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Chloralose induced alteration of visually evoked response from specific and non-specific regions of cat neocortex
198 i
LABORATORY
Electroencephalography and Clinical Neurophysiology, 1975, 39:198--200 Elsevier Scientific Publishing Company, Amsterdam Printed in The Netherlands
NOTE
CHLORALOSE INDUCED ALTERATION OF VISUALLY EVOKED RESPONSE FROM SPECIFIC A N D NON-SPECIFIC REGIONS OF CAT NEOCORTEX JAY D . GLASS AND GERHARD H . FROMM Departments o/Pharmacology and Neurology, University o f Pittsburgh School qf Medicine, Pittsbur.qh. Pa. 15261 ( U.S.A. ) (Accepted for publication: March 6, 1975)
Certain problems in neurophysiology do not lend themselves to investigation with chronically implanted, nonrestrained animals. In the paralyzed, non-anesthetized preparation, the need to eliminate pain involves the administration of large amounts of local anesthetics which may be absorbed and have an effect on the CNS (Bhargava and Srivastava 1966: DeJong et al. 1968: Galindo et al. 1968: Halpern and Black 1968; Demetrescu and Julien 1974}. An alternative is to use animals anesthetized with alpha-chloralose (Balis and Monroe 1964}, offering the advantage of providing sensory evoked responses similar to those obtained in the non-anesthetized animal (Thompson 1967}, although the responses are comparatively larger (Buser et aL 1959; Pradhan and Galambos 1963: Nakai 1964}. During the course of previous work with the chloralose anesthetized preparation, it became apparent that the visually evoked responses (VERs) were extremely labile, seeming to depend on the level of anesthesia. Moreover, the lability of the VER appeared to be different in the specific and nonspecific regions of neocortex. We have therefore studied the changes in the VER and the EEG in both specific and nonspecific regions of cortex as a function of spontaneously changing levels of chloralose anesthesia.
blood pressure was monitored during the entire experiment and the rectal temperature was kept at 38 _+0.5 ° C by a heating pad. Starting 4 h after the injection of the chloralose, recordings of 15 VERs (0.2 c/sec) and 1 min of EEG were made every hour. The EEG and the VER were amplified with Tektronix FM 122 preamplifiers (low frequency 0.8 c/sec, high frequency 1 kc/sec) and stored on an Ampex FR 1300 tape-recorder. The EEG was played back to a Grass model 7 polygraph and the VER to a TMC CAT 400 C. The VERs from the precruciate and marginal gyri were analyzed from the CAT print-out. The baseline to peak of the positive wave from the precruciate gyrus, and the distance from peak to peak for the initial positive-negative wave of the response from the marginal gyrus were measured in millimeters. The VER amplitude at 4 h post-injection was taken as the control, and the amplitude at each successive hour was then expressed as a percentage of the control (Fig. 1, B and C). Positive and negative spikes exceeding 100 pV were counted for a 40 sec segment of EEG for each recording period and the number of spikes expressed as a percentage of the control period {Fig. 2). RESULTS
METHODS The experiments were performed on adult cats weighing 2.2-3.5 kg, and having a rectal temperature of 38.3-38.8°C. The cat's trachea, femoral vein and femoral artery were cannulated under ether anesthesia. The level of anesthesia was then decreased until the cat showed a vigorous corneal reflex, and 65 or 75 mg/kg of alpha-chloralose was injected i.v. The chloralose (Merck, Darmstadt) was freshly recrystallized (Denavit 1963} and dissolved in propylene glycol to produce a solution containing 50 mg/ml. The EEG and VER were recorded monopolarly from the lateral precruciate gyrus and the marginal gyrus (anterior part of area 17) with silver ball electrodes. The reference electrode was connected to the stereotaxic frame. Light flashes were produced by a Grass photic stimulator (intensity setting 1) with the lamp placed 55 cm in front of the cat. The cat's
The changes in the VER and EEG from the precruciate and marginal gyri 4-7 h after the injection of 65 mg/kg of chloralose are shown in Fig. 1, A. The amplitude of the positive component of the VER from the precruciate gyrus increased in five of six experiments (Fig. 1, B). On the other hand, the VER from the marginal gyrus usually showed little variatio,o in amplitude (Fig. 1, C). Similar results were obtained in the experiments in which 75 mg/kg of chloralose was administered. Not only did the VER from the precruciate gyrus vary more than the VER from the marginal gyrus, but a comparison of Fig. 1, B with Fig. 1, C shows that the VERs from these two gyri appear to vary independently. The Spearman rank correlation coefficient (Siegel 1956) for the VERs from all the experiments was r s = O. 14, P > 0.2, confirming the lack of a significant correlation.
