Am I Otolarynsol S:26Z-265, 1s

Effects of Ketamine on the Adaptive Responses of Second- order Vestibular Neurons of the Cat

Jai H. Ryu, Ph.D.,* Richard W. Babin, M.D.,t Chan Liu, M.D.,* and Brian F. McCabe, M.D.*

The adaptive characteristics of 80 neurons in the vestibular nuclei of ketamine-anesthe- tized cats were investigated. All types I and II neurons responded to stimulation of the horizontal semicircular canals by an 8~ 2 stepwise angular acceleration of 40 sec. For the purpose of this study, vestibular adaptation was defined as a decline in response at a rate of greater than -0.01 spikes/sec/sec. According to this criterion, 71 neurons (89 per cent) behaved as adapting neurons, and nine (11 per cent) showed either no adap- tation or reverse adaptation. The rate of adaptation varied from neuron to neuron; the average rate was -0.312 spikes/sec/sec. The average resting discharge rate, the max- imum response level, and the average adaptation rate were compared with similar neural responses in barbiturate-anesthetized cats. Although the average resting discharge rates of the two groups showed no significant difference, the average adaptation rate and the maximum response level of the ketamine-anesthetized group were significantly higher than those of the barbiturate-anesthetized group. These data suggest that the gain of the second-order neurons is higher and more actively modulated in more alert (ketamine- anesthetized) cats than in barbiturate-anesthetized cats.

Two types of response decline, adaptation and habituation, frequently occur in the vestibular system. One of the m a n y differences between adaptation and habi tuat ion is that adaptation is generally considered a peripheral phenomenon, while habituation is generally considered a cen- tral phenomenon. However, previous investiga- tions suggested that adaptation of the vestibular system is probably a combinat ion of peripheral and central phenomena. 2'2 These investigations were pe r fo rmed wi th animals anes thet ized by barbiturates.

This study was concerned wi th the effects of ke tamine on the neu rons in vest ibular nuclei

Received December 21, 1983. Accepted for publication January 17, 1984. Presented at the Annual Meeting of the Association for Research in Oto[aryngology, Anaheim, Cali- fornia, October 22, 1983. Supported by the Medical Research Service of the Veterans Administration Medical Center, Iowa City, Iowa,

* Department of Otolaryngology--Head and Neck Sur- gery, University of Iowa, Iowa City, IA 52242.

Department of Otolaryngology and Maxillofacial Sur- gery, University of Tennessee, Memphis, TN 38163.

* Department of Otolaryngology, Beijing Ton Ren Hospi- tals, Beijing, Peoples Republic of China.

Address correspondence and reprint requests to Dr. Ryu.

and, specifically, on the adaptive responses of these neurons. These experimental results may provide a clearer understanding of the mecha- nism of vestibular adaptation.

METHODS

A total of 24 adult cats, weighing between 2.5 and 3.5 kg, were used in this study. Each animal was anesthetized with an intramuscular injec- tion of ketamine, 25 mg/kg, followed by 5-mg supplemental doses as needed. Responses of 80 canal-sensitive neurons in the vestibular nuclei were recorded extracellularly. The surgical and recording procedures used in this s tudy have been described elsewhere. 2 Responses of canal- sensitive neurons (both types I and II, as classi- fied by Ryu and McCabe 3) were recorded when the effect of ketamine was declining (i.e., the an- imal was anesthetized very lightly). To ensure that the horizontal canals were stimulated max- imally, the head of the cat was tilted forward 25 o so that the horizontal canals were approximately in the horizontal plane. 4

The rate table, controlled by the preprogram-

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RYU ET AL.

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0 0

Figure 1. Paradigm of stimulus (ac- celeration and velocity profiles) ap- ~ plied in this experiment, (CW and CCW ~ indicate clockwise and counterclock- O o~. wise, respectively.)

0 . . . .

