Tobacco Documents Online

!-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 : ~ :.

that this tranWmitter excites neurones in many regions of the brain including! the mcdu11ary and, mesencephalic reticular formation, lateral and medial geniculate nuclei, caudate nucleus, ventrobasal complex of the thalamus, cerebellum, inferior colliculus and! the Betz cells of' the deep pyramidal layer of the cerebral cortex (Phillis, 1'970)1. The cortical cells and caudate nucleus had' definite muscarinic! receptors and were relatively insensitive to nicotine while acetylcholine receptors in the geniculate nuclei, centrobasal thalamus and reticular formation~ nuclei had both nicotinic and muscarinic properties. Cholinergic inhibitory neurones with mixed.nicotinic and muscarinic receptors have been found-at the cortex inn layers II, III and IV of the primary sensorimotor auditory and~visual areas and these seem, to be cholinergic inhibitory interneurones. Im spite of the clear evidence that the: cholinergic neurones at the cortex are predominantly muscarinic, we have seen that "smoking"' doses of nicotine (e:g. 20ug/kg, in the cat) produce! excitation of cortical cells (Knapp, Kawamura, & Domino, 1962; Armitag~e et al, 1969) and release of acetylcholine at the cortex (Armitage et al, 1969). In. the study of Kawamura and Eomino (1969) bloodi pressure was kept.constant with drugs so that the effect of nicotine was not due to this change. Cortical acetylcholiine release and'cortical excitation can be produced by stimulation of the mesencephalic reticular formation and this phenomenon " can be reduced in, one hemisphere by a unilateral destruction, of this region ipsilaterally (Celesia & Jasper, 1966). In a neuropharmacological analysis , of the effects of "smolcing" doses {20ug/Icg) of nicotine after destruction of' the midbrain, (Domino,1967; Kawamura & Domino, 1969) nicotine produced ' cortical desynchronisation and hippocampal synchronization of the EEG in cats with a caudal midbrain transection at the jun;.i+ioni of thepons in 10

exactly the same way as intact animals given nicotine. After bilatcral' lesions in the teginental region of the mid+-brain, nicotine in doses up to five times the 20iug,/kg "smoking" dose did not activate the cortex. Clearly, nicotine's action on the cortex depends on an intact tegmental reg;iony The ventral tegmental region of the mesencephalic reticular formation is the origin of a cholinergic pathway which proj'ects to the cortex (Shute & Lewis,, 1967) and there is good evidence that it excites the pyramidal Betz cells at the sensory cortex and produces electrocortical activation (see review by Warburton, 1981). The most parsimonious conclusion is that "smoking" doses of nicotine ascend in the carotid artery and' excite nicotine receptors on the mid-brain tegmental-neocorticaT cholinergic pathway. it does not act directly on the cortex but the outcome of' activation of this pathway is the release of acetylcholine at the cortex and cortical desynchronisation of EEG of cats. The following sections will critically examine attempts to relate changes iri the electrical activity of intact human brains following cigarette sanokingi ana discuss how the data from animal and human studies may proviidieconvergingi, information about the role of nicotine~ in smoking. 4 SMCKING AND ELECTR00DRTICAL ACTIVITY The appeal.of electrocortical indices is that potentially they can provide us with more direct information about the effects of tobacco smoking on the central nervous system (MIS) of humans. Traditionally, the. EEG has been used as a measure of tonic CNS' "arousal". For example, it is ~ ~ commonly asserted that a shift from high amplitude 8-13Hz to low, aamplitude N' ~ 13-2©Hz activity indicates an increase in alertness. The typical approach ~ i's to compute the level of alpha (8-131iz) activity, the dominant alpha ~ O frequency, the total energy or the variability of EEG activity. It is ~ 11.

assunied~ that the I;EG is a reliable measure of the "etate" of the CNS. However, Gale and Edwards (in press) argue that the EEG may also be a, sensitive measure of phasic events under the appropriate conditions. At this point we must warn the reader that the concept of "arousal" appears throughout the literature as an important explanatory concept. However, this single term is used to interpret datp from a wide variety off studies. Such ubiquitous and often uncritical use of the construct has seriously undermined its explanatory power. The crucial implications for studies of the electrocortica:l co relates of tobacco smoking; are: (i) there is considerable physiological evidence; against the notion of a unitary construct of arousal (e.g. Lacey, 1967); (ii) tYie term has been used in convenient post hoc explanations of unexpected results; (iii) each experiment should be analysed to identify. • important: sources of arousal. Gale (1981) has outlined' an arous l model for the laboratory which has nine components which clearly emphasises the complex nature of arousal-performance interactions. Through systematic identif ication of significant sources'of variability we will be able to generate specific predictions. The alternative is the traditional assortment of "one-shot"' studies providing equivocal results. The averaged'evoked potential and the contingent negative variation (Grlv), collectively, referred to as event-related potentials (ERPs), reflect the response of the- brain; to stimulation. These complex waveforms are external manifestations of CNS processing of simple sensory information and, more important psychologically, complex cognitive processes (Donchin, 1979, 1981). N G N ~ We have described' how n;icotine can cause important changes in the C11 activityof cortical neuro~nesindnimalsa~nd since measurements~ of the ~ ~ 12

