ALTERATIONS OF “SLEEPING TIME” IN THE RAT INDUCED BY DRUGS WHICH MODULATE CENTRAL MONOAMINERGIC SYSTEMS

British Journal of Anaesthesia 1990; 64: 594-600

ALTERATIONS OF "SLEEPING TIME" IN THE RAT INDUCED BY DRUGS WHICH MODULATE CENTRAL MONOAMINERGIC SYSTEMS

for the LC system was proposed: the modulation of action of barbiturate-like drugs. Subsequent The effects of adrenoceptor agonists and antago- investigations [15] showed that i.p. injection of nists have been determined on "sleeping time " some adrenoceptor agonists and antagonists given in the rat—that is, with the animal immobile and before thiopentone could produce significant adopting a sleeping posture. Alterations in their changes in the duration of the resultant anaesgross behaviour patterns were assessed also. The thesia. It was suggested that these drugs might specific CL2-adrenoceptor agonists (yohimbine, influence the overall activity of the LC systems WY 26393, RX 781094 and RS 21361) de- which, in turn, could alter the coerulear moducreased sleeping time, as did the fi-adrenoceptor lation of cortical arousal, wakefulness or the agonist c/enbuterol. The specific ^-adreno- processing of sensory information and thus affect ceptor agonist clonidine gave a large increase in the duration of the anaesthetic effect. sleeping time at doses in excess of 25 ng kg-''. However, behavioural studies in other laboraThe same effect was seen with the ^-antagonist tories have shown wide ranging psychotropic propranolol and the specific fi2-antagonist ICI effects induced by adrenoceptor agonists and 118551. antagonists in man and animals. For example, drugs which caused a prolongation of thiopentone anaesthesia (clonidine and propranolol) have been KEY WORDS reported previously to possess sedative [16] and Brain: central monoamines. Sleep. tranquillizing actions [17], respectively. These effects would imply a general depressant action on It is widely accepted that the majority of central the central nervous system. Generally, if two noradrenergic (NA) neurones originate in the sedatives are administered concurrently, a simple locus coeruleus (LC) [1]. From this small pontine additive or potentiating effect of one upon the nucleus the dorsal noradrenergic bundle (DNB) other would be observed. Conversely, a central ascends to innervate the thalamus, hypothalamus, nervous stimulant would be expected to antagothe basal telencephalon and the entire neocortex nize the depressant action of an anaesthetic [18]. [2-6]. With its extensive distribution, it is not It is thus possible that drug-induced alterations of surprising to find that the LC is implicated in the duration of action of anaesthetic agents might neuronal modulation over a large part of the have been caused solely by non-specific drugbrain. It appears that the LC may play a role in drug interactions per se and not by any modulatory paradoxical sleep, attentional processes, modu- action of a noradrenergic system implicated in the lation of electrophysiological responses of cerebral action of the anaesthetic. Consequently, expericortical neurones, the regulation of autonomic ments have been performed to assess the action of output and the mechanisms underlying vigilance and behavioural arousal [7-13]. Angel and Mason [14] showed that, in the rat, A. ANGEL, B.SC., PH.D. ; A. B. A. MAJEED*, B.SC., PH.D. ; Departof Biomedical Science, The University, Sheffield destruction of the DNB with the selective neuro- ment S10 2TN. Accepted for Publication: December 14, 1989. toxin 6-hydroxydopamine potentiates barbiturate *Present address: Department of Physiology, School of anaesthesia. From this observation, another role Pharmacy, Universiti sains Malaysia, Pilau Penang, Malaya. SUMMARY

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A. ANGEL AND A. B. A. MAJEED

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SLEEP AND ADRENERGIC RECEPTORS

Determination of sleeping time

Sleeping time

The animals were placed singly in a rat cage suspended upon a movement transducer [21]. Briefly, this consisted of a length of silicon rubber tubing filled with mercury and connected as one arm of a Wheatstone bridge, the output of which was amplified, full-wave rectified and integrated over 1-s periods. The integrated signal was displayed on a pen recorder. After a 30-min period of acclimatization the animals were treated with either a drug (made up in normal saline) at concentrations to keep the volume of injectate to 2 ml kg"1, or saline alone. The total amount of "sleeping time", denned as the total amount of time during which the activity from the transducer did not exceed baseline, during the period 20-80 min after injection of drug was then determined. The baseline activity for the animal was represented by the level of activity recorded during the pre-injection period when the animal was immobile and had adopted a sleeping posture. All experiments were carried out at the same time of day for each animal in a quiet room. Each animal was investigated as its own control and for drug treatments. The animals were housed under normal conditions of 12-h light-dark cycle and the experiments were performed between 10:00 and 16:00—that is, during the normal sleeping period. Mean value of sleeping time from control and treated animals were compared for statistical difference using Student's two-tailed t test.

