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Regulation of nicotinic receptors in rat brain following quasi‐irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine
Author(s) -
ElBizri H.,
Clarke P.B.S.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17080.x
Subject(s) - nicotine , chlorisondamine , nicotinic agonist , endocrinology , cytisine , methyllycaconitine , chemistry , pharmacology , medicine , receptor , nicotinic acetylcholine receptor , blood pressure
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 [ 3 H]‐nicotine and [ 125 I]‐α‐bungarotoxin ([ 125 I]‐αBTX) 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 [ 3 H]‐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 [ 3 H]‐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, [ 3 H]‐nicotine and [ 125 I]‐αBTX 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 [ 3 H]‐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 [ 125 I]‐αBTX 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 [ 3 H]‐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 [ 125 I]‐αBTX binding sites may result from receptor activation.