The rate and pattern of lever pressing were studied in 18 rats during 24-h sessions in which responding resulted in intravenous infusions of nicotine. There were four indications of the positive reinforcing effect of nicotine: (1) a greater number of lever presses when nicotine was response-contingent compared to when saline was available; (2) a greater number of responses on the lever resulting in an infusion of nicotine than on the control lever; (3) systematic decreases in the number of contingent nicotine infusions when nicotine was delivered noncontingently; and (4) systematic changes in the frequency of lever pressing as a function of dose. Under a fixed ratio 1 (FR 1) schedule, the number of infusions first increased and then decreased as the dose of nicotine was decreased (64, 32, 16, and 8 microg/kg infusion) and nicotine intake (mg/kg every 24 h) was directly related to the infusion dose. As the FR size was increased from 1 to 6, the number of lever presses increased and the number of infusions (32 microg/kg) remained stable. At FR values greater than 6, both the number of lever presses and infusions decreased. Presession injections of mecamylamine (0.75, 1.5, and 3.0 mg/kg, s.c.) decreased the number of infusions in a dose-related manner. Presession injections of hexamethonium (1.5 and 3.0 mg/kg, s.c.) or naloxone (0.75, 1.5, and 3.0 mg/kg, s.c.) did not alter the within- or between-session patterns of nicotine self-administration. Under the conditions of the present experiment, nicotine served as an effective reinforcer and the behavior was shown to be sensitive to both FR size and infusion dose. In addition, the results suggest that nicotine self-administration involves central nicotinic receptors and that opioid receptor antagonism has no effect on nicotine's reinforcing effects in rats.

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Cook, L., V.J. Nickolson, G.F. Steinfels, K.W. Rohrbach, and V.J. DeNoble: Cognition enhancement by the acetylcholine releaser DuP 996. Drug Dev. Res. 19:301-314, 1990.DuP 996, 3,3-Bis(4-pyridinylmethyl)-l -phenylindolin-2-one, a potent in vitro and in vivo releaser of acetylcholine (ACh), dopamine (DA), and serotonin (5HT) in rat brain, significantly enhanced the performance of rats and mice in several behavioral test procedures. At doses of 0.01-0.1 mgikg S.C. DuP 996 protected against a hypoxia-induced passive avoidance deficit in rats. In active avoidance procedures, DuP 996 enhanced acquisition of responses: in rats, at doses between 0.085 and 0.85 mgikg S.C. and 0.25 and 0.85 mgikg p.0.; in mice, at doses between 0.85 and 2.5 mgikg S.C. These effects occurred without any alteration of sensitivity to foot-shock. In addition, DuP 996 prevented a C0,-induced retention deficit of a passive avoidance response when administered prior to acquisition testing.In a test for acquisition of lever pressing for food in the rat, DuP 996 increased the proportion of animals acquiring this response. Thus, DuP 996 was active in both the shock-and appetitive-motivated procedures and was shown to enhance performance levels when administered post-training as well as before training trials. These results suggest that DuP 996 may be useful in the treatment of cognition dysfunction.

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