Discriminative stimulus properties of nicotine: mechanisms of transduction.
Our thinking about how nicotine might be inducing DS control of behavior has changed drastically in the past 25 years. Our first inclination was that nicotine was mimicking ACh at a variety of specific and select n-AChRs. Then several nicotine researchers suggested that nicotine might be acting via specific and select noncholinergic receptors. At present, we seem to have returned to the view that nicotine may have pronounced effects at the n-AChR (figure 1), at least in some specific cases such as in the development of tolerance and in rats trained to discriminate nicotine (figure 6). The endogenous ligand has not changed, but the mechanism of how it affects presynaptic and postsynaptic receptors appears to have been rediscovered. The concept of rapid ACh-induced desensitization at the n-AChR is not new and appears basic to cholinergic neuronal function (figure 5). The desensitization concept has been revitalized by several investigators who also consider this mechanism important to how nicotine might act in protecting DA neurons from neurotoxicity of chemicals such as 6-OHDA or MPTP (Janson et al. 1988). The overall concept suggests that n-AChR desensitization at presynaptic DA sites may reduce neuronal accessibility to select exogenous neurotoxins and thus attenuate neuronal destruction. This hypothesis has also been partially validated in relation to the cholinergic neuron by providing preliminary evidence that nicotine was able to reduce cholinergic neuron destruction (measured by brain ACh levels) via the intraventricular administration of the neurotoxin AF64A, an ACh nitrogen mustard (Villanueva et al. 1990). Thus, nicotine or compounds acting like nicotine could possibly be beneficial to patients exhibiting the select neurological problems observed in Parkinson's and Alzheimer's diseases. The process of desensitization might also be useful to understanding why humans choose to smoke tobacco products. Perhaps the ability of nicotine to induce such neuronal effects at a specific n-AChR makes it reinforcing (or aversive) to behavior. Such a mechanism of action might explain why nicotine appears to both increase and decrease arousal levels in animals (or humans) exhibiting differential basal level of excitability (Hendry and Rosecrans 1982), or why some people never become dependent on nicotine. How nicotine alters the n-AChR may also be beneficial to our understanding of the subtle nature of cholinergic neuronal function in learning, memory, and other behavioral states. The ability of ACh (or nicotine) to induce an activation or attenuation of some cholinergic or noncholinergic neuron or both may be important to these brain processes.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0001, USA.
J A
JA
Rosecrans
H F
HF
Villanueva
D000818:Animals; D004193:Discrimination Learning / Q000187:drug effects*; D006801:Humans; D009538:Nicotine / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000032:analysis* / Q000187:drug effects
D011950:Receptors, Cholinergic; D009538:Nicotine