electrical activity of the human brain are known to reflect, in part, cortical changes it is reasonable to assume that Ei7G and E1T indices will be systematically related! to the effects of nicotine on the brain. 4.1 SGUECE' OF THE EEG 1y:ND EF2Ps Unfortunately, recording,s from intact humans can only provide gross indices of underlying neuronal activity because they are restricted!to activity picked up by electrodes placed on the surface of the scalp. "Electrodes on the scalp record, mainly the summated! electrical changes of the underlying cortex; they may also record some potential changes• generated in distant parts of the brain and potential-changes produced outside the brain. The amplitude of the recorded potentials depends on the intensity of the electrical source, on- its distance and!spatial orientation, and on the electrical resistance and capaci'tance of thee structures between the source and the recording electrodes. These factors favor the recording of potential changes which (a), occur near the recording electrodes, (b) are generated in, a large area of tissue and (c) rise and fall at slow speed'."' (Spehlmann, 1981; pp 15-16). It is no surprise therefore that the precise sources of human EEG rhythms are by no means completely understood but it is certain that sub-cortical neurones p3,ay a role in EEG activity recorded at the scalip. Consequently, its value ini the analysis of brain, function depends on systematic study of the relationship of changes in the EDG to ongoing behaviour. In the same way, ERPs are statistical measures of' the neural response pattern underlyingi the electrode in which much detail is lost and it will be less thani fully representative of the activity at individual neuroncs/synapses since, for example, some brain processes may not create electrical fields which are measurable at the scalp. 13'

Knowledge of the source of. spontaneous EEG rhythms and! ERPs is important because we need'.to know how different brain areas are involved iin different brain processes. Topographical mapping of EEG' and ERP by multiple site recordings of scalp: activity under a variety`of stimulus conditions will provide information of primary sources of activity.".,...it is incontrovertible that scalp-recorded ERPs are produced by patterns of activity associated' with different neuronal aggregates.... wherever those aggregates are, the sequence with which they are activated and the degree to which they interact with each other reflects intimately the transmissionn of information: and the activation of the information-processing activities withini'untracranial structures.... an ERP component is a subsegment of the ERP whose activity represents a functionally d'istirict neuronal aggregate....A component is a set of potential changes that can be shownn to be functionally related to an, experimental variable or to a combination of experimental variables.... Electrode site is one example." (Donchin, Ritter & MicCallum, 1978; p. 353). 4.2 rIEZ'HODOIi©GIC'AL, ISSUES IN SMOKING RESEARCH Electrocortical measurements associated with smoking present specific challenges to the experimenter. 4.2.1 Sampl ing There must be a theoretical or empirical reason for the time over which the electrical activity is analysed: it would seem logical to link it N O to the time course of nicotine. The EEG~ can be sampled continuously in jy iA milliseconds, seconds, minutes and even hours with the samples partitioned' N CA according to the questions asked. Such flexibility of measurement is a~ ~ source of considerable power only if the rEG is sampled' over the periods ~ 0. 14

when nicotine is known to be active in the brain and also when t})e individual i~s exhibiting any behavioural or experiential effects of smoking. 'Ihis has not been a feature of previous studies. .Similarly,, in ERP studies, the technique of signal • averag,ing depends on repetition of the same stimulus on the assumption that the individual's response to, this event is similar on each occasion. This takes time and since the body concentration of the drug varies across time, reaching a peak and then declining it is even more crucial than in EEG studies that the samples used to make up the ERP are taken during the period when the drug is present and' maximally active. No ERP study of smoking has exercised this. level of care. 4.2:2 Analysis Many different 7nethods have been, used- to quantify electrocortical activity. The wide variety of inethodsused to quantify the EEG - e.g. Fourier 'transf'orms, alpha index, alpha frequency, alpha, abund'ance,, mean dominant frequency - makes it very difficult to compare data derived' from different laboratories and to construct a model of the functional significance of the EEG. A minimum requirement wouldi be to measure a range of frequencies (1-30Hz)'. Mere measurement of gross alp.'la characteristcs (8- 13Hz) may be missing valuable information because other frequencies (betaa and theta, for example) may respond differentially to task conditilons. (Schacter, 1977). ERP analysis also requires a systematic strategy for identifying ERP components (see Donchin, Ritter and McCallum, 1978)1. The crucial point is that electrocortical measures should be carefully integrated with the experimental design and not tagged on as an afterthought. The interested reader is recommended to consult the recent methodological rev~iews~ by dohnso~~n~ (1980; EEG),~ Picton (,11~~98!©; ERP) and; VConnor (19'80; CNV).. 15

4.3' ;,PIOKING 1,TND '111C E3UMAN BRAIN In order to assess: thc psychopharmacological effects of nicotinc, certain, controls must be built into the experimental design: these have generally been ignored in the literature., First, the- state of the subject before smoking has rarely been manipulated in, smoking; research. Thee individual's pre-drug,state must be assessea, since the response! to the drug, may vary as-a function of this initial state., Second, control over drug dbse is vital because many drugs have nonlinear dose-effect relationships. Third, the time course of the drug's activity should be known. These points are particularly apposite in smoking, studies because of the special qualities of nicotine: rapid absorption and wide distribution in the brain together with quick removal. Nicotine is relatively selective by acting on choliinergic neurones but could have simultaneous effects on different cholinergic•brain systems and what is recorded at the scalp might be a function of what demandis are made of the individual's informatiom processing capacities. Here we see a clear case for topographical recording. Furthermore, the relatively brief action of nicotine suggests the drugg can be used as a phasic stimulant which means that the experimenter must take care if he is to synchronise the recordings with this active period,. In an earlier assessment of the EEG effects of nicotine and tobacco smoking Murphree (1974) makes the bold claim that "...since the time of HANS BERGER, certain electroencephalographic (EDG) findings have been known to correlute very closely with behavioral states and' with shifts in those states" (p. 22). Our position is that this is exactly, the opposite: we know relatively little about the relationship •between EL+:`G changes and behaviour andi therefore, if we do not collect information concerning the behavioural [ 16

