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Physiology &Behavior,Vol. 33, pp. 981-984. Copyright ©Pergamon Press Ltd., 1984. Printed in the U.S.A.

0031-9384/84 $3.00 + .00

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Spike and Wave Complexes Produced by Four Hallucinogenic Compounds in the Cat C A R L O S M. C O N T R E R A S , 1 C A R L O S G U Z M A N - F L O R E S , G R A C I E L A M E X I C A N O , F R A N K R. E R V I N * A N D R O B E R T A P A L M O U R *

Departamento de Fisiologia, Instituto de Investigaciones Biomddicas Universidad Nacional Aut6noma de M~xico, M~xico 04510, D. F. M~xico *Department of Psychiatry, Allan Memorial Institute, McGill University Montreal, Quebec H3A 1A1, Canada R e c e i v e d 6 A p r i l 1983 CONTRERAS, C. M., C. GUZMAN-FLORES, G. MEXICANO, F. R. ERVIN AND R. PALMOUR. Spike and wave complexes produced byfour hallucinogenic compounds in the cat. PHYSIOL BEHAV 33(6) 981-984, 1984.--The ability of four hallucinogenic compounds: ketamine, phencyclidine, quipazine and SKF-10,047 to produce spike and wave activity in the limbic system, was studied in cats with permanently implanted electrodes. Electronic frequency integrators were used to analyze the results and the percent of change in electrographic alterations was calculated. All the compounds studied, produced trains of 6/sec spike and waves complexes in the cingulum, rapid synchronous discharges in the amygdaloid complex, and slow wave synchronous activity and spiking in the septal areas. At low but hallucinatory concentrations of these drugs, the cortical EEG was not affected. Exploratory movements directed toward non-existent objects, classified as hallucinatory-like behavior, appeared simultaneous with these changes in the EEG recordings. It was concluded that there could exist a relationship between the appearance of 6/sec spike and wave complexes in the cingulum and the presence of hallucinations, produced by some synthetic drugs in the cat, this activity could be interpreted as the spreading of alterated function of limbic and non-limbic nuclei related with this bundle which explain unspecificity of action. Phencyclidine Ketamine SKF-10,047 Cingulum Septum Hallucinogens

Quipazine

T O L U E N E inhalation by cats produces seeking and orienting movements with forepaws directed to targets not detected by the observer. Simultaneous with these behavioral changes, a spike and wave activity appears in the cingulum E E G recording [4]. Another industrial solvent, benzene produces, in addition to the former changes, dose-dependent twitching, myoclonus or generalized seizures which apparently originate in the basolateral amygdala nucleus [5]. Phencyclidine administration in the same species provoked behavioral and electrographic patterns similar to toluene intoxication [6]. Toluene and phencyclidine have the common characteristics of being abused on the street [13,15]; both produce distortions in sensorial perception [4,16] although they have different chemical structures. The aim o f this study was to determine whether some other compounds which disrupt sensorial perception also produce spike and wave activity in the limbic system. The first criterion of selection was a partially known mechanism of action, but no similarity of chemical structure was sought. Thus phencyclidine was used as a pattern drug. Its effects

Spike and wave

6/sec spike and wave

were compared to those of the phencyclidine analogue Ketamine, of the synthetic opioid compound SKF-10,047 (N-allylnormetazocine [12]) and of quipazine (2-1piperazynil-quinolein maleate [I 1]). METHOD Eighteen adult cats (2.4 kg mean weight) were stereotaxically [19] implanted with bipolar concentric electrodes in cingulum, basolateral amygdala, lateral septal nucleus and mesencephalic reticular formation. Also, recordings from sigmoid gyrus and marginal gyrus were obtained from stainless steel epidural electrodes. Subcortical electrodes had a surface contact of 100 microns, resistance of 100 K-ohms and intertip distance of 1 mm. After surgery a minimum of three weeks was allowed to elapse before drug administration. At the end of the study, animals were sacrificed and their brains perfused with formaldehyde. Electrode implantation sites were verified with a rapid procedure [9]. Several doses for each drug were tested in a quasi-random manner: On a given day a single drug was tested using in-

1Requests for reprints should be addressed to C. M. Contreras, Departamento de Fisiologia, Instituto de Investigaciones Biomrdicas, UNAM, Apartado Postal 70228, Coyoacfin 04510, Mrxico, D. F. Mexico.

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CONTRERAS E l A/, "FABLE I

PCP

Dosis 1 latency duration

Dosis 2 latency duration

Ketamine

SKF- 10047

Quipazine

450/~g/kg (IM)

6 mg/kg (IM)

1 mg/kg (IM)

10 mg/kg (IV)

10-20 rain 180-240 min

3-5 rain 25-45 rain

15-20rain 45-60 rain

immediately 120-180 rain

750/xg/kg (IM)

15 mg/kg (1M)

3 mg/kg (IM)

15 mg/kg (IVl

3-5 min 45-60 min

15-20 rain 120 rain

immediately 240 min

10-20 min 240 min

Dosis 1: produced searching movements with eyeballs, paws and entire body directed to non-observed objects. For quipazine a rage reaction was consistently found Ill]. Dosis 2: typically spasticity of extremities and absence of responses to nociceptive stimulation appeared.

creasing doses given one or two hours apart. One week later other doses of the same drug were administered. When constant dose-related effects appeared another drug was scheduled on the same animal. Baseline EEG recording was obtained for at least 30 minutes; recording following injection of drug ranged from 45 minutes (Ketamine) to several hours (phencyclidine, SKF- 10,047 and quipazine). An anecdotal behavioral recording was kept by at least two observers and only changes detected by both observers were taken into account. Electrographic recordings were analyzed by visual inspection and by a semiautomated system previously described [5].