The results for all the drugs tested are summarized in table I. Saline controls. In the 1-h assessment period the animals were quiescent for 29.4 (SEM l)min. The variation in total sleeping time for the 10 animals tested was from 24 to 35 min.

a-Adrenoceptor drugs. Three of the four a^adrenoceptor antagonists produced a dose-dependent decrease in sleeping time with a potency order of: yohimbine > WY 26392 > RS 21361. For example, at a dose of 1 mg kg"1, yohimbine almost halved sleeping time (15.6 (1.1) min; P < 0.001) compared with a 30% reduction with WY 26392 (21.4 (0.5) min; P<0.01), whereas RS 21361 (29.6 (1.9) min) was ineffective. Of particular interest was RX 781094, which showed a biphasic dose-response relationship. At low doses (0.01 mg kg"1) it caused a slight, but statistically significant increase in sleeping time (38.2 (2.2) min; P<0.01), whereas at greater doses (:> 0.1 mg kg"1) sleeping time was decreased. This can possibly be attributed to a dual action on a-adrenoceptors, acting as an agonist at low doses and an antagonist at high doses [24]. The a,-adrenoceptor agonist clonidine also showed a biphasic dose-response curve. At a dose of 0.01 mg kg"1 it produced a small but statistically significant (21.4 (1.9) min; P < 0.01) decrease in sleeping time, whereas with doses > 0.1 mg kg"1, statistically significant increases in Drugs sleeping time were observed. The dose for agonist 1 The following drugs were used in this study: to antagonist transition was about 0.025 mg kg" clonidine hydrochloride and clenbuterol (Boeh- in the present series of experiments. The sleepringer & Ingelheim); propranolol, yohimbine HC1 promoting effect of clonidine developed extremely and pyrogallol (Sigma); 2[2-(l,4-benzo- rapidly. Values of sleeping time for clonidine and diaxonyl)]-2-imidazoline HC1 (RX 781094, saline during the first 20 min after injection are

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drugs which modulate the effectiveness of the Reckitt & Colman); 2(l-ethyl-2-imidazolyl central noradrenergic pathways to see if they had methyl)-1,4-benzodiaxan (RS 21361, Syntex); Nany effect upon natural sleep in the unanaesthe- [2p",l lbot)-1,3,4,6,7,1 lb-hexahydro-2H-benzotized rat. Brief reports of this work have appeared (a)-quinolizin-2-yl]-N-methylpropane sulphonamide HC1 (WY 26392, Wyeth); erythro-DLelsewhere [19, 20]. l-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118551); chlordiazepoxide (Librium, Roche) and amphetamine. ICI 118551 MATERIALS AND METHODS was heated gently until it dissolved; all other Male albino rats (Sheffield strain) in the weight drugs were dissolved in saline at 37 °C. range 200-300 g were housed in groups of three and allowed free access to food and water except for the short period of testing. RESULTS

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TABLE I. Effects of adrenoceptor agonists-antagonists, pyrogallol, amphetamine and saline on sleeping time in rats. Values are mean (SEM) and were evaluated for significance of difference vs saline controls using an unpaired two-tailed Student's t test: *P<0.05; **P<0.01; ***P < 0.001. Values in [brackets] showed a significant increase in sleeping time. n = 6 in all cases except for saline (n = 10). ns = Not significant. COMT-I = catechol-o-methyl transferase inhibitor. (For drug doses see references cited)

Drug

Action

Dose (mg kg"1)

0,-Agonist

0.010 0.025 0.125 0.25

RX 781094 [36]

a,-Agonist a,-Antagonist

0.01

0.5 0.1 1.0

10.0 Yohimbine [15]

0,-Antagonist

WY 26392 [36]

o^-Antagonist

RS 21361 [36]

a,-Antagonist

0.1 0.5 1.0 0.2 0.5 1.0 2.0 1.0 2.0

10.0 20.0 Clenbuterol [32]

