(1954). the Effect of Some Drugs on the Electrical

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J.Ment. Sc., London lO0_ 125 (1954).

THE EFFECT OF SOME DRUGS ON THE ELECTRICAL ACTIVITY OF THE BRAIN, AND ON BEHAVIOUR.*

By J. ELKES, M.D., C. ELKES M.B., B.S., A_O P. B. BRADLEY, PHD. Department of Experimental Psychiatry, Medical School, University of Birmingham. and Winson Green Hospital, Birmingham.

PERiPHERAl. neuro-effector sites within and outside the autonomic nervous system form useful reference points for the study of the central effects of some agents. Nevertheless, ready analogies between peripheral neurohumoral mediation, and central synaptie transmission may be grossly misleading, and reliance must solely be placed on data derived from within the central nervous system itself. A number of drugs known to have both peripheral and central actions (atropine, d- and/-hyoscyamine, physostigmine, di-iso-propyl-fluorophosphate, d/-, d- and/-amphetamine and d-lysergic acid diethylamide) were studied in terms of their effects on behaviour, and on the electrical activity of the brain in "the experimental animal. Observations on some effects of d-lysergic acid diethylamide on normal volunteers, and of amytal, amphetamine, mephenesin, and d-lysergic acid diethylamide on catatonic stupor were also made. Conscious, unrestrained cats, carrying multiple, permanently implanted cortical and stereotactically placed subcortical electrodes were used for the animal expeximents. (I) Simultaneous observations on behaviour and electrical activity were made possible by. the use of a constant environment chamber. Acute preparations subjected to high spinal or midbrain sections (the so-called en, dphale and cerveau isold) (2), and preparations anaesthetized with pentobarbitone, furnished complementary information. In the conscious animal, large doses of atropine (2-3 mgm./kgm, i.p.) produced large-amplitude, slow waves, interspersed by bursts of fast activity. These patterns bore some resemblance to those characteristic of sleep. They did, however, differ from the latter in their failure to show a cortical alerting response to sensory stimuli, although the animals could, in fact, be roused. /- hyoscyamine induced effects similar to those seen with atropine; the dose, however, was lower (1-2 mgm./kgm, i.p.), d-Hyoscyamine was ineffective, even in high doses. Physostigmine (0.5-1-o mgm./kgm, i.p.) abolished the slow activity induced by atropine and/-hyoscyamine, the resultant low-amplitude, fast activity resembling the normal alert pattern. Such activity was also produced by physostigmine alone. This activity, however, was not necessarily accompanied by a corresponding change in behaviour. Neostig- mine left the electrical activity of the brain unaffected, even in doses which produced marked peripheral parasympathomimetic effects. * An abstract of a paper read at the Annual Meeting of the Medico-Psychological Association held at Barnwood House, Gloucester,on lOJuly, I953. 126 I)Rt'GS ON THE 1-LECTRICALACTIVITYOF THE BRAIN !.Jan.