Ketamtne - G

v

o

RESULTS At the critical dose (Table 1, dose I), for all four drugs produced synchronous rhythms (9 Hz) in the basolateral amygdala. Trains of spike and wave complexes appeared abundantly in the cingulum and to a lesser extent in the mesencephalic reticular formation and lateral septal nucleus. The lateral septal nucleus displayed a mixed activity of synchronous low voltage activity (4 Hz) and spiking. The spike and wave activity appeared at 3 complexes per second, and the average backgroups frequency ranged from 5 to 8 Hz (most commonly 6 Hz). The mean amplitude of the spike was 41.4 I~V and the wave 123.2 /~V. At these critical lower doses, cortical recordings showed slow-low voltage waves (about 6 Hz), but not spike and wave complexes (Fig. 1). Higher doses for each drug increased the amount of spike and wave. Above a critical dose (Table 1, dose 2), the spike and wave also appeared in the cerebral cortex. The behavioral profile was quite different between dose 1 and dose 2. At the low dose, animals remained ataxic and midriatic. Movements directed toward non-existent targets appear. Animals were apparently attentive with some pupillary changes during the appearance of spike and wave trains, but initiated movements of head, eyes and sometimes entire body and forepaws directed to non-existent objects at the end of and between discharges. With high doses, animals remained unresponsive to nociceptive stimulation, with generalized spasticity and full midriasis. At any one of the doses

Ketamlne-I0

FIG. I. The four studied drugs produced bursts of spike and wave activity in the cingulum at dosis in which non-directed movements appeared, but not spasticity and unresponsiveness. The former appeared with higher dosis. In the sample, two dosis (6 mg/kg and 10 mg/kg) of Ketamine. (Abr. f.cx.--frontal cortex; v.cx.--visual cortex; c.--cingulum; sep.--lateral septal nucleus; amyg.--basolateral amygdala. Cal. 50/zV; 1 sec).

SPIKE AND WAVE AND H A L L U C I N O G E N S

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of drug tested, no animal showed twitching of facial muscles nor myoclonus. No convulsive seizure was observed. Also, recordings and behavior differ from drowsiness and sleep. DISCUSSION The general morphology of spike and wave resembles the epileptic absence. However, there are some differences. In the epileptic absence the amplitude of the spike is 100/xV; the wave is still wider than the observed drug effect [7]. Also, as a general rule and by different procedures [2,17], the accepted equivalence for epileptic absence in cats is characterized by spike and wave activity, and behavior includes twitching of facial muscles, eyeblinks, circling and myoclonus. Eventually, convulsive seizures are also present. None of these behavioral effects appeared in this study. There seem to be more differences than similarities in the two processes. Moreover, there is an antagonistic action of phencyclidine on kindling development in cats [1], and although Ketamine produces spiking in cerebral cortex, it also suppresses focal seizures produced by topical cortical application of penicillin [3]. The cingulum is a complex bundle, receiving fibers from many nuclei of the limbic system, and constituting a bridge between these nuclei and cerebral cortex. It could explain the nonspecific action of several drugs with common behavioral effects, regardless of different chemical structures. The hallucinogens studied produced spike and wave activity in some parts of the limbic system without epileptic manifestations, but with a peculiar behavioral profile of non-directed wakefulness, which changes to non-responsive spasticity if such activity reaches the cerebral cortex. Basolateral amygdala, septal areas and cingulum are interrelated structures. Quipazine effects in the cat disappear

by occluding visual input; visual cortex, superior colliculus lesions or by temporal lobe ablation including amygdaloid nuclei [11,18]. Herein sensorial input and amygdala can be included as a partial mechanism of action at least for quipazine. Moreover, electrical stimulation of temporal cortex or amygdaloid region in epileptic patients produced elaborated reminiscences [10]. Meanwhile cingulum electrical stimulation, also in epileptic patients elicited olfactory hallucinations, and the recording of this structure showed spike and wave activity clearly correlated with sensorial disruption [7]. Hence, spike and wave activity produced by all four studied drugs, and recorded in cingulum may represent spreading of this activity from other limbic and non-limbic but related structures with this bundle, since an integrative point of view representing a complex process involving many nuclei functionally disrupted at the same time. The two inhalants, three known psychoactive agents and the synthetic opioid (related to behaviorally active sigma agonists) all produce characteristic EEG patterns in the limbic system. The waxing and waning of these patterns seem to correlate with behavior which is similar to that in humans who can verbally report hallucinatory experiences. The background behavioral state is of interest in that the organism is awake, capable of performing maintenance activities (grooming, lying comfortably, etc.) but apparently "dissociated."

ACKNOWLEDGEMENTS The authors thank Ram6n Tames for technical assistance, Ms. Mercedes V. de del Pozo for secretarial assistance, and Ms. Ma. Isabel Prrez-Montfort and Ms. Marcela Vogt for translating and editing the manuscript.

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984 16. Meyer, J. S., F. Greinfenstein and M. DeVault. A new drug causing symptoms of sensory deprivation. Neurological, electroencephalographic and pharmacological effects of sernyl..l Nerv Ment Dis 129: 54-61, 1959. 17. Pollen, D. A., P. H. Perot and K. H. Reid. Experimental bilateral wave and spike from thalamic stimulation in relation to level of arousal. Electroencephalo~,,r Clin Neurophysiol 15: 1017-1028, 1963.

C()NI'Rt~,RAS t: l A L.

18. Salas, M., M. Cervantes and C. Guzmtin-Flores. Mechanism of action of quipazine maleate on the central nervous system. Bol Estud Med Biol Mex 24: 191-205, 1966. 19. Snyder, R. S. and W. T. Niemer. A Stereomxic Atl~s ,~l'('at Brain. Chicago, 11~: University of Chicago Press, 196[.

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