Psychopharmacology

Psychopharmacology 64, 349-353 (1979)

9 by Springer-Verlag 1979

Electrophysiological Correlates of the Behavioral Effects of Tubocurarine in Conscious Cats R. B. Ashorobi*'**, D. Guha, and S. N. Pradhan Department of Pharmacology, College of Medicine, Howard University, Washington, D. C. 20001, U.S.A.

Abstract. The effects of tubocurarine on behavior, electrical activity, and auditory evoked potentials were studied in restrained conscious cats. Tubocurarine hydrocbloride (doses of 0.05 - 1 gg intraventricularly) produced various central stimulatory effects characterized by E E G desynchronization, decrease in both low ( 7 - 9 H z ) and high ( 1 0 - 1 4 H z ) alpha waves, and decrease in the amplitude and area of the surfacepositive (Pt) wave of auditory evoked potentials. Concomitant with the alterations in brain electrical activity tubocurarine hydrochloride produced generalized behavioral arousal phenomena and the cats became restless and exhibited miaowing and increased movement of the head and ears. Almost all parameters except behavior showed a distinct dose-response relationship. A correlation between the behavioral effects and the E E G analog was thus demonstrated. Key words: Auditory evoked potential Behavior - Tubocurarine hydrochloride

EEG -

EEG, alpha activity, and sensory evoked potentials are closely related parameters indicative of behavioral and neurophysiological states of the subject. Most of these electrical parameters reported in previous investigations have not been studied simultaneously and their correlations to normal conditions and to pharmacological manipulations have yet to be established. Investigations have been conducted with respect to the effects of tubocurarine on the electrical activities of the central nervous system (Beleslin and Ranka, 1976; Feldberg and Sherwood, 1954; Chang, 1953; Blume, 1934; West, 1937). However, effects oftubocurarine on EEG, alpha activity, and auditory evoked potentials concomitant with behavioral manifestations in conscious semirestrained cats have not been reported. The purpose of the present investigation is to study the effects of low intraventricular doses of tub ocurarine hydrochloride (Tc) simultaneously on EEG, alpha activity, and auditory evoked potentials concomitant with gross behavior such as head movements (HM).

Materials and Methods Sensory stimulation, either electrically or chemically induced, has produced E E G desynchronization, reduced occurrence of alpha waves, and decreased the amplitude and area of the primary surface-positive (P1) wave of the auditory evoked potentials. On the other hand, cessation of stimulation and central nervous system depressants produced E E G synchronization and increased occurrence of alpha waves and the auditory evoked responses (Pradhan and Galambos, 1963; Mori et al., 1968; G u h a and Pradhan, 1974). The Present address: Department of Pharmacology, College of Medicine of the University of Lagos, P.M.B. 12003, Lagos, Nigeria ** To whom offprint requests should be sent *

Experiments were conducted with seven cats of either sex weighing 2 - 3 kg. Under pentobarbital anesthesia (30- 40 mg/kg) stainless steel bipolar surface electrodes (0.2 mm diam.) were implanted bilaterally in the topographically demarcated auditory cortex. A screwplaced in the bone over the frontal sinus servedas an indifferent electrode. A cannula was stereotaxically implanted in the lateral ventricle using coordinates from the atlas of Snider and Niemer (i964). A tightly fitting stilet with a round tip prevented outflow of cerebrospinal fluid. After recovery from surgery, evoked responses from the auditory cortex were recorded. During this period the animals were trained to remain in a restraining bag located in a soundproof room. The cat was kept in fixedposition by clampingthe canvas bag to a frame of metal rods. Attached to this frame was an electronic motilitymeter (model Fc 40) about 6 inches away from the cat's head and this was connectedto a digital counter located outside the soundproof room. The number of HM during control and experimental sessions were recorded by the digital counter.

0033- 3158/79/0064/0349/$01.00

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Psychopharmacology 64 0979)

During control and experimental sessions the cat was presented with audio-oscillator clicks from a speaker located about 1 m from the animal's head. These auditory stimuli, triggered (Grass $44 Stimulator) at a 1/s frequency, consisted of 20 ms bursts (2000 Hz) from the audio-oscillator. The cortical activity and the evoked responses were amplified and recorded on a P-7 Grass polygraph. Two channels from this polygraph were fed through an oscilloscope to a computer of average transients (CAT 1000) which was also triggered by the above stimulator and the averaged evoked responses to 200 clicks were displayed on the oscilloscope and recorded on an X - Y recorder. Alpha rhythm (frequency range 7 - 1 4 Hz) has been produced in several cortical areas in relaxed humans as well as in cats. A frequency analysis of cortical activity, particularly the alpha rhythm from the same electrode sites in the auditory cortex, was also performed in these cats. For this purpose, one channel from the polygraph was connected to two frequency analyzers (Multrimetric Industries, Model A F 220) which were set at frequency ranges of 7 - 9 Hz and 10-14 Hz. The output from the frequency analyzers was connected to electronic counters (hp 5201 A 10 MHz) and the counts/30 s were noted and referred to as the index for low and high alpha. The amplitude and the area of surface-positive waves of the evoked potentials were measured with reference to their baseline (Guha and Pradban, 1974). The area under the curve was measured in square inches with a planimeter. The

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amplitude of the wave was determined by measuring the distance in laV from the peak to the base line. Microinjections of Tc into the lateral Ventricle were given in 0.02 ml of normal saline containing 0.05, 0.1, 0.5, and 1.0 gg of drug. Equivalent volumes of saline were injected as vehicle controls. Each cat was injected at a 3-day interval with a dose of Tc to eliminate drug residual effects. For peripheral injections Tc (15 - 3 0 pg) was administered IP. Data for each parameter were collected approximately every 10 min throughout the sessions before and after drug treatment and were expressed as percent change from the respective controls at each dose in each animal. Corresponding data, one measurement from each cat, were used to calculate the mean and SEM at each dose level of the drug. The level of significance was calculated by the student's ttest. Comparative study of drug effects on the two possible recording sites (i.e., the right and the left auditory cortices) was not evaluated. The data presented were obtained from the right auditory cortex.

