Brain noradrenaline and anaesthesia: Behavioural and electrophysiological evidence

BRAIN N~RADRENA~INE AND ANAES~H~SI~ ~E~AV~~~RAL AND ELEC~RUP~YSI~LUGICAL EVIDENCE S. T. MASON*, R. A. J. KING?, P. BANKS? *Dept. Physiology and tDept.

and A. ANGEL*

Biochemistry, The University, She%eid SIO 2TN, U.K.

Abstract-Neonatal administration of 6-hydroxydopamine to rat pups was used to deplete brain noradrenaline in the locus coeruleus projection system to less than 5% of normal and the response to barbiturate and non-barbiturate anaesthetics examined. The sleeping time in response to administration methohexitone or hexobarbitone was markedly increased in of thiopentone, pentobarbitone, 6-hydroxydopamine-trots rats, as it was for the non-barbiturates chloral hydrate and di~~pro~ylpbenol. The sleeping time for otber non-barbiturates such as al&e&, k&amine and eth$ carbamate (urethane) was not affected in noradrenaline-depIeted rats. Similarly, an index of the evoked potential, recorded in the primary somatosensory cortex to supramaximai electrical stimulation of the forepaw, decreased more markedly with increasing doses of thiopentone in 6-hydroxydopamine-treated rats than in controls. Potentiation of the effect of diisopropylphenol on the evoked cortical response was also seen in noradrenaline-depleted rats while the effect of althesin did not differ. It is suggested that brain noradrenaline pathways originating from the locus coeruleus may play an important role in the duration and deptb of anaestbesia resulting from barbiturate and some related agents,

Various neurotransmitters and neuronal circuits have been suggested for the mechanism of anaesthetic drugs (see review in Ref. 3). White predominance has perhaps been given to y-aminobutyrate (GABA) systems, some speculations have centered on the role of catecholamines.20 Thus, brain noradrenaline (NA) systems have been postulated to play a role in determining the level of arousal of the cortex as indicated by the EEG23” and their destruction may affect sleep and wakefulness patterns.‘*~” Chronic recording of the electrical activity of single cells in the locus coeruleus, the pontine nucleus which gives rise to the cortical NA innervation49 has shown that firing decreases on the transition from wakefulness to slow wave sjeep, both in ~mmobilised cats’.‘* and in freely moving animals.’ Further, a sudden increase in tocus coeruleus firing is observed to occur just prior to waking, in a temporal relationship which suggests that it could possibly be causative of that waking.l These findings raise the possibility that activity in the NA locus coeruleus system may be partiaffy responsible for maintained wakefulness and cortical arousal. It may also play a role in modulating the processing of sensory stimuli impinging on the or-

Correspondence to: Dr. S. T. Mason, Dept. Physiology, The University, ShefiieId SfO 2TN, U.K. Ab&-e~~~f~ons:6-UHDA, frhydroxydopamine; i.p., intraperitoneal; i.v., intravenous; GABA, y-aminobutyric &id; EEG, electroencephalogram; NA,‘noradrenaline; ST 587, 2-(2-chloro-5-trifluoromethylphenylimino)~ imidazolidine; DIP, diisopropylphenol.

ganism via a rmmber of modalities. Thus, electrical stimulation of the locus coeruleus increases transmission through the lateral genicuiate nucleus in the visual pathway, possibly by inhibiting inhibitory interneurones.36 Application of NA to the cochlear nucleus in the auditory pathway facilitates detection of a weak tone in a background of noise-‘* and considerable el~truphysiologjca~ work indicates a role for locus coeruleus NA fibres in modulation of transmission through the spinal trigeminal nucleus of the somatosensory system.‘7.4’+42*45 Depletion of brain noradrenaline may also change the response of neonatal rats to various odours, suggesting a role in processing of olfactory stimuli.2”i’8 Finatly, evidence that the locus coerufeus may affect transmission of pain stimuli and the analgesic action of opiates has also been presented.8*1’,43’“*46 The latter findings raise the further possibility that activity in the NA locus coeruleus system may be able to change the degree to which various modaIities of sensory stimuli gain access to the upper levels of the CNS. A common feature of anaesthetic drugs is their ability to induce unconsciousness and to prevent painful and other sensory stimuli from awakening the subject. Indeed, some few tantalising hints may be gleaned from the past litera&e that central NA systems may be. involved in the action of some anaesthetic agents. Thus, for example, halothane and cyclopropane produce changes in the NA content of the nucleus locus coeruleus.4n Destruction of brain NA fibres with 6hydroxydopa has been reported to prolong pento-

