Bozarth, M.A., Pudiak, C.M., & KuoLee, R. Predicting addiction liability from brain stimulation reward data: I. A comparison of the acute effects of cocaine, pseudoephedrine, nicotine, and caffeine. Manuscript under editorial review.


Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were tested using a threshold-tracking procedure. This procedure determined the minimum stimulation frequency (i.e., stimulation threshold) necessary to maintain >30 presses/min during daily 30-min test sessions. Rats were injected with cocaine hydrochloride (2.5 to 20 mg/kg, i.p.), pseudoephedrine hydrochloride (3 to 100 mg/kg, i.p.), nicotine bitartrate (0.063 to 1 mg/kg, s.c.), or caffeine (5 to 80 mg/kg, i.p.) immediately before testing. Peak threshold-lowering effects were determined during 180-min test sessions. Another series of tests compared the facilitatory effects produced by (i) different nicotine bitartrate administration conditions (i.e., pH-adjusted vs. pH-unadjusted solutions and s.c. vs. i.p. injection routes), (ii) nicotine freebase in pH-adjusted and pH-unadjusted solutions, and (iii) repeated nicotine bitartrate injections. These comparisons ensured that the most effective nicotine administration parameters were used.

All compounds facilitated BSR. The prototypic addictive drug cocaine lowered thresholds over twice as much as the nonaddictive compound pseudoephedrine. This shows that BSR facilitation can be used to predict reinforcing drug action, but quantitative measures of facilitation must be used to distinguish drugs with high and low addiction liabilities. Nicotine’s facilitation of BSR was quantitatively similar to that seen with pseudoephedrine and markedly different from cocaine’s effect. Caffeine produced BSR facilitation comparable to that seen with nicotine and with pseudoephedrine. Similar peak-facilitation effects were seen with all nicotine administration conditions. This suggests that even under optimal administration conditions, nicotine’s profile in this animal model is that of a substance with a low addiction liability.

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