NON-SPECIFIC AND SPECIFIC VER IN CHLORALOSE CAT
199
A
The number of spikes greater than 100/iV in the EEG from the precruciate gyrus also increased significantly with increasing time after the administration of chloralose (Fig. 2J. The EEG from the marginal gyrus was not sufficiently ~ctive for this measure to be applied. Although the number of spikes from the precruciate gyrus increased progressively during the experiment, just as the tunplitude of the VER from this gyrus increased, the two did not appear to change synchronously. The Spearman rank correlation coefficient in this case was r, = 0.31, P < 0.1, thus
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Fig. 2. A : The changes in number of spikes greater than 100 /~V in the EEG from the precruciate gyrus at various time intervals following the injection of 65 mg/kg of chloralose, expressed as a percentage of the control value obtained at 4 h after the injection. B: Results obtained in four cats which received 75 mg/kg of chloralose, plotted as in A. showing that there was only a borderline correlation between these two variables. DISCUSSION
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Fig. 1. A : The VER and EEG from the precruciate (P) and marginal (M) gyri at 4, 5, 6 and 7 h after the injection of 65 mg/kg of chloralose. Each VER represents the CAT summation of 15 consecutive responses. Calibration: EEG, 0.5 mV, 10 sec: VER. 0.2 mV, 100 msec. B: The changes in six cats of the amplitude of the VER from the precruciate gyrus following the injection of 65 mg/kg of chloralose, expressed as a percentage of the control value obtained at 4 h after the injection. C: The changes in VER amplitude from marginal gyrus for same cats as in B, plotted as in B.
Our results demonstrate that the amplitude of the VER and the number of spikes in the EEG from the precruciate gyrus increase considerably during the fourth to seventh hour after the administration of an anesthetic dose of chloralose. There was only a borderline. 0.5 < P < 0.I0. correlation between the changes in the VER and in the EEG. The VER and the EEG from the marginal gyrus were much less variable than from the precruciate gyms. Winters and Spooner (1966) concluded that as the animal went from the waking state into chloralose anesthesia and back to the waking state, the variations in the EEG and the auditory evoked response occurred synchronously. Our findings are basically in agreement with this conclusion, but point out that changes in EEG activity and VER amplitude are not correlated as strongly when they are examined more minutely and at closer time intervals. The lack of correlation between the change in amplitude
200 of the VER from the specific visual receiving area {marginal gyrus) and the VER from a non-specific visual receiving area (precruciate gyrus) suggests a functional separation between specific and non-specific sensory pathways, with the latter showing a much greater sensitivity to level of anesthesia. The spontaneous lability of the VER and the EEG in the chloralose anesthetized preparation indicates that one cannot assume these measures to remain stable during the course of an experiment. The low correlation between the changes in the VER and in the EEG indicates that the EEG must be employed very cautiously in determining whether there has been a change in the level of anestbesia during the experiment. An A B A type of experimental design {Glass 1973) or the establishment of a steady control response (Fromm and Kohli 1972) over an adequate period of time are required to ensure that any changes in the response are actually due to the experimental manipulations. SUMMARY Visually evoked response (VER) and EEG from the motor cortex (precruciate gyrus) and the visual cortex {marginal gyrus) & c a t s were recorded from 4 to 7 h after the injection of anesthetic doses of alpha-chloralose. During the recording period the VER from the precruciate gyrus showed a 200 300'!,. increase in amplitude while the VER from the