S. T. Mason

178

barbitone sleeping time3’ whilst the selective alpha, agonist drug, ST 587, which penetrates into the brain, has been found to shorten hexobarbitone sleeping time in mice.” In order to investigate this in a more systematic fashion, beyond that reported by Mueller et a1.35 for some gaseous anaesthetics, we examined animals depleted of NA in the projection areas of the locus coeruleus following neonatal 6-OHDA treatment and their response to sundry anaesthetic agents, as determined both ~haviouralIy and el~trophysioIogi~liy. EXPERIMENTAL

PROCEDURES

Pharmacological

Albino rat pups of the Sheffield strain were injected intraperitoneally with 6-OHDA hydrobromide (lOOmg/kg weight expressed as free base) dissolved in 0.9% saline with on days 1, 3, 5, 7, 9, 11 0.2 kgjmi ascorbic acid antioxidant and 13 after birth.‘” Controls received iniection of an equivalent volume of saiine-ascorbate vehicle (1 ml/kg). After weaning at 3 weeks of age they were allowed to grow to maturity with testing commencing at two months of age. Drugs

The following

drugs

were used:

ahhesin (Althesin, 9 mg alphaxalone and 3 mg alphadolene acetate per ml solution, Glaxo); chloral hydrate (Hopkins and Williams Ltd.); diisoproplyphenol (Diprivan, ICI Ltd.); ketamine hydrochloride (Ketalar, Parke-Davis); thiopentone sodium (Intraval, May and Baker); pentobarbitone sodium (Martindale Samoore Ltd.); hexobarbitone sodium (Cyclonal, May and Baker); methohexitone sodium (Brietal, Lilly); ethyl carbamate (Urethane, Sigma); Ah doses are expressed as weight of salt. Biochemical

After completion of behavioural testing a random selection of control and 6-OHDA treated rats were killed by decapitation and their brains dissected on ice into cortex and hippocampus, hypothalamus and striatum by the method of Mason and fversen.30 These areas were then assayed for endogenous catecholamines by the fluorometric technique of Shellenberger and Gordon4’ This served to confirm that the expected pattern and degree of depletion of brain catecholamines had been achieved. Behavioural

Male rats were injected i.p. with various doses of anaesthetic agents dissolved in 0.9% saline (I-2ml/kg). Controls and 6-OHDA treated rats were tested alternately between 10 a.m. and 4 p.m. Animals were placed in a cage suspended on a movement transducer (a mercury filled silicone rubber tube connected as one arm of a Wheatstone bridge) the output of which was rectified. integrated over 1 s periods and displayed on a chart recorder (Bryans 2700). Table

rl al.

This has been described in full elsewhere2 The first movement recorded on the chart recorder was taken to terminate the duration of sleeping time. Additionally, the dose of the non-metabolised anaesthetic agent ethyl carbamate needed to abolish the withdrawal reflex to pinch of the hind paw was determined. Elecirophysiologicai

Female rats were anaesthetised with ethyl carbamate (Urethane) (1.3-1.5 g/kg) and then underwent a tracheal cannulation, a midline skin incision and the drilling of two holes in the skull, one over the primary somatosensory and the other over the occipital cortex. Silver ball electrodes were placed gently on the durd above these two cortical areas. fixed in place with bone wax (Ethicon) and the cortical evoked response to supramaximal electrical stimulation of the forepaw recorded via resistance-capacity coupled amplifiers and displayed on a cathode ray oscilloscope or averaged on a digital computer (3802, Research Machines Ltd.) and subjected to statistical analysis. Electrical stimulation was accomplished by wrapping gauze strips, soaked in 3 iw NaCI one around the wrist (negative) and the other around the two middle digits (positive). These were connected to an isolated stimulator which provided pulses of up to 100 V of 50 ps duration. Supramaximal stimuli for the cortical response were used and cam was taken not to occlude the circulation of the forepaw with the gauze strips. Additional anaesthetic agents were administered intravenously via a tail vein. This technique has been described more fully.’

