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THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. 900 THIRD AVENUE NEW YORK. N.Y. 10022 DONALD H. P'ORD. PH.D. ABBOCiATS REatARCH DIR=CTCR Memorandum To: Dr. J. F. Glenn and Staff From: D. H. Ford Re: Site visit with Drs Lajtha and Sershen at Ward's Island, NYC, N.Y., August 1, 1988. Grant No.2346 entitled "Mechanisms of regionally specific nicotine effects." of nicotine Goals: To analyze the effect:/on the release and metabolism of a number of neurotransmitters (catecholamines and neuropeptides) known to respond to nicotine by superfusion. By this approach they should be able to pharmacologically map the effect of nicotine on release of neurotransmitters at a particular neuroanatomical site (ie., substantia nigra wherein there are Gabaergic and a number of peptide terminals, etc. and then secondarily, the effect of nicotine on these DA neurons in relation to the release of their transmitter in the striatum, nucleus accumbens or cortex). Results: To date two animals have been cannulated and superfused. The data on the transmitter substances in the perfusate is still under- going analysis. It should be appreciated that it requires one day to insert the perfusing cannulas at the desired loci in the rat brain, particularly when two are in place. However, it is the subsequent analysis which is time consuming. At the conclusion of any perfusion study, the animal is killed and the formalin-fixed brain sections and evaluated for damage to the tissue. So far there has been none of any significance. Later, when chronic studies are undertaken ( one to two weeks), the degree of gliosis will have to be evaluated and studies undertaken to determine if it influences transport of nutrients to and wastes from the neuronal field. Dr. Vizi, a temporary member of the staff from Hungary has been evaluating the effect of nicotine on presynaptic N-cholinergic receptors on the cholinergic terminal at the neuromuscular junction. It turns out that binding of nicotine to these receptors facilitates the release of ACh at the neuromuscular junction. This effect can be mimicked by DMPP ( a nicotinic agonist) and blocked by B-bungarotoxin which binds only to the presynaptic N-ACh receptor. (Alpha-bungarotoxin, as we recell will block the post-synaptic receptor on the muscle fiber). Dr. Vizi has also just about completed a study utilizing an intestinal model evaluating the effect of nicotine on the neurons of the Auerbach plexus. The cholinergic fibers of this plexus normally activate gut smooth muscles. The release of ACh from the axonal terminals is blocked by norepinephrine on presynaptic receptors on the ACh terminals. His study now indicates that NACh presynaptic receptors on the NE terminals will in turn block the release of NE, thus facilitating the release of acetylcholine, indicating how uicotine may facilitate intestinal motility.

2 Dr. Vizi is currently initiating a study utilizing the super- fusion technique on rat striatal slices. In the striatum, nicotine has been shown to terminate presynaptically on ACh.terminals arising from neurons in the cortex, facilitating the release of ACh. At the same time, activation of presynaptic DA-"terminals inhibit the relase of acetylcholine..(These are receptors of the DA2) type). This effect of DA appears to over-ride the facilitatory effect of nicotine on ACh release. Since nicotine also appears to play a role in the release of DA, the superfusion technique would appear to be an excellent method to attempt to determine the balance of what is happening in the striatum in relation to nicotine... direc(t.facilitation of ACh release or inhibition mediated by an increase in DA release. Which transmitter will eventually be the one which over-rides the other. (There appear to be many areas in the CNS wherein a single transmitter may produce different effects on a particular system, depending on whether or not it acts pre- or post synaptically or has indirect effects through other neuronal terminals which are effective in the same region.) Comment: This program has only been supported by CTR since the first of July. Thus, it is far too early to judge the progress accomplished, though it appears to be considerable. What seems of interest to this observer is that the superfusion approach, as applied to the cortical-striatal-nigral-striatal-cortical motor system will provide a considerable understanding of the effect of nicotine on the function of the various components in the circuit. While it may not explain why Parkinson patients are rarely smokers, it would seem likely to explain interactions between the elements of this part of the motor system which relate to possible dysfunction in disease. Don Ford