COMPARISON OF THE ABILITY OF DIRECT-ACTING AND INDIRECT-ACTING NICOTINIC AGONISTS TO INDUCE NICOTINIC RECEPTOR UP-REGULATION IN RAT CEREBRAL-CORTEX

Chronic twice daily systemic administration of nicotine (1 mg [2 mu mo l]/kg, sc) over 10 days to rats produced a significant increase in the apparent B-max for cortical nicotinic receptors. Similar results were obtained whether the labeled ligand employed was [H-3]methylcarbamyic holine ([H-3]MCC) or [H-3]cytisine. Rats were treated twice daily for 10 days with the cholinesterase inhibitor physostigmine (25 mu g [64 n mol]/kg, sc) to indirectly activate nicotinic receptors. This regimen inhibited cortical cholinesterase activity by about 51%. Binding analy sis of physostigmine-treated rat cortical tissue indicated that while the B-max for muscarinic receptors was significantly reduced, there wa s no change in the binding parameters for neuronal nicotinic receptors . In the next series of experiments, chronic twice daily intracerebrov entricular (icv) injection of 30 mu g [108 nmol] of MCC, like nicotine , also produced a significant increase in the B-max for cortical nicot inic receptors. MCC treatment also produced a small but significant in crease in the apparent K-d. Twice daily icv injection of 6 mu g [23 nm ol] of the competitive nicotinic antagonist dihydro-beta-erythroidine hydrobromide (DHBE) for 10 days did not itself alter the apparent B-ma x for cortical nicotinic receptors. In a separate group of rats 6 mu 8 [23 nmol] icv of DHBE preceded by 15 min the icv injection of 30 mu g [108 nmol] of MCC. This regimen was administered twice daily for 10 d ays. Under these conditions the DHBE produced a significant 44% inhibi tion of the MCC-induced increase in B-max. Antagonist pretreatment als o blocked the small MCC-induced increase in K-d. Thus, direct activati on of the agonist binding site of the neuronal nicotinic receptor foll owing chronic administration of nicotine or the acetycholine-like MCC leads to receptor up-regulation. Indirect activation through cholinest erase inhibition was not effective in this regard. (C) 1994 Wiley-Liss , Inc.