RESULTS

Neonatal administration of 6OHDA resulted in more than 95% depletion of forebrain NA in the cortex-hippocampus of the adult rat (see Table 1). No effect on brain dopamine was seen in either the hypothalamic or striatal region. Additionally, complete sparing of the ventral bundle NA system was achieved since hypothalamic NA remained intact in the 6-OHDA treated animals. Thus, a profound and permanent

destruction

of

the

1

Noradrenaline Cortex-hippocampus ~lypothalamus

328 + 4.8 1585&115

9.7 f 1.4 1513+t23

97 -

P < 0.001 NS

Dopamine Hypothalamus Striatum

399 * 90 7053 + 574

379+ 123 6904 k 1070

.-

NS NS

Mean with SEM in nanogram NS, Not significant

amine

NA

The sleeping time in response to various bdrbi&rate andesthetics is shown in Figs 1 and 2. In Fig.

6-OHDA (n = 3)

assays

coeruleus

Bthavioural

Control (n = 3)

Catecholamine Region

locus

system innervating the forebrain via the dorsal bundle49 was achieved with no damage to the ventral bundle NA pathway or to brain dopamine systems. This is in agreement with the results of previous wor~ers~‘*.29.‘0.il

per gram

‘I0 depletion

wet weight

of tissue.

Brain noradrenaline

and anaesthesia

179

150

0-a nl,“S

*

i1

OOnoA 4

cow1)ol.s

THlOPENTONE

I

CONTROL

I

6-OHDA

Smstc

0

100

DOSE

200

Fig. 1, Left: Sleeping time (mean of 9 rats in min with vertical bars showing SE&l) of control and 6-OHDA treated animals to thiopentone. Middle: Evoked cortical response measure (mean with SEM, see text) under i.v, thiopentone in the ethyl carbamate anaesthetised rat for control (n = 4) and 6-OHDA treated groups (n = 4). Right: Waveform of 4 superimposed averaged evoked cortical responses (n = 60 stimulation rate = I/s) in a control and a 6-OHDA rat following 0 or 50mg/kg of thiopentone. Vertical calibration bar is on left 35 pV, on right 70 pV. Horizontal bar is 5 ms.

1 (left) the sleeping time of control (n = 9) and 6-OHDA treated rats (n = 9) to thiopentone is shown and at all doses of the anaesthetic the treated rats slept significantly longer than controls (two-taited

Student’s r-test, P < 0.05). Similar potentiation of sleeping time in the 6-OHDA treated rats (n = 5) compared to controls (n = 5) was seen for barbiturates hexobarbitone, methohexitone and pento-

~11~

,,,J #/’ I’ ,’

,I’*’

1 I’

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I’

I -

I

I

0

I M

I

I

im .--.

C~~AL-~RA~

6-OHDA

o-QCoNTRMS

tm I’*# L’

,,nl-:-2

::_I:_;-I’ :

,’ f

w

50

25

DOSE mgfKg

--

UN

MO DOSE nwJfKg

Fig. 2. ~havioural sleeping times (mean with SEM in min) for control (n = 5) and 6-OHDA treated (n = 5) animals in response to i.p. injection of A: hexobarbitone, B: me#ohexitone, C: pentobarbitone and D: chloral hydrate.

180

S. T. Mason rf ul. tot-

0.

EVOKED RESPONSE

(; x PI, 5

l* 40 -

0

‘all-

l*

ai--

M-

00. 20-

0

CR475t3.7 M-

oo”

Ti:4bdtI.5

0

CONTROL rl~9

.