d- and/-Amphetamine in full doses (3-5 mgm./kgm, by mouth) produced rhythms resembling those of the normal alert animal, i.e., low-amplitude, diffuse fast (15-3o cycles per second) activity in all regions. This was accompanied by a corresponding change in behaviour, the animal regularly becoming more attentive and excitable. The cortical response to rhythmic photic stimulation recorded over the visual area was increased in amplitude at all frequencies between 2 and 25 cycles per second, d-Lysergic acid diethylamide (15-25 microgm./kgm, by mouth) exerted effects somewhat similar to those of amphetamine on both electrical activity and behaviour. There was, however, no change in the response to photic stimulation. In preparations anaesthetized with pentobarbitone (3° mgm./kgm, i.p.) the characteristic waxing and waning activity (the so-called barbitonc " spindling") was changed by both physostigmine (o"5-1.o mgm./kgm, i.v.) and D.F.P. (administered i.v. in divided doses up to a total of 3 4 mgm./kgm.) ; the spindle bursts were abolished, and replaced by continuous rhythmic activity at 44 cycles per second. Atropine sulphate abolished this continuous activity, and restored spindle bursts. Mid-brain section either reduced or abolished the D.F.l°.-induced rhythmic activity, and restored an intermittent waxing and waning activity. Amphetamine had little effect on the electrical activity of a barbiturate anaesthetized animal as recorded at the cortical level. There was, however, some increase in the response to photic stimulation when recorded at the level of the lateral geniculate body. Large doses of d-lysergic acid diethylamide (5O-lOO microgm./kgm, i.p.) completely abolished the electrical activity characteristic of moderate barbiturate anaesthesia ; the anaesthesia continued apparently unaffected. The characteristic waxing and waning activity seen in the corticogram of the brain sectioned in situ at the level of the first cervical vertebra, or superior colliculus (2) was abolished by physostigmine and restored by atropine. In such experiments, simultaneous recordings of blood pressure and electrico- cortical activity showed the cortical activity to be unrelated to the transient changes in blood pressure produced by these drugs. The intermittent electro- cortical activity of the encdphale isold was abolished by amphetamine (in doses of 1.5-3.o mgm./kgm, i.v.). This activity was, however, restored by section at mid-brain level in the same preparation, and remained unaffected by the administration of further doses of amphetamine, d-lysergic acid diethylamide (in doses of up to ioo microgm./kgm, i.p.) had no effect on the electrical activity of either of these acute preparations. The effects of amphetamine and d-lysergic acid diethylamide on the corticogram thus differ from those of atropine, l-hyoscyamine and physostigmine in their apparent deperrdence upon mesencephalic or spinal connections. Again, there is better correlation between electrical activity and behaviour in the case of amphetamine and d-lysergic acid diethylamide, than there is with atropine, l-hyoscyamine and physostigmine. Magoun (3) has drawn attention to the existence in the upper brain stem of a reticular activating system, concerned with arousal by sensory stimuli. It is possible that amphetamine may act on receptots related to this arousal system. Amphetamine is structurally related , to tyramine, re,r-adrenaline, adrenaline, and not unrelated to mescaline, d-lv- I954i BY J. ELKE%, C. b2LKF%, AXD 1'. B. BRAI)I.EV 12 7 sergic acid diethylamide is related to other adrenaline blocking agents of the ergot group. It is perhaps of interest that nor-adrenaline (4) and 5-hydroxy- tryptamine (5) have been recently identified in some areas of the brain, and that d-lysergic acid diethylamide has been found to antagonize 5-hydroxy-tryp- famine (6). Possible effects of these drugs on the general and local cerebral circulation, and on intermediate metabolism (7) must, however, be very clearly borne in mind. The symptoms of d-lysergic acid diethylamide (L.S.D.-25) intoxication were studied in 12 male and 3 female volunteers. The drug was administered in doses of 15 to IOOmicrogm, by mouth, and particular attention was paid to the effects of rhythmic photic stimulation (at 4 to 24 cycles per second) on the symptoms of intoxication. Subjective sensations, including the peculiar illusions of form, colour and movement experienced under these conditions, were sound recorded for each frequency, both before and after the administration of the drug. The sound-record was transcribed, and the transcript subsequently analysed independently for relevant elements. E.E.G. records were also taken. The symptoms described by Stoll (8) were confirmed. Depersonalization, heightened awareness and fluctuating incongruous affect were the common symptoms. Visual symptoms were seen in 8 subjects, and 7 experienced dis- tortion of body image. Mild dysarthria was seen in i i, and thought-blocking in 6 subjects. Rhythmic photic stimulation enhanced the symptoms in 12 out of 15 subjects; in 3 out of these 12, symptoms were brought out where no symptoms of any kind had been experienced before. An uncommunicative, trance-like state during photic stimulation following L.S.D.-25 was experienced by six subjects ; and in three there was a slight, transient, but quite definite alteration in muscle tone, not unlike that seen in catatonia. This persisted for up to 20 minutes after photic stimulation had ceased. E.E.G. records were taken in 13 subjects. In terms of resting record, 2 of the subjects belonged to the micro-alpha, 5 to the responsive alpha, and 6 to the persistent alpha group (9) Following L.S.D.-25 the micro-alpha subjects showed little change in their resting record. One responsive subject showed micro-alpha activity, and four others became more responsive. Of the 6 persistent alpha subjects, 5 became completely responsive, and one remained persistent. The effects of amytal (12o-24o mgm. i.v.), amphetamine (7-15 mgm. i.v.), mephenesin (75O-l,OOO mgm., administered as a 5 per cent. solution in saline) and d-lysergie acid diethylamide (6O-lOO microgm, by mouth) were compared in 9 cases of catatonic stupor. The mental response was assessed in terms ot verbal productivity and of drawing. The somatic changes recorded included blood pressure, pulse rate, foot temperature (recorded by multiple thermo- couple), muscle tone (as measured in the flexors of the elbow by a simple weight- ing device) and sweat secretion. The well known effect of amytal on accessibility showed itself as an increase of both verbal productivity, and of drawing. There was better correlation between this change, and a rise in foot temperature, than between accessibility and muscle tone. An optimum mental response was only rarely accompanied by full muscular relaxation. Amphetamine de- creased accessibility (IO), a Iinding unlike its more common effects in normal subjects. Mephenesin regularly reduced muscle t.ne without chamzin,,., either 128 DRUGS ON THE ELECTRICAL ACTIVITY OF THE BRAIN [Jan.

