From M.A. Bozarth, C.M. Pudiak, & R. KuoLee (1997). Self-limiting action of nicotine on brain reward mechanisms. Society for Neuroscience Abstracts, 23, 1843.

SELF-LIMITING ACTION OF NICOTINE ON BRAIN REWARD MECHANISMS. M.A. Bozarth,* C.M. Pudiak, & R. KuoLee. Addiction Research Unit, Department of Psychology, University at Buffalo, Buffalo, NY 14260-4110.

Previous work has shown that nicotine facilitates brain stimulation reward (BSR) but that the maximum effect obtainable with nicotine is similar to that seen with compounds having a low addiction liability (e.g., caffeine, diphenhydramine, pseudoephedrine). Two studies further explored nicotine’s effects on BSR using a threshold-tracking procedure. Male, Long-Evans rats were implanted with stimulating electrodes at the lateral hypothalamic level of the medial forebrain bundle. Nicotine bitartrate (doses expressed as the freebase weight) was injected subcutaneously, and its effects on BSR were measured 15-30 min post injection.

The first study examined the effects of daily nicotine injections (0.5 mg/kg/day) across 21 consecutive days of testing. There were no changes in nicotine’s facilitatory action across the 21-day test. The second study examined the effects of escalating nicotine doses: 0.5, 1, & 2 mg/kg/day were administered in sequential 5-day cycles. Nicotine lowered thresholds across the first two 5-day cycles (i.e., 0.5 & 1 mg/kg/day doses) but thresholds returned to baseline levels during the last 5-day cycle (i.e., 2 mg/kg/day). When the effect of the 2 mg/kg dose was examined in naïve rats, a time-course analysis revealed a biphasic action, with nicotine elevating thresholds 30-45 min post injection and lowering thresholds from 75-210 min post injection.

Nicotine activates the brain reward system also activated by addictive drugs, but it appears to have a self-limiting action on this system—some neurophysiological process limits the maximum activation produced by nicotine. Consideration of the BSR data suggests that nicotine’s reward activation is limited by fractional activation of the reward substrate and by a high-dose self-inhibitory action at afferent neurons. These two mechanisms may explain why nicotine has a modest reward-modulating effect but fails to produce a potent rewarding action like addictive drugs.

Supported by Philip Morris Research Center (Richmond, VA).

© 1997 Addiction Research Unit/University at Buffalo

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