(5-Agonist

2.0

20.0 Propranolol [32]

f$- Antagonist

ICI 118551 [32]

p,-Antagonist

Pyrogallol [22] Librium [23] Amphetamine [23] Saline

COMT-I Anxiolytic Stimulant Control

shown in table II. At all doses tested, clonidine was found to produce a statistically significant decrease in activity during this time period. /?- Adrenoceptor drugs. The P-adrenoceptor agonist clenbuterol produced a significant decrease in sleeping time at a dose of 20 mg kg"1 (18.5 (3.1) min; P < 0.01). In contrast, both propranolol (a P-adrenoceptor antagonist) and ICI 118551 (a selective P,-adrenoceptor antagonist) caused a marked increase in sleeping time at the same dose (35.9 (1.4) and 37.3 (2.0) min,

1.0 2.0

10.0 20.0 10.0 20.0 30.0 125.0 20.0 2.0

21.4(1.9) ** 30.6 (5.3) ns [41.5(2.6)]*** [45.8(1.6)]*** [47.7 (2.2)]*** [38.2 (2.2)]** 24.7(1.3) * 21.4(2.1) ** 19.0 (0.9) *** 20.0(1.5) *** 18.9(1.8) *** 15.6(1.2) *** 33.4 (1.7) ns 24.8(1.3) * 21.4(0.5) ** 20.9(1.7) ** 29.6(1.9) ns 28.8 (1.9) ns 23.5 (3.3) ns 13.0 (2.4) *** 24.4 (3.7) ns 18.5(3.1) ** 26.4 (2.2) ns 29.3 (1.3) ns 32.4 (3.0) ns [35.9(1.4)]** 28.2 2.4 ns [37.3 (2.0)]** [42.8 (2.9)]*** 34.1 (2.0) ns [43.0 (2.7)]*** 0

29.4 1.0

respectively). As was seen with clonidine, the sleep-promoting effect of these two drugs was apparent also in the 20-min period immediately after administration. Paradoxically, during this period, a low dose of propranolol was found to cause a small but statistically significant decrease in sleeping time (table I). Anxiolytic agent. Chlordiazepoxide 20 mg kg"1 produced a significant increase in sleeping time (43 (2.7) min)—an effect which also showed a rapid development (table II).

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Clonidine [15]

Sleeping time (min)

SLEEP AND ADRENERGIC RECEPTORS

597

TABLE II. Total sleeping time during the first 20 min immediately after the injection. Significance compared with saline controls: * P < 0 . 0 5 ; **P<0.01; * * * P < 0.001. Values in [brackets] show a decrease in sleeping time

Drug

Action a,-Agonist

Propranolol

p-Antagonist

ICI 118551

P,-Antagonist

Librium Saline

Anxiolytic Control

Sleeping tune (min)

0.010 0.025 0.125 0.25 0.5 1.0 2.0 10.0 20.0 10.0 20.0 30.0 20.0

4.8 (0.8) * 5.6(1.4)* 6.2 (0.9) *** 7.6(1.2) *** 8.5(1.4) *** [1.1(0.4)]** 4.5 (1.3) ns 7.0 (1.7) ns 10.0(1.4) ** 4.8 (1.7) ns 4.5 (0.9) ns 7.2(1.5) *** 9.4(1.1) *** 2.9 (0.3)