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mable function generator, was used to ensure de- livery of accurate and repeatable angular accel- eration. The rate table was brought te a constant velocity of 160~ by clockwise (or counter- clockwise) subliminal acceleration of 0,5~ z. (The threshold for the perception of angular ac- celeration by the semicircular canals was deter- mined by Mulder in 1908; the value of 0,5~ 2 was confirmed by Green and Jongkees in 1948,)

Before neural activity was recorded, a two- minute period was provided so that the cupu- loendolymph system could reach equilibrium. After this period, the resting discharge rate was recorded for one minute; a preprogrammed stim- ulus, consisting of constant angular acceleration and deceleration of 8~ 2, was then applied (Fig. 1).

Data were collected with an instrument corn-

TABLE 1. Differences in Neural Responses of Vestibular Neurons from Two Groups of Animals

KETAlvlINE- PENTOBARBITAL- ANESTHETIZED ANESTHETIZED

GROUP GROUP

Resting discharge (spikes/sec; tonic neurons only)

Sample size 69 88* Mean 22.1 21,3 SD 11.7 12,6

Adaptation rate (spikes/sec/sec)

Sample size 71 40~" Mean -0,312 -0,211 SD 0,295 0,307

Maximum response level (spikes/sec)

Sample size 80 40~r Mean 26,1 19,2 SD 11.4 17,1

* From Babin et al, 1 t From Babin et el. 2

purer and displayed in digital form on linograph paper and in analog form on X-Y oscilloscope and graph paper. The resting discharge rate and neural response to the stimulus were recorded. At the end of each experiment a small electro- lyric lesion was made, The locations of recorded neurons were determined histologically,

RESULTS

The resting discharge rates and the neural re- sponse characteristics of 80 semicircular canal- sensitive neurons in the vestibular nuclei of 24 cats were recorded, All 80 neurons were within the boundaries of the vestibular nuclei by the

h i s t o log i c criteria es tab l i shed by Brodal. 5 Among the 80 neurons, 32 (40 per cent) were type I and 48 (60 per cent) were type II. Sixty- nine neurons (86 per cent) were of the tonic type, and 11 (14 per cent) were of the kinetic type,

Resting Discharge Rate

The resting discharge rates of 69 tonic neurons varied from unit to unit in the same preparation. The discharge rates ranged from 1 to 46 spikes per second (sps); the average was 22,1 sps (SD, 11,7 sps) (Table 1), This result was compared with similar data obtained by studying pento- barbital (Nembutal)-anesthetized cats, A paired t-test at a confidence level of P = 0.001 indicates that there was no difference in resting discharge rates between the ketamine-anesthetized and the barbiturate-anesthetized groups.

Maximum Response Level

The maximum response level was defined as the difference between the maximum discharge rate for the given stimulus and the resting dis-

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ADAPTIVE RESPONSE OF VESTIBULAR NEURONS

40 E 3 0

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Figure 2. The m a x i m u m r e s p o n s e level is de f ined as the d i f ference be- tween the maximum discharge rate due to a given st imulus and the resting dis- charge rate,

L I 1 I _ _ 1 I . I I

I 0 20 3 0 4 0 5 0 6 0

T IME (seconds)

charge rate (Fig. 2). The average maximum re- sponse level was found to be 26.1 sps (SD, 11,4 sps) (Table 1). This result was also significantly higher (paired t-test, P = 0.001) than the average maximum response level in the barbiturate-anes- thetized group.

