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PHILIP t.19RRIS U. S. A. INTER-OFFICE CORRESPOBDENCE RICHMOND, YIRGINIA F ram : Dr. R. B. Sellgman W. L. Dunn The. Nicotine Receptor Program Date: Marci~ C80- t 1078 In responding to your query l'm going to First address the more inclu, ve topic of the psychopharmacology of nicotine. Abood's nicotine receptor program is included, as is the internal nicotine analogue program and the internal animal behavior program. All three of these efforts are aimed at understanding that specific action of nicotine which causes [he smoker to repeatedly introduce nicotine into his body. The psychopharmacology of nicotine is a highly vexatious topic. It is where the action is for those doing fundamental research on smoking, a~d from where most likely will corae siqnificant scientif;r ~leveI,,l~ments i~ofounJly influcr, cing tt~c industry. Yct it is where u_,, ,~t~,,~cys l{:ast want us to be, for two reasons. It is important to have these two reasons expressed and distinguished from one another. The first reason is the oldest and is implicit in tile legal strategy employed over the years defending corporations within the industry from the claims oI- heirs and estates of dece.~sed smokers: "We within the industry are ignorant of any relationship between smoking and disease. Within our lab(,r,~tolies :ir~ wor~ is being conducted on biological systems." That posture has modc~,,ted considerably as our attorneys have come to acknowledge that the original carte blanche avoidance of all biological research is not required in to plead ignorance about any pathological rclationshi;: between smoke smoker. There is an important distinction that has been made heru. whicl, it is well to articulate: The acute, transient, short-llved effects nicotir.e upon a physiolo~]ical system (a'monq which are those effects o(~ ~.h.a't effect sou~qht by the s~-k6r) are Whc;l]y" [~-d~p~]~'e~ 7D-~ those al1~qed, cumulative, long-term contributions of smoke compounds to disease proc.ess~t-. We are now being allowed to conduct r(;search on the immediate effects of nicotine because of this distinction, i.le can work with biological systc~ms; we can inject nicotine in rats and we can perform the surgery r~qulrcd fur implanting cannu',~,~. But in doing so we are engaging in r~search c,,~ the pharmacological action of nicotine, which brings us to the s(~cond concern of our attor(~eis. This is a n~re recent concern arising fror~, increasingly favorable prospects for the success of a legislative effort to transf~'r autt~ority for :he regulation of tobacco I~anufacttirc to) h Fectel~l (F.b.R.) known to have interests and powers antithutical to the intcl-c~,tt. of the industry. Any ac[ion on our par~, such as rcsc,~rch on the psych~- pharmacology of nicotine, which impl ici tly o,- oxpl icit ly tit'.att; llioot as a drug could well be viewed as a tacit acknowledge~i'.c,l,t that nicoti~c a drug. Stict~ acknowledgement, contend our attornovs, v,ould bt, untimo~ Therefore, although permitted to continue the dcw:lopmc.nt of a tl~reu-prcmgc.<t program to study the drug nicotine, we must not be visible about

WHAT OUR LAWYERS SHOULD KNOW ABOUT NEUROSCIENCES AND PM R&D PM sells cigarettes. Cigarettes deliver nicotine. I~icotine probably delivers change at the synapse in the central nervous system. The synapses affected are yet to be identified. The nature of the change (histoch~mical? neuroelectrical?) is yet to be determined. Even the manifestation at the psychological level, which we infer the shaker is seeking, is yet to be specified. New knowledge about the working of the brain is accreting at a rapid pace. Traditional neurophysiological models are having to be abandoned in face of recent findings. Impulses still follow nerve pathv~ays, but the critical events are now seen to take place at the junctions, or synaptic connection, of these pathways. The liquid medium wherein these cc)nnections are suspended were describe:,.' to ~)rc,d~[~tc sit,dents as ~stabl:: and irrelevant to conductions a mere f~, decades a3o. loday the bio- chemical composition of that medium is being discovered to be in contin- ual flux, composed of a varying host of "neurotransmitter" and "neuro- inhibiter" substances of complex molecular structure, and the momentary state of this synaptic bath is now understood to fix the momentary proba- bility of conductance across that synapse. The many enkephalins (long chain peptides manufactured and released in the brain), other endocrine substances, and internalized exogenous compounds capable of c~ossing the blood-brain barrier are now believed to seek out specific synapses where each has its unique action potential. Nicotine is one of those exogenous compounds capable of crossing the blood- brain barrier. At this point in time its action is still unk,~own, but there are many laboratories funded to study the question. The major fund- ing is from anti-tobacco sources, the rationale being that knowledge of nictolne action could lead to prophylactic or therapeutic b~-eakthroughs to reduce the incidence of snaking. Philip Horris should be committed both defensively and opportunistically. Our own internal programs and our support of Abood's program do, indeed, constitute attu~ed commitment. But there is a hole in the center'. On thz one hand we are manipulating the structure of the nicotine ~lec~le, whil~ on the other we look at the nicotine-likeness of these altered molecules as they affect animal behavior. None among us are focused upon that synapse and its bath and nicotine's action there. Except Abo<)d. Is Abood enough? Should we rely solely upon him as our only informant/investigato~ in the neurosciences?