marginal gyrus rarely varied more than 50"0 in amplitude. and did so independent of the changes in the VER from the precruciate gyrus. The number of large amplitude spikes in the EEG from the precruciate gyrus also increased dramatically during the recording period, but no definite correlation between changes in VER amplitude and in the number of spikes in the EEG could be demonstrated. These observations suggest a functional separation between specific and nonspecific sensory pathways, with the latter showing a considerably greater sensitivity to level of anesthesia. RESUME ALTERATION INDUITE PAR LE CHLORALOSE SUR LA REPONSE EVOQUEE VISUELLE AU N1VEAU DE REGIONS SPECIFIQUES ET NON SPECIFIQUES DU NEO-CORTEX DU CHAT La rOponse evoqu6e visuelle (VER) et I'EEG du cortex moteur (gyrus precruci+) et du cortex visuel (gyrus marginal) ont 6t6 enregistr6s chez le chat pendant 4 fi 7 h apr6s injection de doses anesth6siques d'alpha-chloralose. Au cours de la p6riode d'enregistrement, la VER au niveau du gyrus pr6cruci6 montre une augmentation d'amplitude de 200-300°~, tandis que la VER au niveau du gyrus marginal varie rarement en amplitude de plus de 50'~o et varie independamment des modifications du VER enregistr6 au niveau du gyrus precruci6, Le hombre de pointes de grande amplitude enregistries 'a I'EEG au niveau du gyrus prbcruci6 augmente 6galement de fa~on extr~mement marqu6e au cours de la periode d'enregistrement, mais aucune corr+lation d6finie
J . D . GLASS AND G. H. FROMM entre les modifications d'amplitude de ce VER et les modifications de nombre de pointes fi I'EEG n'a pu ~tre mis en 6vidence. Ces observations sugg&ent une s~paration fonctionnelle entre les voles sensorielles sp6cifiques el non-sp6cifiques, ces derni6res montrant une beaucoup plus grande sensibilit6 au niveau d'anestbesie. REFERENCES BALLS, G. U. and MONROE, R. R. The pharmacology of chloralose, Psl'chopharmacolo¢ty. 1964, 6:1 30. BHARGAVA. K. P. and SRIVASTAVA,R. K. Effects of d-tubocurarine and decamethonium on the central integration of somatic reflexes. Brit. J. Pharmacol.. 1966, 28:328 339. BUSER, P., BORENSTE1N,P. et BRI:NER, J. Etude des syst6mes "associatifs" visuels et auditifs chez le chat anesthdsi6 au chloralose, Electroenceph. olin. Xeurophw'iol.. 1959, 11: 305-323. DEJONG, R. H.~ ROBLES,R. and MORIKAWA,K. I. Actions of immobilizing drugs on synaptic transmission. Exp. Neurol., 1968, 21:213 218. DE~aE'rRESCt;, M. and JULIEN, R. M. Local anesthesia and experimental epilepsy. Epilepsia (Arnst.), 1974, 15: 235-248, DENAV1T, M. Action diff&entielle du quelques anesth~siques sur les rdponses de structures aliment~es par les voies sp6cifiques ou associatives. Anesth. Anal 9. ROanim,, 1963, 20:747 809. FROMM, G. H. and KOHLI, C. M. The role of inhibitory pathways in petit-mal epilepsy. Neurolo.q.v (Minneap.), 1972, 22: [012- 1020. GALINDO, A., KRNJEVIC, K. and SCHWARrZ, S. Patterns of firing in cuneate neurones and some effects of Flaxedil. Exp. Brain Res., 1968, 5: 87-101. GLASS. J. D. Photically evoked potentials from cat neocortex before and after recovery from visual deprivation. Exp. Neurol., 1973, 39: 123-139. HALPERN, L. M. and BLACK, R. G. Gallamine triethiodide facilitation of local cortical excitability compared with other neuromuscular blocking agents, a, Pharmacol. exp. Ther., 1968, 162: 166-173. NAKAI, Y. Effects of intravenous infusion of central depressants on the evoked potentials of the auditory cortex in the cats Jap. J. Pharmacol., 1964, 14:235 255. PRADHAN, S. N. and GALAMBOS, R. Some effects of anesthetics on the evoked responses in the auditory cortex of cats. J. Pharmacol. exp. Ther.. 1963, 130:97 106. S~EC31~L S. Nonpararnetric statistic,~. McGraw-Hill. New York, 1956:202 213. TIt~)XlSOy. R. F. Foumh~tion.~ ~)/ phvsioh)ftica] p~w'holo~ly. Harper and Row, New York, 1967: 477. WINTERS, W. D. and SPoo~rER, C. E. A neurophysiological comparison of alpha-chloralose with gamma-hydroxybutyrate in cats. Electroenceph. olin. Neurophysiol., 1966, 20:83 90.