efiects of drugs concurrently with eiectrocortical measures then we will not be able to identify the functional significance of these changes. Nlurphree also makes the: strange statement that although the drug effect may be the same the EEG changes may be differentl1: "The, point is not ..., that the, in'stial state determines the drug, action as such, but that the subject begins somewhere along the parallel spectra of EEG' and behavioral state and! that the drug, acting as a constraining influence, pushes him: toward other parts of those spectra. The same -kind and degree of drug effects in subjects with different initial states may then produce records having very different appearances." (P. 23). We argue that the point is that unless behaviou;ral andl experiential . data are available in such circumstances there is no way of'verifying that a drug has the same effect on individuals when their brain shows signs of something different happening~ Indeed, one of the most serious criticisms of studies of the effects of' tobacco smoking: on electrophysiological activity is that subjects are maintained at rest and unoccupied prior to and after smoking. For example,. Murphree, Pfeiffer and Price (1967) recorded the EEG of smokers puffing andinhaling,on lighted and uniighted cigarettes in a supine position with eyess closed: hardly normal smoking behaviour. There is little positive evidence for the validity of these contrivedllaboratory experiments and, as a result, there will always be problems with.generalising to active smokers in "real-life" settings. Prior to an evaluati on of the literature, certain necessary design~ constraints will be outlined in order to provide a yardstick for assessing! the quality of the data: obtained. 4.3'..1 Smoking Controls The typical design of these studies compares electrocortical activity 17~

of smokers beforc and after smoking: a study of the acute effects of smoking. While this is a logical strategy, such an apparently simple d!esigm must incorporate appropriate controls. Recording during smoking has b::cn ignored due to the obvious difficulties with movement induced artifacts. However,, with careful control over the smoking behaviour such, studies should be possible and might provide useful informe'-ion about the immediate effects of nicotine. The main difficulty would be that the subject might not be smoking naturally and the signif icance of the datai for normal smoking will be. lessened,, A first step in solving; these problems would be to incorporate a detailed's analysis of' normal smoking behaviour. Without adequate controls for the smoking action any electrocortical changes cannot be confidently attributed to nicotine. The problem of whatt constitutes an adequate control is a matter of debate and different- researchers appear to havie their own favourite. At the very least a nonsmoking condition is needed to control for the effects of the laboratory environment. By including the smoking of a nicotine free cigarette in the design it should be possible to partial out the effects of the environment, smoking action and nicotine on brain activity. Suitable controls are more readily available in nicotine tablet or injection studies but, as we have argued above, there are difficulties in extrapolating from the results of these studies to the results of cigarette smoking; particularly when the dose administered bears little relation to that typically obtained, fr= cigarette smoking (see Section 4. In addition to~analysing the "cigarette end" of'smoking, useful information can: be gathered about subjective aspects of' smoking~ behaviour.. Individual differences in; smoking, behaviour and smoking motivation have been~ negleftedin the literature with the exception of two CNV stud~ies 18

(Ashton, h3illman, Telford &'i:hompson, 1974; Binnie & Comer, 197'3'). 4.3.2' The Cigarette Only Knott and' Venables (19 7', 1979) and! Binnie and'. Comer (197'a), provide machine smoking estimates of the nicotine and tar deliveries of'the test cigarettes. 2'be remainder merely report that subjects smoked one or two cigarettes during the experiment. While the Fhl-Acal characteristics of the cigarette only provide limited information about the dose of nicotine obtained,during smokingi (see next section) these data can assist comparison across studies.= 4.3.3 Smoking Behaviour "Cigarette smoking .... is a drug-delivery system for nicotine, "tar"' and carbon monoxide that affords no .... straightforward' way of monitoring dose. Although the words on cigarette packs and advertisements appear t© indicate. the dose of tar and nicotine to be found' in a cigarette, smokers can easily double or triple yields beyond the nominal levels by taking,more frequent, larger, or high velocity puffs.." (Kozlowski,, 1981;p213'). Standard smoking machine deliveries do not ariequately reflect normal human smoking: because the machines take a 2 second, 35 ml puff on, a cigarette per minute until a fixed length butt is obtained: human smoking is much too variable to b properly represented by such an arbitrary average puffing schedule. Thus, even if studies of the electrocortical effects. of smoking had included standardl machine delivery information we would still not know- the nicotine dose that the subject obtained from snriking that particular cigarette. A number of parameters of smoking bchaviour are measurable: number of puffs per cigarette, puff duration, inter-puff' interval, puff volume, butt length,, butt nicotine analysis,- percentage tobacco burned, 19