6-OHOA n-9

20 -

o--o *-*

CONTROL

n-6

b-OHDA n 4

0 o-

I’ 0

0

@-

11

3

11

11 6

11

9

11

1 ”

12

1 ”

15

1

IS

RANK ORDER

Fig. 3. Left: Scatter diagram of sleeping times (individual values, in min) for control and 6-OHDA treated rats (both n = 9) in response to 60 mg/kg i.p. diisopropylphen (see text). Right: Evoked cortical response (mean with SEM, see text) under i.v. DIP in control (n = 6) and 6-OHDA treated rats (n = 4).

as well as for the non-barbiturate chloral hydrate (Fig. 2). The sleeping time to a dose (60mg/kg i.p.) of the non-barbiturate diisoprophylphenol (DIP) is shown in Fig. 3 (left) for individual control (n = 9) and 6-OHDA treated rats (n = 9). Here, the sleeping times of both groups are

barbitone

ordered according to their rank, retaining the identity of each point as control or 6-OHDA. The sleeping times are then plotted against their corresponding rank order. It may be seen that the 6-OHDA rats slept for longer than controls and hence tend to appear on the right hand side of

l

c

Fig. 4. Scatter diagram of sleeping times (individual values, in min) for control and 6-OHDA treated rats to althesin (50mg/kg i.p., left) and ketamine (lOOmg/kg i.p., right).

Brain noradrenaline and anaesthesia the graph, while controls appear on the left hand side (control mean f SEM = 17.5 + 3.7 min; 6-OHDA = 46.4 f 3.5, t (16) = 5.32, P < 0.001). However, similar scatter diagrams for the nonbarbiturate drugs althesin and ketamine (Fig. 4) at 50 and 100 mg/kg, respectively, indicated that the control and 6-OHDA treated rats slept for similar durations and so the points of the two groups on the scatter diagram are inter-mixed. Sleeping times for a range of doses of althesin and ketamine are shown in Table 2 and in no case did the control and 6-OHDA treated animals differ significantly. The dose of ethyl carbamate required to abolish the withdrawal reflex was found to be for the 8 controls 1.27 f 0.06 g/kg and for the 7 treated rats 1.26 + 0.82 g/kg (P = 0.99). Electrophysiological Quantijication of the evoked cortical response. In female rats surgically anaesthetised with ethyl carbamate (1.3-1.5 g/kg) the early part of the evoked cortical response appears as a wave of surface positivity interrupted by a prominent early negative component (Fig. 5, left). This is in agreement with other workers.4.5 Two parameters of the early part of the evoked cortical response may be defined; the latency (L) to the initial positive component and the amplitude of that positive component (Pi) prior to the occurrence

181 Table 2. Sleeping times

Drug Althesin,

Ketamine,

Control

and dose (i.p.) 25 35 50 50 100 150

mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

12.5 + 0.3 21.2 + 0.9 27.1 + 2.3 7.2 k 0.9 12.7 k 2.3 41.0+5.1

6-OHDA 13.2 20.6 29.1 10.0 16.3 42.2

Values are means with SEMs of five rats per group, for 50 mg/kg althesin and lOOmg/kg ketamine were determined with ten rats per group.

!' !

(tx Pi)%

o---o

6-OHDA

-

CONTROLS

5 msec DOSE FOR LOSS OF WITHDRAWAL REFLEX CONTROLS n=8 1.27k0.06gmlKg

0.8 1.5 3.1 1.1 2.3 2.6 except which

of the first negative phase (Fig. 5, left). The effects of increasing doses of ethyl carbamate is to increase the latency and to decrease the amplitude of the first positive component. Thus, a compound measure of Pi x l/L was calculated. This will very rapidly diminish as the level of anaesthesia goes from surgical to deeper states.’ For additional doses of barbiturate or nonbarbiturate drugs this compound measure was expressed as a percentage of its value found under ethyl carbamate anaesthesia (1.3-l .5 g/kg) alone. These values were determined at the moment of peak effect of the anaesthetic agents. For ethyl carbamate this was 3 min and for thiopentone and diisopropylphenol 5 min after intravenous administration. Thus, in Fig. 5 (right) is shown the effect of giving additional doses of ethyl carbamate above and beyond that required

EVOKED RESPONSE URl3HANE

k f k + + +

O-

6-OHDA n=7 1.26k0.82gmlKg DOSE mg/Kg Fig. 5. Left: Waveform of early part of the evoked cortical response in the ethyl carbamate anaesthetised rat. L is the latency to the first positive component and P, is the amplitude of that component. Vertical calibration bar is 25pV, horizontal bar is 5ms. Right: Evoked cortical response (mean with SEM, see text) for control (n = 8) and 6-OHDA treated (n = 7) rats receiving additional doses of ethyl carbamate.