LABORATORY
Electroencephalography and Clinical Neurophysiology, 1975, 39:198--200 Elsevier Scientific Publishing Company, Amsterdam Printed in The Netherlands
NOTE
CHLORALOSE INDUCED ALTERATION OF VISUALLY EVOKED RESPONSE FROM SPECIFIC A N D NON-SPECIFIC REGIONS OF CAT NEOCORTEX JAY D . GLASS AND GERHARD H . FROMM Departments o/Pharmacology and Neurology, University o f Pittsburgh School qf Medicine, Pittsbur.qh. Pa. 15261 ( U.S.A. ) (Accepted for publication: March 6, 1975)
Certain problems in neurophysiology do not lend themselves to investigation with chronically implanted, nonrestrained animals. In the paralyzed, non-anesthetized preparation, the need to eliminate pain involves the administration of large amounts of local anesthetics which may be absorbed and have an effect on the CNS (Bhargava and Srivastava 1966: DeJong et al. 1968: Galindo et al. 1968: Halpern and Black 1968; Demetrescu and Julien 1974}. An alternative is to use animals anesthetized with alpha-chloralose (Balis and Monroe 1964}, offering the advantage of providing sensory evoked responses similar to those obtained in the non-anesthetized animal (Thompson 1967}, although the responses are comparatively larger (Buser et aL 1959; Pradhan and Galambos 1963: Nakai 1964}. During the course of previous work with the chloralose anesthetized preparation, it became apparent that the visually evoked responses (VERs) were extremely labile, seeming to depend on the level of anesthesia. Moreover, the lability of the VER appeared to be different in the specific and nonspecific regions of neocortex. We have therefore studied the changes in the VER and the EEG in both specific and nonspecific regions of cortex as a function of spontaneously changing levels of chloralose anesthesia.
blood pressure was monitored during the entire experiment and the rectal temperature was kept at 38 _+0.5 ° C by a heating pad. Starting 4 h after the injection of the chloralose, recordings of 15 VERs (0.2 c/sec) and 1 min of EEG were made every hour. The EEG and the VER were amplified with Tektronix FM 122 preamplifiers (low frequency 0.8 c/sec, high frequency 1 kc/sec) and stored on an Ampex FR 1300 tape-recorder. The EEG was played back to a Grass model 7 polygraph and the VER to a TMC CAT 400 C. The VERs from the precruciate and marginal gyri were analyzed from the CAT print-out. The baseline to peak of the positive wave from the precruciate gyrus, and the distance from peak to peak for the initial positive-negative wave of the response from the marginal gyrus were measured in millimeters. The VER amplitude at 4 h post-injection was taken as the control, and the amplitude at each successive hour was then expressed as a percentage of the control (Fig. 1, B and C). Positive and negative spikes exceeding 100 pV were counted for a 40 sec segment of EEG for each recording period and the number of spikes expressed as a percentage of the control period {Fig. 2). RESULTS
METHODS The experiments were performed on adult cats weighing 2.2-3.5 kg, and having a rectal temperature of 38.3-38.8°C. The cat's trachea, femoral vein and femoral artery were cannulated under ether anesthesia. The level of anesthesia was then decreased until the cat showed a vigorous corneal reflex, and 65 or 75 mg/kg of alpha-chloralose was injected i.v. The chloralose (Merck, Darmstadt) was freshly recrystallized (Denavit 1963} and dissolved in propylene glycol to produce a solution containing 50 mg/ml. The EEG and VER were recorded monopolarly from the lateral precruciate gyrus and the marginal gyrus (anterior part of area 17) with silver ball electrodes. The reference electrode was connected to the stereotaxic frame. Light flashes were produced by a Grass photic stimulator (intensity setting 1) with the lamp placed 55 cm in front of the cat. The cat's
The changes in the VER and EEG from the precruciate and marginal gyri 4-7 h after the injection of 65 mg/kg of chloralose are shown in Fig. 1, A. The amplitude of the positive component of the VER from the precruciate gyrus increased in five of six experiments (Fig. 1, B). On the other hand, the VER from the marginal gyrus usually showed little variatio,o in amplitude (Fig. 1, C). Similar results were obtained in the experiments in which 75 mg/kg of chloralose was administered. Not only did the VER from the precruciate gyrus vary more than the VER from the marginal gyrus, but a comparison of Fig. 1, B with Fig. 1, C shows that the VERs from these two gyri appear to vary independently. The Spearman rank correlation coefficient (Siegel 1956) for the VERs from all the experiments was r s = O. 14, P > 0.2, confirming the lack of a significant correlation.