cigarette duration, salivary nicotine lcvcl, plasma cotinine and nicotine level and alveolar carbon monoxide: These measures provide a means of estimating the amount of nicotine obtained by the smoker. t,lithout such an estimate there is (i) no possibility of identifying the active epoch of the drug (ii) no satisfactory way of distinguishing between the electrocortical effects of' the smoking act and! the effects of the inhaled nicotine. 4!.3.4 Task Feq}airements The most serious deficiency of these studies is the lack of systematic collection of behavioural and experiential data: specifically, requiring the subjects to perform tasks which either have a sound basis in experimental psychology, or are similar to activities assflciated with. "real-iife" smoking or, preferably, tasks which combine both.- This has not been attempted. This is not because of' any logical impossibility of such am approach: rather, research to date.has adopted a simplistic approach to a complex problem. For the most part, previous research has addressed'three questions. First, are there basic electrophysiological differences between smokers arn6 non-srr,okers (e.g. Brown, 1973; Roos, 1977')?' Second, what are the effects of'f smoking on electrocortical activity (e.g.Friedmanr Hbrvath~ & Meares, 1974; Friedman, Goldberg, Horvath & Meares, 1974; Murphree et al, 1967; Philips, 1971)? Finally, do smokers need to smoke in order to maintain a "normal" or"optimal" level of arousal (U1ett & Itil, 1969; Ulett, 1969; Itil, Ulett, Hsu, Klingenberg & U1ett, 1971; Knott & Venables, 1977, 1978, 1979)? 5 F:FG slvLiES Thp early studies by Brown (1968, 1973'), Friedman, Hiorvath and Meares 20

(197'4') are dogged by design li'mitations and equivocal interpretations of marginal results (see Edwards, in press). Friediman, Harvath and Meares (1974) examined the effect of smoking on habituatiom of' the EDG component of the orienting reflex (OR). Their measure of orienting was alpha desynchronisation at the vertex andi the habituation criterion was the number of stimuli at which the EEG' showed no, des_ nchro~nisation to two successive stimulii. They used three conditions: normal smoking„ smoking after 12 hours deprivation and placebo smoking on separate occasions. Each session consisted of two habituation series, one before and one after smoking. This is a serious design flaw since habituation, by definition, shows transfer over time and thus it is not appropriate to compare two sequences which, fo3low closely in time and this error was compounded by using a fixed order of treatment presentation. They did find that the habituation criterion was reached faster in the two smoking conditions althoughy interestingly, they found no differences in the response" to the first stimulus after smoking. Interpretation of this habituation data is made difficult because the method of indexing habituation presumes the same level of cortical respond'ing in all conditions before the experiment begins otherwise any differences may be due to different basal levels of activation. Brown (19i68), found consistent differences between very heavy smokers -(5© to 100 cigarettes/day for at least 2 years) and non-smokers: 11 out of 13' heavy smokers exhibited large amounts of high frequency rhythmic 12-25nz activity and minimal amounts of' alpha activity even with the eyes closed, while non-smokers showed more alpha and negligible rhythmic activity compared to heavy smokers. Brown argues that although the EEG is activated~ the p:,-~ttern is not that of "alertness;/arour.al"' since it involves rhythmic, 21

sustained, high amplitudcy fast activity. However, as she included no measure of behavioural or even subjective activation we have no way of meaning,fully interpretingi these differences in EM activity. Thus, it is not clear whether these differences are a function of tobacco smoking or merely due to the different reaction of smokers and non-smokers to a novel laboratory environment. Brown (1973) again reported differences in "rhythmic beta", alpha abundance and variability of alpha freguency betweem very heavy smokers and other smoker and'non-smoker groups but because her experiments provide suc.h an unstructured environment for the subjects it cannot be conclur3er3 that the differences obtainedi are directly related to use of cigarette smoking in "real-life". The subjects did not smoke during the recording sessions so there are no datairelevant toit~e hypothesis that smoking rate is regulated to maintain an effective balance between the behavioural accompaniments of EEG synchronisation and desynchronisation: In addition, the most reliable findings come from very extreme groups of smokers who may differ from other smokers on a number of characteristics other than just number of cigarettes smoked per day so that it is by no means clear that EEG patterns of' her sample are related to! a physiological predisposition to smoke. She did find' some evidence for a positive relationship between the amount of smoking and the degree of EEG activity in that very heavy smokers had half the abundance of al'pha per unit time and rhythmic beta amplitude nearly, twice that for non-smokers and former smokers. But the functional relationship between these EEG changes and brain activation, has yet to be established, particularly in the. case of "rhythmic beta". Roos (1977) examined whether non-smokers, light, and moderate-to-heavy smokers would differ in their tonic CCG levels and electrocortical reaction to Yarious auditory stimul.i: ranging from non-signal sounds through 22

emotionally lad'eni words and did find diiferenc!es betwEen, hissub-groups: Light smokers (less than 12 per day) showed the greatest variability in alpha. Roos argues that they smoke to! mani'pulate their level of arousal to meet environmental demands. Moddrate sniokers (12-18 per dlay), exhibited thee largest amounts of alpha, of all groups but they were less reactive to rnild stimulation and'i so Roos claims they smoke to push themselvescloser to thee optimum level. Heavy smokers (20+ per day), had the smallest aQnount of alpha of all groups and also exhibited little reactivity, perhaps because they could not show°any further decrease in alpha. In this case it woul'd'! havee been very useful to have data from other frequencies to clarify the significance of the alpha characteristics of this group, particularly in relationito whether,these findings for alpha abundance are more than superficially similar to those of Brown ('1973) since she also found' differences in beta and theta activity between, her groups. Roos proposes that heavy smokers "'....smoke a large number of cigarettes for the inhibitory.effect of large doses of nicotine in order to enhance their amount of' alpha waves to the optimal level"'. (Roos, 1977; p. 240). While Roos provides an interesting analysis of the.role of nicotine in the smokingi habit he goes well beyond the available data. He presents no performance data and so his explanations of the function of smoking in terms of reaching and' maintaining an optimal level of "arousal" have a ' hollow, ring since they were not based onidirect evidence of changes in task. performance following smoking. Eurther, Roos takes the level of alpha shown by non-smokers as the optimal: surely an empirical decisioni dependinq on the situation. It is interesting that Brown's concern with the chronic effects: of' cigarette :;rriolti.ng prod^uced data on short-term deprivation which conflicts 23

