The Reward System as Neural Substrates of the Reinforcing Properties of Nicotine

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Most of our knowledge about the neural mechanism of reinforcement stems from the experiments of Olds and Milner (15) using intracranial self-stimulation (ICSS) procedures. ICSS can be triggered when the electrodes are targeting several discrete brain regions, spanning from the ventral tegmental area (VTA) to the lateral hypothalamus, via the medial forebrain bundle, to the nucleus accumbens and prefrontal cortex. The ensemble of these structures has been loosely defined as reward system (16). At first, nicotine (0.2-0.4 mg/kg) was shown to enhance the rate of responding for ICSS in the rat VTA or medial prefrontal cortex without changing the current threshold (17). Years later, Huston-Lyon et al. (18), using an auto-titration procedure, showed that nicotine indeed lowered the current threshold for ICSS in a dose-dependent fashion, demonstrating the reinforcing efficacy of low-dose nicotine. More recently, nicotine was shown to produce a leftward shift of the ICSS curve relating the frequency of currents and the response rate in rats (19). These data indicate that nicotine is acting directly on the reward system, affecting its efficiency in positive terms.

Other lines of investigation, using neurochemical-electrolytic brain lesions, local microinjections of antagonist drugs, or local measurements of neurotransmitter levels with microdialysis probes, have shed some light on the relevance of certain structures in mediating the rewarding effects of addictive drugs (9,13,20). According to recent neurobiological models (12,20), it is surmised that: (a) the complex processing involving cognitive and associative mechanisms associated with drug-taking, such as subjective attribution, cue assessment, and craving, is assumed to depend on the prefrontal and associative cortex, as well as the amygdala and hippocampus; (b) the meso-corticolimbic dopamine (DA) system, projecting from the ventral tegmental area to the nucleus accumbens and medial prefrontal cortex, is implicated in the control of instrumental behaviors and their outcomes; (c) the dorsal striatum, which receives projections from the DA neurons of the substantia nigra, is suggested to participate in habit formation.

Finally, chronic exposure to pharmacological doses of addictive drugs, by acting on some components of the reward system, in particular the mesocorticolimbic DA system, are believed to produce adaptive modifications of neural functioning. These changes result in several behavioral changes, some not related to changes in reward-dependent behavior—for example, locomotor sensitization, place preference, latent inhibition, increased DA release to addictive drug challenge, increased sensitivity to stress exposure, reduced palatable food consumption, and maintenance of drug self-administration (21). It is interesting to note that most of these behaviors are observed neither in rats chronically self-administering nicotine nor in human smokers. In addition, it is not automatic to suggest that exposure to nicotine, independent of the paradigm of administration, produces dependence in individuals. In fact, continuous vs pulsed administration, or passive vs active self-administration, may differ importantly in defining the total dose effects, the neurobiological changes in the substrates, and the tolerance or sensitization profile of the drug (10).

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