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!-TUD~. .X.>MW wlzrif-tN>K,. SMIKING;, A'I0.~^`MM At~'D TP=MchL AC'rZVITY. JOHN A. EDiAMS. AND DAVID M. WRRBUPTal - DEPAKItr1M OFPSYCHQIAGY UNIVERSITY OF REP;DIh1G . READINGiJ. K'- To appear in Pharrr.acola3y aradTherapeuties ;r

AI3STRT,CT «e assume smokers smoke to obtain nicotine and that they can accurately manipulate the dose from a cigarette to meet the demands of the situation. Animal studies using~ smoking doses show that nicotine acts on cholinergi~cc receptors in the mesencephalic reti~cular •formation: which controls electrocortical activity. There is evidence for ii,creased braiin activation and improved information processing following smoking~ Systematic studies of changes in, the Electroencephalogram (EEG) and Event-Related Potentials (ERP) - particularly the P300i - hold great promise for elucidating, the neuropsychological effects of smoking provided the dynamic nature of' the interaction between smoking, brain activity and behaviour is full!y - recogpised. While critical of previous studies we predict a bright future for this research in providing a greater understanding of the effects of nicotine on neural eff,iciency and whether smokers differ constitutionally from non-smokers.

Requests for reQrints should be sent to Johni Ay Lc3warr3s, Department of Psychology, Ur,iversity of Reading, Earley Gate, Whitcknights, Reading, RGb 2AL, U.K. c 2

1 IN1"RODIJCTIbn We present the case that direct studies of the effects of "smaking doses" of nicotine on neuronal activity in animals and indirect scalp recordings of aggregate neuronali activity in the intact human brain following cigarette smoking will eventually provide evid'ence about the biological motives for cigarette smoking. While we are~ critical of the existing literature we 'are also optimistic that the problems facing the researcher are logistical rather. than logical and predict a bright future for this type of research provided a more sophisticated approach to experimental design is adopted,, particularly in human studies. The animal studies are crucial to our understanding of the neuropharmacological effects of nicotine once it is in~ the brain. Hiuman studies are equally crucial in the identification of the neuropsychological effects of'nicotine. Cigarette smoking is not like other drug use because not only cam smokers introduce nicotine rapidly into their bloodstream but they can also maintain control over the concentration once it is in there by a.dj;usting, puf~fing•and'in!halation. We argue that both animal and human studies are necessary if we are to understand'. the neural substrates of the smoking habit. We begin with a selective review of the animal literature. 2 IDISTEI'E'UIION'' GF NIODT1I4E TG TH'E NE&"~ICXJS SYSTEti' In, a, medium delivery cigarette there are about 25 to 30mg of nicotine andl 14 to 20% is transferred into the mainstream~ smoke. The pH of the mainstream ranges between 5.5 and 6.2 for cigarette smoke and between 6.5 and 8.8'for cigar and pipe smoke. The level of acidity is crucial in, determining the amount of. and site of absorption of the nicotine from, the

aerosol taken in by the' smokcr. Free ni.cotine base is readily absorbed bythe buccal membrane and so the amount of nicotine absorbed orally depenc3s' on smoke pIh Animal studies have shown~ that there is ai fourfold diff+err:nce in, carotid levels of nicotine when mouth pH is 6.01 compared to when mouthi pH is 8.& (Armitage & Turner, 1970). In our own research (Russell andl Wesnes, unpublished) buccal absorption from 1.5mg nicotine tablets gave 6.Ong/ml at pH 6.0 and 10.5ng/m1 at pH 9.0. Beckett and Triggs (1964) found'; that from 1.2mgi of nicotine base about 6% was taken up at pH 5.5 and 25% at pH 8.5. From these data it would be expected that very little nicotine is e absorbed orally from, cigarette smoke (pii 5.5, to 6.2; 'Armitage, 1973): but much more from cigar smoke (pH 6.5 to 8.8). F3owever, the crucial part of the smoking habit is inhaling the smoke. During inhalation the smoke aerosol passes down the bronchi and into the alveoli. Nicotine diffuses so rapidly across the alveolar membrane; and the velocity of blood flow through the capillaries is so slow, that equilibrium is probably reached betweeni alveolar nicotine and capillary nicotine ensuring maximum nicotine uptake. It has-been estimated that over 1.3mg of nicotine.is taken by inhalation from a medium delivery cigarette (Armitage, Dollery, George, F3puseman, Lewis & Turner, 1974). Of course, the actual values depend on the puffing pattern, depth and degree of inhalation and contact time with the alveoli. After absorption into the pulm~onary capillaries the nicotine loaded blood leaves the lungs via the pulmonary veins and passes through the left atrium of the heart into the left ventricles. From there, the nicotine passes out into the aorta from which the carotid arteries branch off, the major branch direct to the brain. in this way absorbed~ nicotine can pass directly and unmctGbolised from lung to brain within 10 seconds. About 20% of the blood' with the absorbed nicotine travels to the brain (O1c3Fnc3orf,