with those of Ulett and Itil (1969) and Knott and Venables (1277', 19719). Brown (1968) reported no differences in the L•'L•'G'of 12 hour deprived smokerss and satiated smokers. Ulett and Itil (19G9) found that smoking afiter 24 hours deprivation resulted in a return to a pre--sJnoking baseline. The deprived state was associated with a decrease in the mean dominant EEG frequency from 10.5Hz to 9.5Hz, accompanied by a significant increase in 3.5 to 7.0Hz activity and non significant increases in the higher frequency range. All these changes were reversed folldwing,smoking. Deprived smokers also showed a slower pulse and increased systolic s blood pressure, which was also reversed after smoking. However,, Ulett and Itil do, not provide any behavioural or experiential data apart from feelings of dysphoria reported by the deprived smokers. No controi for the ac't of smoking was attempted so it cannot be firmly concluded that the. changes are associated with nicotine uptake. Imsubsequent, better designed studies, Knott and Venables (1977, 1979) challenged Brown's suggestion that smokers become dependent because of the tranquilising effect of nicotine and/or the smoking act itself. They postulated that, nicotine isi a CNS stimulant and its withdrawal is sedative and~ depressant. In order to test this hypothesis, Knott and Venables (1977) employed a between subjects design to: construct five groups: non-smokers were compared with both 12 to 15 hour d4rived smokers and non-deprived smokers. A randomi selection of. these latter two groups szmoked two cigarettes within a ten minute period, inhaling at thirty second'intervals. The remaining subjects inhaled through an unlit cigarette according~ to the same protocol. Two EEG measures - alpha amplitude and dominant alpha frequency - were compute& Alpha amplitue;e revealed no significant effects although deprived smokers showed'higher. amplitudes than non-smokers. Dominant alpha freguency 24

was more illuminating. Before smoking, deprived smokers had significantly lower alpha frequency than non-smoker and non-deprived groups but smoking prodiuced'l*a significant increase in dominant frequency for the dieprived smokers. Beprivedismokers who were not allowed to smoke had significantly lower dominant frequency compared to the other groups. There were no significant differences between these other groups. Because they used, a control for smoking activity there is a reasonable case for concluding that smokers smoke to obtain nicotine in, order to reach "normal" operating levels of brain activity. However, because they included no behavioural measures this conclusion is weakenedl: they have no evidence that these EEG changes are related to an individual's ability to "operate". Their position is strengthened', to some extent by their experiment on, the jioint effects of alcohol and~ cigarette smoking on the EEG (Knott &. Venablies, 1979)!. Using a similar design Knott and Venables found once again that, in the non-alcohol condition and prior to smoking, deprfved', smo,kers had significantly lower alpha frequency than non-smokers or non-deprived smokers. After smoking, without a,Icohol, these smokers showed; a, significant increase in frequency comparedi with non-deprived smokers. Also, smokers, allowed to smoke, showed.a significant increase in alpha frequency compared with nonrdeprixted smokers who did not smoke. These last data suggest that the effects of smoking on the EEG are more than the restorationi of normal . operating levels. Alcohol alone proJvicedl an overall reduction of 0.2iiz in .dominant alpha but when smoking had taken place this decrease in alpha frequency EEG was not present. A within subjects design woulid have been more appropriate in order to look at the effects of dieprivation: and smokiing within the same individuals. Since, this requires repeated e::posure to the, laboratory sucii a des,ign, would 2I5

moderate the interactions betweeni the subject's state, smoking: and'' the laboratory environment. It is also unfortunate that only alpha activity was analysed since useful information could have been obtained from the other \ frequency bands. Although Knott and Venables.can be criticised for not including an estimate of how much nicotine was absorbed by the individuals and the likely time of its effects their dsta give strong evidence for cigarette smoking and, probably, perhaps, nicotine modifying cortical activation, If these EEG effects could~ be tiedo to both amount of drug reaching then brain and changes in task performance within the same subjects they would' help clarify the nature of the hypothesised central antagonism of alcohol and nicotine.. In summary, given the clear methodological limitations of these EEG studies they do provicie evidence that smoking produces a shift in, EEG in the direction of higher frequency which is consistent with the effects of nicotine described in Section 3.2. There also appear to be interesting differences between the EEGs of non-smokers, deprived smokers and non- deprived smokers but the exact significance of these differences has yet to be established. i 6 ERP STUDIES With repetitive stimulationi the positive-negative fluctuations of the: ERP waveform up~to 25©msec post-stimulus have beeni shown to be essentially constant in amplitude, latency and scalp distribution for a given stimulus. The amplituds and latency are affected by the physical parameters of the stimulus and -their scalp distribution depends on the stimulus modality (Regan, 1972). These components are labelled exogenouE because they are evoked by events. external to; the nervous system and their occurrence does 2G

