Introduction and Summary

A relatively small number of cholinergic neurons provide broad, sparse innervate into nearly every region of the CNS. Nicotinic acetylcholine receptors (nAChRs) also are widely distributed throughout the CNS. Nicotinic AChRs serve mainly modulatory roles that influence many neurotransmitter systems. Nicotine obtained from tobacco initially acts at these same nAChRs to begin the processes that lead to addiction. In 1997, the World Health Organization reported that 1/3 of the world’s population over 15 smokes tobacco, and 1/2 of those who continue smoking from adolescence are expected to die of smoking related disease. In the US from 1965 to 1990 there was a steady 40% decline in smoking, but despite increased social pressures there has been no further decline in the '90’s, indicating that nicotine addiction continues to be a major health problem. In 1997, tobacco companies spent 12 times more on advertising than NIDA's budget. The poster depicts 2 mechanisms mediated by nAChRs that influence the addiction process.

Nicotine, at the concentration obtained from tobacco, first activates then desensitizes nAChRs (Figs 1, 2, 3). Among the neurons influenced are the dopamine (DA) neurons from the ventral tegmental area (VTA). When the nicotine initially arrives, nAChRs are activated; and VTA DA neurons can fire a burst of action potentials. After a variable length of time, the nAChRs desensitize and further activity is prevented. This desensitization process also can decrease the endogenous excitation coming from cholinergic afferents into the area (Figs 3, 4).

In addition to their roles on cell bodies, nAChRs influence the release of many neurotransmitters via presynaptic mechanisms. In brain slices (Fig 5) from the VTA and nucleus accumbens (NAc), inhibition of nAChRs by mecamylamine (Mec) decreases evoked glutamatergic transmission (eEPSCs) into the VTA and decreases DA release into the NAc. By measuring calcium signals initiated by nAChRs in single presynaptic terminals (Fig 6), we have directly shown that presynaptic nAChRs can influence the release of neurotransmitters (Fig 7). Nicotine obtained from tobacco influence these same cellular and synaptic mechanisms.

Co-workers and Collaborators

References

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     Dani and Heinemann, '96 Molecular and cellular aspects of nicotine abuse. Neuron 16:905.

     Pidoplichko, DeBiasi, Williams, Dani, '97 Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401.

     Ji and Dani, '00 Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons. J Neurophysiology 83:2682.