1977) and the amount of' nicotine getting to the brain is proportional~ to the cardiac output to the brain, i.e. 20% of .1.3mg or about 250ug. Nicoti!nee is soluble in liquid and passes freely through the blood-brain barrier: in fact, well over ninety percent of the nicotine (over 200ug) reaches the brain (Olldtndorf, Hyman, Braun & Oldendorf, 1972)1. Autoradiograms of mice given intravenous doses of 14G-nicotine show a high accumulation of nicotine in. the grey matter with much, smallerr quantities in the white matter. There is radioactivity in cortical cellsy, high levels in molecular and'pyramidal cells of the hippocampus and molecular layer of the cerebellum and the nuclei of' the hypothalamus and brain stem (Schmitterlow, Hansson, Applegren & Hoffman, 1967). This pattern of distribution of nicotine through the brain allows wide scope for interaction: with brain neurones. The time course of nicotine distribution in the mouse shows that the. maximum concentration is reached within one minute of an intravenous: injection and then decreases rapidly to about 50$ in five minutes and 1'%in an hour (Stalhandslte, 1970). Similarly, Sdhmstterl'ow et al (1967) founa a rapid - decrease from 3.93ug/g at five minutes to 0.7lug/g at twenty minutes.and 0.10ug/g after one hour. The brain does not metabolize nicotinee but the drug, washes out very quickly from the brain and''so is likely to, give a short duration of action there. In , the following sections, we shall be discussing the actions of nicotine on the nervous system, and so! on behaviour,, which may be used to account for the smoJting, habit.. The literature is vast andl so only illustrative experiments will be cited. In Section 3 the emphasis is on the neurochemical and neurophysiological changes produceo' by smoking doses of' nicotine. ln Sections 4 to 7 these changes will be related to what measures 5

of the clectrical activity of' the human brain can tell us about the effects of nicotine and how, these changes are related to behaviour.. 3 hL•'UROCI3CMICAh ACTICNi OF t91iOJTINE There is evidence in, the literature from in vivo~studies that nicotine produces changes in the brain levels of' catecholamines, indoleamines and acetylicholine in animals. The crucial question is whether these data can be extrapolated meaningfully to humans in order to~explain the smoking habit? A major problemi with the majority of these studies is that the dose levels r of nicotine do not approximate "smoking" doses. As a rough guide, al 75kg person, who takes between 0.75 and' 3.emg of nicotine from a cigarette into his mouith, will be receiving, a maximum dbse of 40ug/kg. There will be obvious differences due to route of administration (inhalation and - intravenous injection versus subcutaneous and intraperitoneal injection) and the different metabolic rates of different species but it is probably safe to conclude that in mice, rats or cats a7ny dose which is over ten times this dose (0.4img/kg) is well outside the "'smoking" dose range. The time course of nicotine presence in human plasma has been stuciied! most extensively by Dr N.A.H. Russell. Smokers puffed ten times on a: cigarette and plasma, samples were taken every five minutes from an indwelling needle in ai forearmi vein. There was a rapid increase in plasma nicotine with each puff and peak venous nicotine levels of 15.5 to 38.4ng/ml were reached at theend~ of the cigarette: aboutone; fi~fth, orone sixth of the carotid artery levels. The estimated half-life in humans is around twenty minutes after finishing the cigarette and baseline levels off about 7ng,/ml are reached in forty minutes. 6