not depend on the psychological state of the individual (Donchin, et al, 1978).. Previous studies were confined to evaluating the effects of tobacco smoking on the CNS modulation of sensory input (Friedman, Goldberg, Horvath & rieares, 1974; Hall, Rappaport, Hopkins & Griffin, 1973a; Brown, 1967,. 1968; Knott & Venables, 1978). They were particularly concerned' with the amplitude: of tfie positive-negative compl;ex of' the flash evoked potential formed by events IV and V at around 100 and 125mser- latency (also referred to as P10i0 1N140) which according to H'a l1 andl his co-workers reflects "subjective responsiveness" to weak and strong stimuli. (Hall, Rappapoxt,. Hopkins & Griffin, 1973b). Using four levels of flash intensity and measuring, vertex potentials, they found that the amplitude envelope decreased after 12 and' 316 hours deprivation compared with non-deprived and this decrease was reversed after smoking in: eight out of nine subjects. After, 36 hours deprivation the dtop in IV-V'amplitude was inversely proportional to~flash intensity for the two dimmest flashes. After smoking there was a trend towards a significant increase in amplitude associated with these two intensities. Hall, Friedman and their associates are seriously in error when they attempt to relate a gross measure of ERP magnitude to brain states suich as as~ arousal or alertness (Donchin, 1979). While the assumption that srnolkirg -- or, in particular, nicotine uptake alters the manner in which the.brain processes sensory stimuli is not disputed , Hall et al and Friedman et ali have not adeo,uatel'y demonstrated the nature of' the changes. Knott and Venables (1978) , in a well designed study assumed that CNS modulation of stimulus intensity is associated with the acquisition and, mai.ntcnwnce of smoking behaviour, in a manner related: to Petrie's construct 27

conclusion about the siginficance of thie cortical effects of ci~garette smoking or, more specifically, nicotine on the basis of the evidence gathered to date. Certainly, there is evidence that nicotine has effects on exogenous components of the EFcP but it has: yet to be clearly demonstrated what these effects meanL Psycholog,ically more fascinating are the so-called end'ogenous components (Sutton, Tueting,, Zubin & John, 1967), which: can be elicited by environmental contingencies but are also emitted in.ttle absence of external stimulation. Their characteristics are partially independent of' the physical parameters of the eliciting stimulus and~ they are important because, of their association with, an individual's prior experience, -intentions and dec,isions~ and! their systematic variation with task requirements and experimental instructions (Donchin, 19'81; Pritchard, 1981). With one exception, (Edwards, Wesnes, Warburton & Gale, Note 1; see below) none of the studies have examined the effects of nicotine on complex information processing. Wesnes and'. Warburton (see Warburton, & Wesnes, 1978; Wesnes & Warburton,, 1978), in an extensive series of experiments concerned with the~ effects of tobacco smoking and nicotine on performance on a task requiring rapid information processing, have clearly demonstrated that smoking speeds up reactions, increases the number of signals cietected and prevents the usual decrement in performance over time typical of sustained attention tasks. The same results were obtained im three studies on smokers and non-smokers with nicotine tablets which~ contained doses similar to~ those received' by smokers. These data are strong evidence that nicotine is the significant component of cigarette smoke that results in more efficient information processing. 2'9

These results have prompted the question: what are the specific cortical effects of smoking?' Recent evidence indicates that the latency of the P300 or late positive component (LP'C) of the ERP reflects the time taken for stimulus evaluation andl does not necessarily correlate with response output latency whi ch includes stimulus evaluation and!response mobilisation components ( Donchin, 1981; McCarthy & Donchin, 1981'; Pritchard, 19'81). Edwards et al tested the hypothesis that these improvements in performance following cigarette smoking are a funetian of more efficient stimulus evaluation6 The study is unique in that it. incorporates both behavioural and~, physiological inaicesof''theeffectsof tobacco smoking on cortical information processing within.a single design. Us,iing the same task as Wiesnes and' Warburton (1978), subjects monitored a series of digits presented singly upon a TV'*screen, at a rate of 100 per minute: Their task was to detect series of three consecutive odd or even digits. Eighteen male smokers (smoking more than 15 cigarettes daily) completed three sessions having the format: "Baseline"' 10 minutes on the task; "Treatment" phase of 10 minutes smoking one cigarette (0.9mg or 1.5mgg standard machine delivery of nicotine) or not smoking; "Post-treatment" phase of 20 minutes on the task. Before each session subjects abstained from smoking for at least 12 hours. Alveolar carbon monoxide was measured before and after treatment in, order to estimate the degree of' inhalation and butts collected'for analysis in order to assess puffing strength. . The effects of smoking on performance replicated previous findings by Warburtoni and Wesnes. Probability of correctly detectingi a signal increased and RT decreased, compared' with baseline, in the first 10 minutes after smokingl The improvement in RT was maintained over the final ten minutes but correct detections declined. In, the nonrsmoking condition both rreasuress of pcrformaroce showed a consi:.tent decline over both time periods. 30