NON-SPECIFIC AND SPECIFIC VER IN CHLORALOSE CAT
199
A
The number of spikes greater than 100/iV in the EEG from the precruciate gyrus also increased significantly with increasing time after the administration of chloralose (Fig. 2J. The EEG from the marginal gyrus was not sufficiently ~ctive for this measure to be applied. Although the number of spikes from the precruciate gyrus increased progressively during the experiment, just as the tunplitude of the VER from this gyrus increased, the two did not appear to change synchronously. The Spearman rank correlation coefficient in this case was r, = 0.31, P < 0.1, thus
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INJECTION
Fig. 2. A : The changes in number of spikes greater than 100 /~V in the EEG from the precruciate gyrus at various time intervals following the injection of 65 mg/kg of chloralose, expressed as a percentage of the control value obtained at 4 h after the injection. B: Results obtained in four cats which received 75 mg/kg of chloralose, plotted as in A. showing that there was only a borderline correlation between these two variables. DISCUSSION
IZ
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POST
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INJECTION
Fig. 1. A : The VER and EEG from the precruciate (P) and marginal (M) gyri at 4, 5, 6 and 7 h after the injection of 65 mg/kg of chloralose. Each VER represents the CAT summation of 15 consecutive responses. Calibration: EEG, 0.5 mV, 10 sec: VER. 0.2 mV, 100 msec. B: The changes in six cats of the amplitude of the VER from the precruciate gyrus following the injection of 65 mg/kg of chloralose, expressed as a percentage of the control value obtained at 4 h after the injection. C: The changes in VER amplitude from marginal gyrus for same cats as in B, plotted as in B.
Our results demonstrate that the amplitude of the VER and the number of spikes in the EEG from the precruciate gyrus increase considerably during the fourth to seventh hour after the administration of an anesthetic dose of chloralose. There was only a borderline. 0.5 < P < 0.I0. correlation between the changes in the VER and in the EEG. The VER and the EEG from the marginal gyrus were much less variable than from the precruciate gyms. Winters and Spooner (1966) concluded that as the animal went from the waking state into chloralose anesthesia and back to the waking state, the variations in the EEG and the auditory evoked response occurred synchronously. Our findings are basically in agreement with this conclusion, but point out that changes in EEG activity and VER amplitude are not correlated as strongly when they are examined more minutely and at closer time intervals. The lack of correlation between the change in amplitude
200 of the VER from the specific visual receiving area {marginal gyrus) and the VER from a non-specific visual receiving area (precruciate gyrus) suggests a functional separation between specific and non-specific sensory pathways, with the latter showing a much greater sensitivity to level of anesthesia. The spontaneous lability of the VER and the EEG in the chloralose anesthetized preparation indicates that one cannot assume these measures to remain stable during the course of an experiment. The low correlation between the changes in the VER and in the EEG indicates that the EEG must be employed very cautiously in determining whether there has been a change in the level of anestbesia during the experiment. An A B A type of experimental design {Glass 1973) or the establishment of a steady control response (Fromm and Kohli 1972) over an adequate period of time are required to ensure that any changes in the response are actually due to the experimental manipulations. SUMMARY Visually evoked response (VER) and EEG from the motor cortex (precruciate gyrus) and the visual cortex {marginal gyrus) & c a t s were recorded from 4 to 7 h after the injection of anesthetic doses of alpha-chloralose. During the recording period the VER from the precruciate gyrus showed a 200 300'!,. increase