| Abstract: | Chronic twice daily systemic administration of nicotine (1 mg [2 μmol]/kg, sc) over 10 days to rats produced a significant increase in the apparent Bmax for cortical nicotinic receptors. Similar results were obtained whether the labeled ligand employed was [3H]methylcarbamylcholine ([3H]MCC) or [3H]cytisine: Rats were treated twice daily for 10 days with the cholinesterase inhibitor physostigmine (25 μg [64 nmol]/kg, sc) to indirectly activate nicotinic receptors. This regimen inhibited cortical cholinesterase activity by about 51%. Binding analysis of physostigmine-treated rat cortical tissue indicated that while the Bmax for muscarinic receptors was significantly reduced, there was no change in the binding parameters for neuronal nicotinic receptors. In the next series of experiments, chronic twice daily intracerebroventricular (icv) injection of 30 μg [108 nmol] of MCC, like nicotine, also produced a significant increase in the Bmax for cortical nicotinic receptors. MCC treatment also produced a small but significant increase in the apparent Kd. Twice daily icv injection of 6 μg [23 nmol] of the competitive nicotinic antagonist dihydro-β-erythroidine hydrobromide (DHBE) for 10 days did not itself alter the apparent Bmax for cortical nicotinic receptors. In a separate group of rats 6 μg [23 nmol] icv of DHBE preceded by 15 min the icv injection of 30 μg [108 nmol] of MCC. This regimen was administered twice daily for 10 days. Under these conditions the DHBE produced a significant 44% inhibition of the MCC-induced increase in Bmax. Antagonist pretreatment also blocked the small MCC-induced increase in Kd. Thus, direct activation of the agonist binding site of the neuronal nicotinic receptor following chronic administration of nicotine or the acetycholine-like MCC leads to receptor up-regulation. Indirect activation through cholinesterase inhibition was not effective in this regard. © 1994 Wiley-Liss, Inc. |