of augmentir,g-rcdixcing (Pctrie, 1967). On a kinesthetic figural after- effects (KFA) task aug,menters typically judged the magnitude of the standard stimulus as larger whereas rediucers judged the standard as much smaller after kinesthetic stimulation. Petrie has reported that reducers were more likely to be smokers and less likely to cease, once started', than augmenters. Knott and.Venables found that deprivedi smokers showed greater peak IV and' peak V' (P100-N1410) amplitude than non-smokers or non-deprivedi smok'ers, who had similar values. While this effect was significant for the two ' Ir lowest intensities the amplitude-intensity effects characteristic of cortical augmenting-reducing (Buchsba.umy 19716) did not reach significance, 2: latency of peak IV was shorter for deprived' smokers compared to non- sinokers and non-deprived smokers: again significant for the two lowest intensities. These results are consistent withi the "normalising" hypothesis and Knott and Venables suggest that deprived' smokers are characterised by CNS hyper-sensitivity and'experience stimulus input more readily and!more strongly. Smoking reverses this trend. This approach certainly warrants extension and' may provide some insight into individual differences within smoker populations in the need for the kind of brain changps induced by nicotine. The major problem with interpretation of'the results described above derives from the fact that, although the authors continually refer to corroborating behavioural evidence, they did not gather relevant datai from ~ ~ ' their samplesand as ai conseqpence, the changes observed in particular NViA electrocortical mcasures can be organised post hoc to fit any favoured ~' explanation. ~ N It would therefore be presumptious to make more than a tentative IM 28

Performance after smoking was superior to that following non-Wmoking, Analysis of ERPs at the vertex to corect detections of a target following smoking comparedi to non,smoking revealed a significant overall reduction in P300latencyi~.n, boththefirst andl second time periods. P30& was def ined as the most positive peak of the ERP having a latency betweem 25'& and' 500mSec post stimulus. No other components showed systematic changes. This preliminary result provides an important clue about the neural effects of cigarette smoking; smoking, has speeded up the stimulus, evaluation processes in these individuals. This is an important finding because it implies that the effects of smoking are not confined to the improved regulation of sensory input and provides neural support for the common, self-report by smokers that smoking helps them concentrate. In this, study we have demonstrated both increases in performance on a: demanding task and, concurrent electrocortical changes which ref-lect cortical information processing. We are carrying,out a more fine-grained analysis of' the relationship between ERP components and'.performance across trials: in particular, the interaction between the estimated dose of nicotine obtainedl by individual smokers, the time course of' the improvement in performance and late ERP components. 7CNV STUDIES The QNV is another endbgenous component of the ERP, first described by Walter, Cooper, Aldridge, McCailum and~ Winter (1964). It appears as a slow negative shift of potential duringi the period' between a warning signal and an imperative stimulus requiring a motor response or a mental decisioft. Unf ortunately, the precise psychological si.gnificance of the CNV is unclear N. ~. IV N ~ ~. 31

since wignificant relations have been claimed between Ct4!V amplitude and arousal, selective attention, conation, motivation, expectancy to name but a few. This has imposed a heavy expl,anatory burden on this single index pf cortical activity eveni though it can be argued that these constructs have overlapping terms of'reference... Ashton and her co-workers (Ashton, Milirnan, Telford & Thompson~ 1973,. 1974; Ashton, Marsh, I4illman, Rawlins, Telford & Thompson, 1978; take the view, - which is a matter of some debate (Donchin, et al, 1978; OFConnor, 1980) - that "the origin of the CNV is in, the arousal systems of' the brain, It including the ascending reticular activating system....and probably the. lilmbic system." (p. 54). Therefore, they assumed that there would'be a positive relationship between CG]U magnitude, activity in these systems and level of activation of' the individual. They also proposed that centrally active drugs should have effects on the CNV directly related to their knownn effects on animal neurones. They believe that cigarette smokinq and nicotine ingestion can have both~ stimulant and depressant effects on the cortex, based on the assumption that smoking doses of nicotine can have a biphasic effect on neuronal activity (but see the discussion in Section 3.1). Ashton et al (1974) found' that, after smoking, CN7 amplitude increased'. in 7 subjects, decreased in 11 and~ showed a biphasic response in 4. "Smoking" an unlit cigarette by 3 other subjects resulted in no CNV amplitude changes. Repetition of the smoking sessions for 11 of - the subjects on a different occasion proouced the same directional changes in the CNV in these individuals. They also found~ a significant negative correlation, (-0:61) between reaction time and CN!V magnitudes. The lack of correlated changes in heart rate, blood pressure, fingertip temP`rature arid blood carboxyhacnroglobin level eliminated 3'2'

artifactual i'nfluenccs and' stxongly indicates that cortical changes are indiuce.d by smoking which are reflected in the CNV (hshton et al, 1974). Ashton et al estimated', the amount of nicotine taken into the mouth of each subject from an analysis of the cigarette butts. By dividing their group at the extraversion mean they found surprisiingly that the eight more extraverted subjects took a smaller dose of nicot.ii_'-'A pe minute and showed a mean, increase in Q,1V magnitude after smoking, while the eight more introverted showed the reverse. Bxperiential reports did not provide clear data perhaps: duQ to the subjects' difficulty with labealling feelings other than relaxation. In Part 2 of their study, however, there is some evidence from, 7' suibjects that self-report of a relaxing effect of smoking was associated with a fall in CNV whereas feelings of' stimulation were associated with a rise in QNV. We should be, more confident of these data if the subjects had been pre-selected. Ashton, Marsh, M'i1lman,, Rawlins, Telford and Thompson (1978) evaluated the contribution of nicotine by intravenous delivery of a nicotine dose which was similar to that obtained by a smoker who had inhaled a cigarette delivering;1-2mg: of nicotine. Nicotine produced the same direction of change as smoking in individuals who took part in both sessions while saline injiections produced no significant changes. In order to study the dose-response relationship they injected subjects with doses of nicotine ranging from 12.51 to 800ug.they found'. a biphasic pattern in the CNV' magnitude. With lower doses (12.5-50ug) the CNV increased as dose increased, but with further increases (100-II00iug) there ~ N was a progressive reduction in (I+AT magnitude. This pattern.was evident for o;A all subjects although the precise d'ose-response relationship varied over ~ the seven subj'ects. Bowever, smoking and injection of nicotine cannot be ~ z0 33,

