lesion with no change in EC50 values. Two weeks after lesion, this increased response was much attenuated; tissue slices from denervated cortex showing a strong acetylcholinesterase decrease (36-66%) showed an increase of just 30% above normal.(ABSTRACT TRUNCATED AT 250 WORDS)
Reed
L J
LJ
Department of Biochemistry, Charing Cross and Westminster Medical School, London, England.
de Belleroche
J
J
D000109:Acetylcholine / Q000502:physiology*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003714:Denervation; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D013377:Substantia Innominata / Q000502:physiology; D013403:Sugar Phosphates / Q000096:biosynthesis*
D007295:Inositol Phosphates; D011976:Receptors, Muscarinic; D013403:Sugar Phosphates; D007294:Inositol; D002217:Carbachol; D000110:Acetylcholinesterase; D000109:Acetylcholine