182

S. T. Mason et 01.

for surgical anaesthesia per se. It may be seen that P, x l/L decreases rapidly to some 20% after a further dose of 2 g/kg ethyl carbamate. The decline in the evoked cortical response seen for additional doses of ethyl carbamate did not differ between control rats (n = 8) and 6-OHDA treated animals (n = 7). This indicates that any differences to subsequent administration of barbiturate drugs between control and 6-OHDA rats is not due to the drug used for basic surgical anaesthesia (ethyl carbamate) or to changes in its disposition or brain concentration.

Figure I (middle) shows the effects of giving additional amounts of the barbiturate thiopentone on the evoked cortical response measure P, x l/L. In control rats (n = 5) this measure decreases with increasing dose of thiopentone (see Angel and Gratton, 1982”). However, a much more precipitous decline was seen in the 6-OHDA treated animals (n = 4). For example, at 50 mg/kg thiopentone the control measure was some 70”/<, of normal while that of the 6-OHDA treated animals had dropped to 45%. Four superimposed average (n = 60. rate l/s) tracings of the early part of the evoked cortical response for 0 and 50 mg/kg doses of thiopentone are shown in the right panel of Fig. I for a control and a 6-OHDA animal. It may be noted how much smaller the amplitude of the 50 mg/kg tracing relative to the 0 dose tracing is for the 6-OHDA rat than for the control. Thus, the effect of the barbiturate thiopentone on the evoked cortical response was clearly potentiated by prior depletion of brain noradrenaline.

For the non-barbiturate drug DIP a similar effect may be seen (Fig. 3, right). Increasing doses of DIP in the control rats (n = 6) produced only a mild reduction in the evoked cortical response measure to which was nonetheless around SOY,, of normal significant (P < 0.05) whereas a much greater decline was seen in the 6-OHDA treated animals (n = 4) to less than 50:; at the largest dose tested. Thus, the effect of DIP too, on the evoked cortical response, was potentiated by prior depletion of brain noradrenaline. However, for the non-barbiturate althesin (Fig. 6, top) no effect of NA depletion was observed. The time course of the drug, as determined by the evoked cortical response in 4 controls and 4 6-OHDA treated rats measured at various times after administration of a single dose of 6 mg/kg althesin i.v. was the same in the two groups. Thus, the effect of althesin on the evoked cortical response was not altered by prior depletion of brain noradrenaline. In contrast, a similar time course experiment for DIP (5 mg/kg i.v.) in one control and one 6-OHDA rat clearly showed a marked potentiation of the effect of DIP in decreasing the evoked cortical response measure following prior depletion of brain noradrenaline (Fig. 6,

Fig. 6. Top: Time course of evoked cortical response changes (mean with SEM) to a single dose of althesin (6 mg/kg i.v.) in controls (n = 4) and 6-OHDA treated rats (n = 4). Bottom: Timecourse of evoked cortical response changes for one control and one 6-OHDA rat to a single dose of DIP (5 mg/kg i.v.). No significant reduction in the evoked response was seen at this dose in the control rat but a very marked effect occurred in the 6-OHDA treated animal.

bottom). Here, no significant decrease was seen in the control rat but a highly significant effect occurred in the 6-OHDA treated rat. DISCUSSION

Noradrenaline systems in the brain have been postulated to play a role in a wide range of disparate physiological and behavioural processes (see reviews by McNaughton and Mason,” Mason’*). One set of interrelated suggestions implies an action in the control of cortical arousal,*‘.‘” sleep-wake cycles’,‘” and selective attention.‘7.30 As a consequence, it would be expected that NA systems may also have some role to play in the alterations of arousal, sleep and sensory processing induced by exogenous anaesthetic drugs. The work reported here is the first systematic demonstration of such a role. Depletion of NA in the projection pathways of the locus coeruleus to less than 5’>,; of normal was achieved through the use of the selective neurotoxin 6-OHDA. Complete sparing of the ventral NA system and also of brain dopamine was apparent (Table I). The NA loss resulted in the potentiation of