equated fully because the time course of the drug's activity is differentt in the two cases (see above; Ashton & Stepney, 1982). hls o, a smoker can change the amount of nicotine delivered with each, puff whereas an inj'ection gives a specific dose. Nevertheless, these results have important implilcations. First, cigarette smoking and~ nicotine appear to produce similar changes in the. CNN. Second,- nicotine has a biphasic effect on the CNV which is dose related. Third, introverts andl extraverts appear to modify their smoking behaviour in order to achieve a particular dose. Unfortunately, the picture is compiicated' by a report of Binnie and Cbmer (Binnie and' Comer, 1978; Comer, Binnie, Burnett, Darby & Thornton, 1975), which claimed that half' their subjects showed a QNV increase and half , a decrease. Further analyses showed ".... a tendency for subjects showing a signif icant CNV change - to have smoked more intensely than those showing no significant change and that a CNV increase was associated with greater smoking intensity than a CNU decrease." (Binnie & Comer, 1978; p72). While they carefully selected their subjects and measured a comprehensive range of smoking behaviour and personality variables they did' not present the data and' we are restricted to accepting these conclusions at face value.. Thus we do not know whether the discrepancy between Binnie and Comer and Ashton et al concerning the relationship between Ct'aV change and smoking: intensity is real but the differences in the results do serve to reinforce both the complex nature of the interaction between smoking and electrophysiological activity not to mcmtion the uncertainty surrounding CNV' measurements. However, these QqV studies are woriln extension, provided recent developments in the undlexstandling of' the complex nature of el'ectrocor:tical mcasures are taken into account. 3'4

8 oolaCLUsTONs The fundamental assumption guiding this review has been that smokers smoke to obtain nicotine and that they can accurately manipulate the dose of nicotine they require from a cigarette in a particular situation. Our argument is that systematic study of changes in the electrical activity of the brain holds the greatest promise for evaluating this hypothesis and, thereby, elucidating the neuropsychological effects of smoking doses of nicotine. Animal studies have provided valuable information about the neural action of nicotine but many of these-experiments have little relevance to human smoking because the doses that are used are outside the smoking range. The major findings fromr animal studies using smoking doses is that nicotine acts on nicotinic, cholinergic receptors in the mesencephalic reticular for ationi and activates the ascending cholinergic pathway to the cortex. This pathway releases acetylchoiine and'.controls electrocorticali activity (Warburton, 1981). This pathway occurs in man and, so it is not surprising that human electrophysiological studies of smoking have observed more fast activity and changes in the sensory ERP's at the cortex. Of particular interest is the reduction in the latency of the P3M which indicates more, efficient neural processing of information. The latter fihding assumes greater significance because concomitant behuvioural testing also revealed' more efficient information processing, inc)'uding reduced response latency. Altogether these data fit the hypothesis that smoking's beneficial effects on, performance (see Wesnes & Warburton, in, press) are the outcome of nicotine's action on the cholinergic pathway controlling electrocortical activity. Unfortunately, most of the previous hur:tan studies have lacked 35

" information about the dose of nicotine cntering the smoker, let alone reaching the smoker's brain. While it is not yet a straightforward matter to~ estimate this amount accurately (without using invasive techniques) measures such as butt nicotine analysis, alveolar carbon monoxide, salivary nicotine analysis can provide some estimate of the dose obtained. An extensive methodological review of this literature is provided by Eciwards (in press) and while he is critical of the shortcomings of previous research he is also confident that by judicious use of appropriate• experimental designs less equivocal data will emerge. He advocates the use of tasks for which some of the psychological relationships have a moree aevelopedidata base and a strategy for research which emphasises the study of underlying processes in a dynamic interaction between cigarette smoking, electrocortical activity, and! behaviour. We envisage a bright and busy future for this research. Through contiguous measurement of'EEG and ERP changes during the performance of a task it should be possible to niap the change in the state of re+adiness of different parts of' the brain to respond (EE)G' record) and the efficiency of a particular response required of the individual (ERP record) associated with cigarette smoking. Future experiments might shed light on the hypothesis that individuals adjust their smoking behaviour to receive a dose of nicotine which would _ place them at- a particular point on the response curve and find how this point depends on the individual's constitutional and situation specific needs. Thus, the same individual may use a cigarette to provide a, stimulant effect on one occasion and'a, depressant effect on another. I't remains to be demon:.trated what are the important individual differences mediating smoking, behaviour. This hypothesis implies that experimental designs must i~ncorporate behK:vioural and experiential measures of the functional. 36

significance of the electrocortical chang~esinorticr to discover whether this variation in smoking pattern has significant implications for the person. Another exciting prospect would be longitudinal studies following individuals from before they become smokers through the initiation and strengthening of the habit which, will provide important information about the tonic effects of nicotine on the nervous system. These studies will also enable us to decide between the competing hypotheses (i)that chronic exposure to nicotine impairs neural efficiency and only continued smoking maintains normal function. (ii) smokers differ constitutionally from non- smokers and need nicotine to "normasise" their operating level and (iii) smokers and non-smokers do not differ constitutionally but~ smokers use nicotine to enhance their performance. 37

This work was supported by agf-ar~C from Carreras Rothnrans Ltd. t IR

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