Doctor of Philosophy
Pharmacology & Toxicology
John A. Rosecrans
Arecoline and nicotine are two psychoactive cholinergic alkaloids. Arecoline is primarily a muscarinic agonist while nicotine, at low doses, is a nicotinic agonist. The experiments in this dissertation investigated two major areas: (1) the role of different factors in the development of tolerance to the behavioral effects of arecoline and nicotine, and (2) the possible mechanism and site of action of the discriminative stimulus (DS) effects of arecoline and nicotine.
The role of dispositional and physiological factors comﬁared to behavioral factors in the development of tolerance to the effects of arecoline and nicotine on operant behavior was assessed in Experiments I and II, respectively. In part one of Experiment I, rats were trained to respond (M1 a variable-interval 15 second (VI-15) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days Of arecoline administration prior to the session, the dose-effect relationship for total responses was not shifted. However, the dose-effect relationship for total reinforcements was shifted to the right. In part two of Experiment I, rats were trained to respond on a fixed-ratio 20 (FR-ZG) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the seSsion and a second group received arecoline injections after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship in the pre-session group compared to the post-session group. These data demonstrate the importance cﬂf behavioral factors in the development of tolerance to arecoline.
In Experiment II, rats were trained to respond on a VI-15 second schedule of milk reinforcement. Dose-effect relationships were determined prior to and during chronic nicotine (2.28 mg/kg/day) administration. One group of rats received daily injections Of nicotine prior to the session, another group received nicotine injections after the session. After 36 days of chronic treatment, similar degrees of tolerance were observed in both groups, however the group receiving post-session nicotine developed tolerance at a faster rate. The data suggested that 21 complex interaction of nicotine and the experimental environment affected the rate of tolerance development.
Experiment III characterized the DS effect of arecoline. Using a two-lever operant paradigm, rats were trained to discriminate arecoline from saline on a VI-12 second schedule of milk reinforcement. Rats could learn to discriminate 1.74 mg/kg arecoline from saline, but not 0.58 mg/kg from saline. Agonist and antagonist studies demonStrated that the DS effect of arecoline is mediated through central muscarinic receptors.
In Experiment IV, the ability of physostigmine to interact ﬁith the DS effect of nicotine (1.14 mg/kg) and arecoline (1.74 mg/kg) was assessed. Physostigmine (0.125 mg/kg) pretreatment shifted the dose-effect relationship for arecoline to the left but did not affect that of nicotine. Physostigmine (0.25 mg/kg) almost completely generalized to the DS effect of arecoline but not to the DS effect of nicotine. These data suggest an interaction of endogenous acetylcholine with muscarinic receptors but not with nicotinic receptors.
In Experiment V, the ability hf arecoline and nicotine injected directly into the dorsal hippocampus (DH) and mesencephalic reticular formation (MRF) to generalize to the DS effect of peripherally administered arecoline (1.74 mg/kg) and nicotine (1.14 mg/kg) was assessed; Nicotine injected into these sites generalized in a dose-related manner to nicotine. The MRF was slightly more sensitive than the DH. Arecoline injected into either site did not generalize to the DS effect of, peripherally administered arecoline. However, a decrease in response rates was observed.
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