Tobacco Documents Online

Tnr ('oi•-Xcii. To~ii Tc»;,eccu RLSLAHCii-U.S.A.. I.Nc. September 9, 1981 NE4DRAMM1 TO: Drs. S. C. Srnmers and Staff F1tCM D. H. Fbrd and R. C. Hoc]cett N Kp1 1 b508' SUBJDCT: Site Visit with V. G. Fsiain, School of Pharmacy, University of Colv:ado, Boulder, Colorado - August 26, 1981 Grant No. 1251B "Actions of Nicotine on Isolated Perfused Mouse Brain" Although this grant was not renewed, work was continued on the effect of nicotine on catecholamine metabolism by the isolated perfused mouse brain (IPNID). I Harovanilic acid (HVA) levels have been measured in perfusion fluid to which 1.0 mg of nicotine/liter had been added before passage. (HVA is a metabolite of dopamine (DA), hence its levels in perfusion effluent reflect levels of dn'pamine metabolized.) With C3H mice, levels of HVA increase, while in C57B1 mice they de- creased (Fig. 1). Note; C3H mice respond positively to nicotine in a learning paradigm, while C57 mice respond in the opposite direction (reduced learning) or show no change at all. When the metabolite of norepinephrine (NE) was measured (3-mettio)y-4-hydroxyphenethyleneglycol 04HPG) )(Fig. 2) it was observed that there was an increased production of NHPG in C3H mice (increased turnover of NE) and a decreased production in C57 mice (decreased NE turnover). This data would tend to support the concept that individual responses to nicotine or individual smoking behaviours may have a genetic origin which related directly to the release, neta- bolism and turnover of CNS transmitters. Table 1 presents data on regional effects of nicotine on NE and dopanine (DA) levels in relation to mouse strain and nicotine effect. Several significant effects ware observed.

6_s~s..~ ..... .........~.....a...rw+flv'Ras~~.m:+ Page 3 Tni: Corxrn. Tonr'1'uBarco JtESeaxCtt-I'.S..1.. INc•. 16508£ production induced by nicotine in C57 mice appears to be associated with an increase in NE in the cerebellum, hypothalamus, midbrai,n and medulla/pons as wall as in wliole brain and striatum. While the &ta so far eollected, as represented in the two figures and the Table suggest str~ongly tlhat thexe ar+e differences in rrDuse strain response to nico- tine in relation to NE and DA, the nubers of animals arre too small to be oohclusive. Further, only one dose has as yet been attenptPd. Plans to repeat with a dose of C.5 mg/liter of perfusion fluid. Since oampletiizg his sabattical at the Salk Institute with W. Vale, Erroin has done some studies on growth hommne in the efflmit of the perfusion fluid with the IPNID nodel and fotmd there to be strain differences. Plans to mntinue this in relation to niootine and pre-exposure of the mice to smoke. Will also be moiutoring somatostatin and scanatanedin as well as TSH in an attenpt to detenni_ne if nicotine and smoke exposum induce lower weight gain than in controls (despite slightly higher caloric intake) in relation to pituitary loamonPs associated with growth. Also plans sane immmocytochenistry for these peptide/prot:ein hormones to determine nieotine effects on localization. Is considering a new application to CTR based on the neurci- endocrine responses to nicotine and smoke, using the basic C3H, C57, DBA carparison with the IPNB model. A future study being planned by Erwin in relation to the alcohol study pro- gram at Boulder will utilize hwnan twins (ncno and dizygotic) compared with related and adopted sibs in snakers, non-smokers, ex-si8akers and withdrawn smokers in rela- tion to their neuroendocrine responses. Co*= This is still an interesting program M~hich would appear likely to provide same clues as to underlying differences in respbnse to nicotine or stro3ce of a genetic origin, expressed in relation to basic transnitter substances in brain and their me- tabolism. D. H. FORD R. C. HOQ~.'1T /am

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