Brain noradrenaline anaesthesia to a number of agents as demonstrated both by behavioural and electrophysiological indices. Thus, the sleeping time to all the barbiturates examined here and to several non-barbiturate agents was markedly prolonged in the 6-OHDA treated rats. This would seem to be a general effect since it was seen for thiopentone, pentobarbitone, methohexitone and hexobarbitone of the barbiturates and also for DIP and chloral hydrate. However, of equal importance is the related discovery that the sleeping time to althesin and ketamine and the threshold dose of ethyl carbamate needed to abolish the withdrawal reflex were not changed by NA depletion. Hence, the increased response to the barbiturates cannot be due to a general change in the permeability of the blood-brain barrier or of the metabolic disposition of drugs as a result of the lesion. Not only the duration of anaesthesia, as judged by behavioural sleeping time, but also the depth of anaesthesia, as indicated by the reduction in the evoked cortical response, was increased by prior NA loss. Thus, the potentiation of thiopentone and DIP anaesthesia have been shown in parallel in a behavioural and an electrophysiological methodology. Similar agreement between the techniques was found for the action of althesin which was not altered by NA depletion in either the behavioural or the electrophysiological test. Possible mechanisms Clearly, the anaesthetic agents studied here fall into two groups, those whose action is potentiated by NA depletion (barbiturates, DIP and chloral hydrate) and those which remain unaffected by such NA loss (althesin, ketamine, ethyl carbamate). These chemical agents have a wide range of chemical structure and it is as yet unclear what determines which group a given compound falls into. However, two generalisations about anaesthetics have been noted in the past. Anaesthetic potency correlates with lipid solubility, as first proposed by Meyer33 and Overton. This has repeatedly been extended and confirmed.‘4,34 Anaesthetic action can also be reversed by increasing the ambient barometric pressure (for example Refs 15,22). These two lines of evidence would suggest that there might indeed be a single neurochemical action common to all anaesthetics and which is the necessary basis of their action. Whatever this final common mechanism might be it cannot be directly an effect on brain noradrenaline systems, since some agents were affected by NA loss whereas others were not. Nonetheless, it is clear that some part of the anaesthetic action of the barbiturates and some other

183

and anaesthesia

agents is modulated by brain noradrenaline. A prolongation of duration by anything from 100 to 500% (Fig. 2) and an increase in a measure of the depth of anaesthesia between 100 and 400% (Figs 1 and 3) is a quite marked effect. While the detailed mechanism of action must remain a matter for speculation (Although the type of adrenoceptor involved has been further clarified6), it would appear that the locus coeruleus NA pathways may be one of a number of systems which by their activity maintain cortical arousal and promote the processing of sensory stimuli. Thus, Waterhouse, Moises, and Woodward” found that microiontophoretic application of an alpha agonist to cells in the rat somatosensory cortex increased their response to tactile stimulation of the skin. Similar increased responsiveness was also seen with the natural neurotransmitter noradrenaline.” That this electrophysiological phenomenon has significance in the behavioural response of the whole animal is indicated by de Jonge et al.,13 who found the centrally active alpha, agonist drug ST 587 to shorten hexobarbitone sleeping time in mice by over 50%. All this is thus very direct evidence for a role of locus coeruleus NA systems in facilitating the processing of somatosensory stimuli. As such, one of the actions of the barbiturate and related agents may be to reduce the availability of NA in the somatosensory cortex. This could come about by a presynaptic effect on the release of NA from terminals as suggested by the findings of Haycock et aLI that pentobarbitone markedly reduced the calcium-stimulated release of NA from mouse forebrain synaptosomes. A second mechanism might be a change in the overall firing rate of cells of origin in the locus coeruleus and Akaike’ has indeed reported that in the rat these cells increase their firing as the animal wakes from anaesthetic, show bursting patterns and then decrease their activity if the animal returns to the anaesthetised state. Comparisons of locus coeruleus firing rate in anaesthetised with immobilised” and with freelymoving rats’ show that the locus coeruleus is much less active during anaesthesia, as indeed it is during natural slow-wave sleep.7,9 From our present results it would appear that the change in locus coeruleus firing (or presynaptic change in NA release) may be in part responsible for, and causative of, some aspects of the anaesthetic state for barbiturate type drugs. It is, however, not the single common mechanism necessary to all anaesthetic agents, if such exists. Acknowledgements-Work G973/403/C).

supported by the MRC (Grant

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1 March 1983)