Results EEG. The EEG and the evoked potential tracings

obtained from the right auditory cortex during control and drug conditions are shown in Fig. 1. Under control

HM 20 Control

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Fig. 1, The effects of low doses of tubocurarine (Tc) on electrical activity, auditory evoked response (AER), and head movement (HA/)

R. B. Ashorobi et al. : Behavioral Effects of Tubocurarine

351

conditions the E E G pattern recorded f r o m both right and left auditory cortices in these cats showed activation with a mixture o f slow and fast waves. Tubocurarine (0.05 - 1 ~tg intraventricularly) produced fast frequency, low amplitude waves. The development o f these wave patterns varied s o m e w h a t with individual cats and with the doses. Tubocurarine (0.05 gg) caused E E G activation with occasional slow waves. These changes occurred within 5 - 1 0 rain and lasted more than 120 min. Larger doses (0.1 - 1 lag) p r o d u c e d predominantly fast frequency, low amplitude waves.

not possible due to inconsistency. However, the normal P1 wave had an amplitude o f 8 0 - 1 2 0 laV and area of 1 . 7 - 2.4 square inches. Tubocurarine ( 0 . 0 5 - i gg) caused reduction in amplitude and area o f the primary (P1) wave in the evoked responses. The m a x i m u m reduction in amplitude and area was - 1 4 and - 3 0 ~ , respectively, at 30 min (0.05 lag dose) while peak effects were - 50 and - 2 9 ~ reduction, respectively, at 60 min (0.1 lag dose). A t higher doses the peak effect (reduction by - 5 8 ~o) on amplitude and area ( - 4 0 7oo)was at 40 min (0.5 lag dose). With the 1 gg dose, the m a x i m u m reduction in the amplitude was by - 7 2 ~ which occurred between 1 0 - 2 0 rain and that on the area was by - 5 0 ~ which appeared to occur in the same period (Tables 3 and 4). A n insignificant reduction in the peak latency was observed at the 0.05 gg dose level, while at 0.1 - 1 lag a marked reduction was observed. These responses were consistent in m o s t of the cats even t h o u g h doses were given in an increasing order with 3-day intervals to prevent residual drug effects.

Alpha Activity. In unanesthetized restrained cats the alpha wave counts range 1 3 5 - 1 8 5 (low) and 2 1 0 - 2 7 5 (high). Within 5 rain after administration o f all doses there was a reduction in b o t h low and high alpha counts which persisted t h r o u g h o u t the experimental sessions. M a x i m u m reduction in low alpha counts, i.e., an average o f - 16 ~ , was observed with 0.05 gg dosage. The doses o f 0.1, 0.5, and 1 lag p r o d u c e d m a x i m u m reduction o f average - 32, - 41, and - 59 ~ , while the m a x i m u m reduction in high alpha observed with similar doses were - 2 8 , - 3 2 , - 2 9 , and - 3 7 ~ , respectively. A gradual decline in response was observed at 80 rain but did not reach the control level during the 2-h period. However, a decrease in b o t h counts showed a dose-response relationship (Tables 1 and 2).

Evoked Responses. U n d e r control conditions the average evoked responses from the right auditory cortex consisted o f an initial surface-positive ( P 0 wave, sometimes followed by a small amplitude negative (N1) wave, in most o f the cats. Evaluation o f N1 waves was

Behavior. C o n c o m i t a n t with these changes in electrical activity, Tc caused an increase in H M indicative o f behavioral arousal. However, l o c o m o t o r activity could not be determined since the cats were kept in a canvas bag. The cats became restless and exhibited miaowing and gross a u t o n o m i c changes (e.g., salivation) which lasted 2 0 - 30 min. W h e n the experimenter entered the r o o m the cats showed signs o f hyperexcitability marked by extensive and r a n d o m movements o f only the head in all directions. These behavioral responses occurred simultaneously with E E G activation, decrease in the

Table 1. Effect of tubocurarine on low alpha index at different periods following intraventricnlar administration"

Dose

10 rain

20 min

30 min

40 min

60 min

80 rain

100 min

120 rain

0.05gg 0.1gg 0.5gg 1.0gg

- 7_+ b - 9-+ -18_+ -35-+

- 3-+0.4 -25_+3.3 -25-+3.0 -39-+

-13_+2.5 -32_+6.2 -41_+6.9 -53-+7.7

-16+2.8 -32_+6.2 -39_+4.7 -59_+8.0

-12-+1.5 -25-+3.6 -33_+6.4 -59_+8.0

- 9_+1.1 - 18 -+4.1 -33_+6.4 --49+7.4

- 7+0.9 -10_+1.6 --24+3.2 -41+6.9

- 7-+0.9 -10_+1.6 -19+4.2 -32-+5.9

a Mean -+ SE. For all data P

Electrophysiological correlates of the behavioral effects of tubocurarine in conscious cats.

Psychopharmacology Psychopharmacology 64, 349-353 (1979) 9 by Springer-Verlag 1979 Electrophysiological Correlates of the Behavioral Effects of Tub...
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