REGULATION OF NICOTINIC RECEPTORS IN RAT-BRAIN FOLLOWING QUASI-IRREVERSIBLE NICOTINIC BLOCKADE BY CHLORISONDAMINE AND CHRONIC TREATMENT WITH NICOTINE

1 Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [H-3]-nicotine and [I-125]-alpha-bungarotoxin ([I-125]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker chlorisondamine, given either alone or in combination with chronic nicotine administration. 2 In rats that had not received chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg(-1) s.c., twice daily for 12 days) increased [H-3]-nicotine binding density (B-max) in forebrain tissue sections by 19% with no change in the apparent dissociation constant (K-D). Chlorisondamine (10 mg kg(-1), s.c.), given once prior to the chronic treatment phase, neither increased [H-3]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3 In a second experiment, [H-3]-nicotine and [I-125]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of chlorisondamine pretreatment, chronic nicotine administration (1 mg kg(-1) s.c., twice daily for 12 days) increased the B-max of [H-3]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); K-D was unchanged. As before, this up-regulation was neither mimicked nor blocked by chlorisondamine pretreatment (10 mg kg(-1), s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine. Chronic nicotine treatment also increased the B-max (but not K-D) of [I-125]-alpha BTX binding in cerebral cortex (by 35%), hippocampus (by 46%) and midbrain (by 35%). Chlorisondamine altered neither B-max nor K-D when given alone, but significantly attenuated the nicotine-induced up-regulation of toxin binding sites in midbrain, with a similar trend in the other two regions. 4 The finding that chronic receptor blockade neither mimicked nor blocked the agonist-induced up-regulation of [H-3]-nicotine binding sites suggests that up-regulation of these receptors is not determined by their functional status. In contrast, it appears that chronic nicotine-induced up-regulation of [I-125]-alpha BTX binding sites may result from receptor activation.