in amplitude while the VER from the marginal gyrus rarely varied more than 50"0 in amplitude. and did so independent of the changes in the VER from the precruciate gyrus. The number of large amplitude spikes in the EEG from the precruciate gyrus also increased dramatically during the recording period, but no definite correlation between changes in VER amplitude and in the number of spikes in the EEG could be demonstrated. These observations suggest a functional separation between specific and nonspecific sensory pathways, with the latter showing a considerably greater sensitivity to level of anesthesia. RESUME ALTERATION INDUITE PAR LE CHLORALOSE SUR LA REPONSE EVOQUEE VISUELLE AU N1VEAU DE REGIONS SPECIFIQUES ET NON SPECIFIQUES DU NEO-CORTEX DU CHAT La rOponse evoqu6e visuelle (VER) et I'EEG du cortex moteur (gyrus precruci+) et du cortex visuel (gyrus marginal) ont 6t6 enregistr6s chez le chat pendant 4 fi 7 h apr6s injection de doses anesth6siques d'alpha-chloralose. Au cours de la p6riode d'enregistrement, la VER au niveau du gyrus pr6cruci6 montre une augmentation d'amplitude de 200-300°~, tandis que la VER au niveau du gyrus marginal varie rarement en amplitude de plus de 50'~o et varie independamment des modifications du VER enregistr6 au niveau du gyrus precruci6, Le hombre de pointes de grande amplitude enregistries 'a I'EEG au niveau du gyrus prbcruci6 augmente 6galement de fa~on extr~mement marqu6e au cours de la periode d'enregistrement, mais aucune corr+lation d6finie
J . D . GLASS AND G. H. FROMM entre les modifications d'amplitude de ce VER et les modifications de nombre de pointes fi I'EEG n'a pu ~tre mis en 6vidence. Ces observations sugg&ent une s~paration fonctionnelle entre les voles sensorielles sp6cifiques el non-sp6cifiques, ces derni6res montrant une beaucoup plus grande sensibilit6 au niveau d'anestbesie. REFERENCES BALLS, G. U. and MONROE, R. R. The pharmacology of chloralose, Psl'chopharmacolo¢ty. 1964, 6:1 30. BHARGAVA. K. P. and SRIVASTAVA,R. K. Effects of d-tubocurarine and decamethonium on the central integration of somatic reflexes. Brit. J. Pharmacol.. 1966, 28:328 339. BUSER, P., BORENSTE1N,P. et BRI:NER, J. Etude des syst6mes "associatifs" visuels et auditifs chez le chat anesthdsi6 au chloralose, Electroenceph. olin. Xeurophw'iol.. 1959, 11: 305-323. DEJONG, R. H.~ ROBLES,R. and MORIKAWA,K. I. Actions of immobilizing drugs on synaptic transmission. Exp. Neurol., 1968, 21:213 218. DE~aE'rRESCt;, M. and JULIEN, R. M. Local anesthesia and experimental epilepsy. Epilepsia (Arnst.), 1974, 15: 235-248, DENAV1T, M. Action diff&entielle du quelques anesth~siques sur les rdponses de structures aliment~es par les voies sp6cifiques ou associatives. Anesth. Anal 9. ROanim,, 1963, 20:747 809. FROMM, G. H. and KOHLI, C. M. The role of inhibitory pathways in petit-mal epilepsy. Neurolo.q.v (Minneap.), 1972, 22: [012- 1020. GALINDO, A., KRNJEVIC, K. and SCHWARrZ, S. Patterns of firing in cuneate neurones and some effects of Flaxedil. Exp. Brain Res., 1968, 5: 87-101. GLASS. J. D. Photically evoked potentials from cat neocortex before and after recovery from visual deprivation. Exp. Neurol., 1973, 39: 123-139. HALPERN, L. M. and BLACK, R. G. Gallamine triethiodide facilitation of local cortical excitability compared with other neuromuscular blocking agents, a, Pharmacol. exp. Ther., 1968, 162: 166-173. NAKAI, Y. Effects of intravenous infusion of central depressants on the evoked potentials of the auditory cortex in the cats Jap. J. Pharmacol., 1964, 14:235 255. PRADHAN, S. N. and GALAMBOS, R. Some effects of anesthetics on the evoked responses in the auditory cortex of cats. J. Pharmacol. exp. Ther.. 1963, 130:97 106. S~EC31~L S. Nonpararnetric statistic,~. McGraw-Hill. New York, 1956:202 213. TIt~)XlSOy. R. F. Foumh~tion.~ ~)/ phvsioh)ftica] p~w'holo~ly. Harper and Row, New York, 1967: 477. WINTERS, W. D. and SPoo~rER, C. E. A neurophysiological comparison of alpha-chloralose with gamma-hydroxybutyrate in cats. Electroenceph. olin. Neurophysiol., 1966, 20:83 90.