accessibility or foot temperature. L.S.D.-25 produced a response peculiar to itself, and unlike that seen either with amytal or amphetamine. This was characterized by unmotivated laughter and crying, bizzare uncontrolled behaviour, and an apparent activation of hallucinatory and delusional material. There was a blunting of the amytal response with repeated administration. Premedication with neostigmine (0"5 to 0"75 mgm. s.c.) or physostigmine (I.0 mgm., s.c.) did not modify the amytal response. The above phenomena suggest the existence of elective affinities within the central nervous system. It is possible that chemical evolution has, at certain stages, accompanied phylogenetic evolution and, in the central nervous system, made use of selected variants of substances familiar to us as powerful neurohumoral transmitters at the periphery. There may be subtle and definite chemical differences between phylogenetically older and newer parts of the brain ; and even if such differences be confined to a few nodal points, a delicate shift in balance at these points could have profound effects on the function of the brain as a whole. Clear cut " levels" of action are perhaps less likely than changes in the temporal relation between the activities of unevenly distributed cell groups.

The above material was communicated to the Physiological Society at its, meetings of January 16th (II, I2), and June 5th (13, I4), 1953. We wish to express our thanks to the Superintendent of Wjnson Green Hospital, Dr. J. J. O'Reilly. for the facilities so generously put at our disposal , at the hospital.

REFERENCES.

(x_,BRADLEY, P. B.. and ELKES, J., BEG Clin. Neurophysiol., 1953, 5, 45 I. (2) BREMER,F., L'activit_ _l_ctrique de l'_corce c_r_brale, 1938, 46 pp. Hermann : Paris. (3) MAGOUN,H. W., Res. Publ. Ass. Nerv. Ment. Dis., 1952, 30, 480. (4) VOGT,M., Communication to the British Pharmacological Society, 5 January, 1952. (5) AMIN, A. H., CRAWFORD,T. B. B., and GADDUM,J. H., Communication to the Britisl_ Pharmacological Society, 7 July, 1952. (6) GADDUM,J. H., J. Physiol., 1953 121, I5P. (7) 1VIAYER-GROSSV,V., MCADAM,W.. and WALKER, J. W., Nature, i951 , 168, 827. (8) STOLL,W. A., Schweiz. Arch. Neurol. Psych., 1947, 60, 279. (9) GOLLA,F., HUTTON,E. L., and WALTER,W. G., J. Ment. Sci., 1943, 89, 2i(_223. (IO) DELAY, J., Proe. 1_. Soc. Med., 1949.42, 491. {11) BRADLEY,P. B.. and ELKES, J., J. Physiol., I953, 120, 13. (lZ) BRADLEY, P. B., and ELKES, J., Ibid., 1953, 120. 14. (t3} BRADLEY, P. B., ELKES, C., and ELKES, J., Ibid., I953, 121, 5o. (I4) BRADI.EY, 17. B., CERQUIGLINI, S., and ELKES, J., Ibid., 1953, 121, 51.