3.1 PHRIPIiCRA,L Nt:UROPHYSIiOLOGICAIL 11CT'10N OF N100'1'IIaE The action of nicotine has-been~ explored by using the readily accessible neurones in the peripheral nervous system. Thus, the first studies will describe the action of nicotine on these neural junctions: Some caution must be exercised when using these data to explain central nervous system phenomena but, ini general, the principles that have been dierived from such studies have proved useful in understanding the activities of drugs in the brain. The action of nicotine on the nervous system has b--en known since the pioneering work of Dale (1914)i. This work established that nicotine mimicked the action of' acetylcholine at the autonomic ganglia and the neuromuscular junction. The effects of different doses of nicotine on cell meirbrane depolarizatiQn andl subsequent action potentials were compared with, acetylcholine by Paton and Perry (1953), using the cervical ganglion preparation. A 5Oug dose of'nicotine tartrate in 0:2m1 of liquid wass injected into the carotid artery which gave a somewhat larger dose than the 20-30ng/ml found in the femoral vein after smoking, (see Section, 3) but closer to the concentration ascending in the carotid artery after inhalation. The effect of this dose was a transient depolarization of the membrane but some reduction of the subsequent action potentials; aichange that was similar, to but more transient than a small dose of acetylcholine. However, six times this nicotine dlose, 0.3Img„ produced prolonged depolarization and the action potentials were abolished. A challenge with a second dose of nicotine after the original depolarization, but before recovery of the action potentials, produced less depolarization than previously which demonstrated nicotine was producing a competitive block of receptors at very high d;oses. Whatever the reason for this blockade it seems: unlikely that blood conctntrations some 100,000 times those found in 7

the femorai vein after smoking even occur in~ the smoker's brain and that a, biphasic action will be produced: in brain neurones (see Section 7). Thus, at "smoking" doses nicotine precisely mimics acetylcholine and produces the same neural changes that would occur after natural activation of that synapse. The reason for the exact mimickingi of acetylcholine by nicotine at some synapses is the remarkable similarity of the structures of' the twoo molecules. Both nicotine and acetylcholine have a positively charged, methylated tertiary nitrogen group in the pyrollidine ring (N+-CH3) which in nicotine is attached~ to a negatively charged, isosteric nitrogen in the pyrid'ine ring at just the distance to match the negatively charged, oxygen of' acetylcholine. 3.2 CENFRAL hIEUROPHYSIOLAGICp.h ACTiON OF IaIIO(JT723E Nicotine depletes whole brain acetylicholine in the rat (Pepeuj 1965) and mouse (ESsman, 1971) ins doses of lmg/kg. ) Depletion could be a consequence of (i)d'ecreased synthesis, (ii) release from storage, (ii), increased'release or (iv) more effective enzymatic activation. There is noo evidence that nicotine modifies: (Hrdina, 1974) and the enzymatic inactivation of acetylcholine is extremely ef'fective, which argues for aa change ini either storage or release. The question of nicotine-induced changes in acetylcholine storage pools was tackled by Essman (1971). He found evidence of a decrease in bound acetylcholine and acetylcholine in synaptic residues in neocortex samples which suggested acetylcholine release from storage. However, there was no increase in the free acctylcholine pool aoncentrati~on which, argues for increased release of the unbound transmitter and'.subsequent 8

inactivation by acetylcholincsterase. Miore importantly, there is strong evidence for acetylcholine release at the cortex after a"smokingl' dbse (40ug;/kg intravenously) in the cat (Armitage, Hall & Sellers, 1969) which is consistent with the release hypothesis. The phenomenon of increased release at the cortex would~ be explained if nicotine enhanced' presynaptic release mechanisms in cortical tissue but there is no in vitro evidence of enhancement (Hrdina, 1974). If the major effect with "smoking" dbses is to increase cortical release of acetylchoTine but there is no evidence that release is due to a T direct effect on the presynaptic release mechanisms of cortical neurones, then the solution, to the paradox must lie in indirect activation of acetylcholine neurones which form part of the ascending cholinergiic pathways to the cortex: This possibility will be considered next. The first evidence for "nicotinic" receptors in the central nervouss system came from studies of the Renshaw cell in the spinal cord (Eccles, Eccles & Fatt, 1956). It wa shown that when either 200ug of acetylcholine or lugi of nicotine were injected close •to the cell there was an action potential. The response to nicotine was more prolonged than that to acetylcholine because, unlike acetylcholine, nicotine was not inactivated by acetylcholinesterase. When acetylcholinesterase was inhibited by physostigmine, acetyicholine produced a much larger response but the response to nicotine was unchanged. This result showed that nicotine's effect was directly on post-synaptic receptors of' the Renshaw cell directly and not via the release of acetylcholine. Nicotine antagonists rEdiuced! thee response to both, acetylcholine and'nicotine, further indicating that nicotine was acting directly on cholinergic synapses as it did in thee peripheral nervous system~ Studies with iontophoretically applied acetylcholine have revealed : ~ :.