Adaptation Rate

For the purpose of this study, adaptation was defined as a negative response slope following the maximum response after the beginning of constant acceleration of greater than - 0 . 0 1 spikes/sec/sec, By this criterion, 71 neurons (89 per cent) adapted to constant angular accelera- tion of 8~ 2. The average rate of adaptation

TABLE 2. Possible Generating Sites of Vestibular Adaptation

Cupula Hair-cell level Primary afferent level Efferent system Vestibular nuclei Other central nervous system sites

was -0 ,312 spikes/sec/sec (SD, 0.295 spikes/sec/ sec) (Table 1). These results were compared with previously reported experimental results. 2 The adapta t ion rate of the ke tamine-anes the t i zed group was significantly higher (paired t-test, P = 0.001) than that of the barbi turate-anesthe- tized group (Fig. 3). 2

DISCUSSION

The mechanism of ketamine anesthesia is not understood. It seems that the influence of ke- tamine on neural activity is complex. 6 Corssen and Domino 7 described ketamine as a dissocia- tive anesthetic because sensory input reaching cortical receiving areas is disrupted in the as- sociation area under ketamine anesthesia. Both spontaneous and evoked activity is increased fol lowing low doses of ketamine, whi le de- creases in activity are typical at higher doses. 6 Ketamine also s imul taneous ly excites and de- presses neural activities of different systems, s

The experimental results indicate that low doses of ketamine have no effect on the resting

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Figure 3. The average adaptation rate and the max imum response level in the k e L a m i n e - a n e s t h e t i z e d g roup were c o m p a r e d w i t h s im i l a r n e u r a l re- sponses in the barbiturate-anesthet ized group,

TIME (seconds)

RYU ET AL.

discharge rate of the neurons in vestibular nu- clei. If such a resting rate is, in fact, directly pro- port ional to hair-cell activity, then ketamine does not appear to influence the peripheral end- organ. Ketamine does, however, appear to have significant influence on the gain and modulation of the vestibular neuronal response at the level of the second-order neurons.

The experimental results also suggest that the vestibular adaptation phenomenon is not solely a peripheral event, as stated by Mathews and others. 9 If the response of the neurons of the ves- t ibular nuclei were exclusively a reflection of end-organ responses , similar maximum re- sponse and adaptation rates would be expected in ketamine- and barbiturate-anesthetized ani- mals. The data clearly do not support such a hy- pothesis. The difference between the two groups suggests that pentobarbi ta l inhibits central mechanisms that facilitate both response and adaptation during prolonged rotatory accelera- tion.

References 1, Babin RW, Ryu JH, McCabe BF: Responses to step and

repeated impulse accelerations in second order yes-

tibular neurons of the eat. Am J Otolaryngol 1:385- 392, 1980

2. Babin RW, Ryu JH, McCabe BF: Second order vestibular adaptation and cupular dynamics. Ann Ore] Rhino] Laryngol 89:262-267, 1980

3. Ryu JH, McCabe BF: Neural activity in the vestibular nuclei of the cat. Ann Otol Rhinol Laryngol 82(suppl 9}:1-28, 1973

4. Blank RHI, Curthoys IS, Markham CH: Planar relation- ships of semicircular canals in the cat. Am I Physiol 223:5S-62, 1972

5. Brodal A: Anatomical organization and fiber connec- tions of the vestibular nuclei, in Fields WS, Alford BR (eds): Neurological Aspects of Auditory and Vestib- ular Disorders, Springfield, Ill, Charles C Thomas, 1964, pp 107-149

6. Ducan GH'. Effects of ketamina on response properties of neurons in the primary somatosensory cortex of Ma- cara fasicularis (dissertation]. Chapel Hill, University of North Carolina, 1981

7. Carssen G, Domino EF'. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 45:29-39, 1966

8, Celesia GG, Chen RC', Effects of ketamine on EEG activity in cats and monkeys. Electroencephalogr Clin Neu- rophysiol 37'.345-353, 1974

g. Mathews BH: The response of single end-organ. J Physiol 71:64-110, 1931

10. McCabe BF: Vestibular suppression. Tech Dec Report No. AMRL-TOR, 63-119:1-13, 1963

11. Monnier M, Berlin I, Polc P: Facilitation, inhibition and habituation of the vestibular responses. Adv Otorhi- nolaryngel 17:28-55, 1970

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