Effect of chronic central treatment with the acetylcholine analog methylcarbamylcholine on cortical nicotinic receptors: correlation between receptor changes and behavioral function.

Chronic administration of nicotine results in increased numbers of specific nicotinic acetylcholine receptors (nAChRs) within the central nervous system. The purpose of this study was to determine: 1) whether chronic administration of the nicotinic agonist, methylcarbamylcholine (MCC) or the competitive antagonist dihydro-beta-erythroidine (DHBE) in rats could alter brain nAChRs; 2) whether DHBE could inhibit the alterations produced by MCC and 3) whether such changes could be correlated with alterations in animal behavior. MCC (3-60 micrograms) or DHBE 6 or 60 micrograms) alone, or DHBE 15 min preceding MCC (30 micrograms) was injected via previously implanted i.c.v. guide cannulas, twice daily for 10 days. Chronic administration of MCC reversibly increased the apparent Bmax and Kd of cortical nAChRs in a dose- and time-dependent manner. Chronic central administration with DHBE also increased Bmax. Chronic i.c.v. pretreatment with DHBE inhibited the elevation in Bmax and Kd produced by chronic MCC injection. In freely behaving animals, MCC evoked the expression of a characteristic posture assumed in response to central nicotinic stimulation. Chronic administration of MCC resulted in tolerance to this behavioral response. DHBE pretreatment inhibited the MCC-induced behavioral changes. The time course of the development of tolerance to MCC as well as the extent of inhibition of DHBE were well correlated with the time course for receptor up-regulation and inhibition of the increase in binding parameters, respectively. Like chronic MCC treatment, chronic DHBE increased the number of [3H]cytisine binding sites but without concomitant development of behavioral tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)