COMT inhibitor. The catechol-o-methyl transCatecholamine and catecholaminergic neurones ferase inhibitor, pyrogallol [25], gave only a slight have been implicated in the mechanism of action increase in sleeping time which was not stat- of anaesthetic agents. Muller and Frouts [28] istically significant (table I). reported that adrenergic blocking drugs caused a prolongation of hexobarbitone sleeping time in Psychostimulant drug. None of the animals mice. Such action was attributed to both a drugtreated with amphetamine 2 mg kg"1 showed any induced inhibition of liver microsomal enzymes signs of sleep during the entire period of ob- and decrease in body temperature. On the other hand, Miller, Way and Eger [29], suggested that servation. the anaesthetic requirement for volatile anaesthetics (the minimal alveolar concentration, DISCUSSION MAC) might be related to the NA content of the In the present series of experiments, we have brain. Their hypothesis was based on the findings attempted to use the same variable as that in the that patients receiving drugs which effectively previously reported experiments on potentiation reduced brain NA (guanethidine or methyldopa) of barbiturate anaesthesia, that is, the duration of required lesser concentrations of halothane than time during which the total locomotor activity of normal patients. Similar observations were made the animal did not exceed the level of a pre- by Johnston, Way and Miller [30], who showed determined baseline (see below). The descriptive that acute treatment with D-amphetamine resulted term "sleeping time" was adopted rather than in an increase in halothane MAC in animals. "time of zero locomotor activity", "immobility Conversely, chronic treatment with drugs which time", "period of inactivity " etc., for a variety of deplete brain catecholamines caused a decrease in reasons. The baseline was taken as that at which halothane MAC. Later Roizen and colleagues [31] the animal was completely immobile and assumed showed that halothane and cyclopropane could a sleeping posture. None of the drugs used alter NA concentrations in discrete brain nuclei produced motor freezing (no locomotor activity such as the LC and nucleus accumbens. without the adoption of a sleeping posture). In More recently, Mason and Angel [15,32] addition, it has been shown that clonidine pro- demonstrated that the duration of barbiturate duces changes in EEG pattern which resemble anaesthesia was dependent upon the overall those seen in sleep in the rat [26] and clinically it activity of the central NA system. Drugs which produces prolonged sleep in man [27]. reduced the activity of the system, for example a2-

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Clonidine

Dose (mg kg"1)

598

demonstrated a strong inhibitory action of clonidine on discharge of central NA neurones [37-39]. However, propranolol has been shown to be without action on the firing rate of LC cells [40] even at very high i.v. doses. Thus it is possible that drug-induced alterations of sleeping time may not be dependent upon the availability of NA at the LC neuronal terminations per se. In the present studies pyrogallol, a COMT inhibitor, which would tend to increase the accumulation of NA in the vicinity of the postsynaptic adrenoceptors, failed to cause a shortening of sleeping time. This chemical did, however, produce a small increase in sleeping time at a dose of 125 mg kg"1. At this dose, in the chick, it produces complete somnolence [Angel and Dewhurst, unpublished observations]. There have been some contradictory suggestions on the mechanism of the central action of propranolol. Mason and Angel [32] proposed that its P-blocking action might be responsible for potentiation of thiopentone anaesthesia in the rat. Murman, Almirante and Saccani-Guelfi [41] and Hermansen [42] suggested that the prolongation of hexobarbitone action in mice could be caused by a pure depressant action of propranolol on the CNS. Similarly, the tranquillizing [17] and anticonvulsant [41] effects of propranolol have been attributed to an intrinsic CNS depressant action [43]. There have been reports also of the sleepinducing effect of propranolol in mice [44] and rats [45]. Many, but not all, of the pharmacological effects of P-blockers may be attributed to their Padrenoceptor antagonist activity per se. They do, however, possess other properties, such as acting as local anaesthetics or having intrinsic sympathomimetic activity. There have been suggestions that aberrant activity of drugs may be related to their chemical structure. Lesvkovsky and Tardos [43] proposed that the CNS-depressant action of propranolol might be a result of the presence of a methyl group, and a similar explanation has been essayed for the naphthyl group of pronethalol [41]. In the present study both propranolol and ICI 118551 (which has an indalyl group) induced an increase in sleeping time. The latter and another P-blocker, pindalol, have been shown to potentiate the effect of thiopentone in the rat [32] and pindalol has been shown to increase the effectiveness of chloral hydrate in mice [44]. From these observations it is interesting to note

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agonists and P-antagonists, potentiated thiopentone sleeping time, whilst drugs which enhance LC-NA activity, for example, a2-antagonists and P-agonists, gave a decrease in the effectiveness of thiopentone. However, not all anaesthetic agents have their activity modulated by interference with the central NA system. Adrenergic drugs were shown to have no effect on ketamine, urethane or Althesin (alphadolone/alphaxalone) anaesthesia [15,32]. In the present series of experiments it has been found that drugs which shortened thiopentone sleeping time could induce "stimulant" effects in unanaesthetized rats. Assessment of behavioural signs such as awareness, consciousness, spontaneous activity, stereotyped movements and motor co-ordination generally showed an increase. The degree of CNS excitation obtained was, however, not as great as that produced by the more conventional CNS stimulants. For example, the increased motor activity seen after yohimbine was intermittent compared with the continuous activity seen after amphetamine. Nonetheless, by measuring total locomotor activity it has been shown that yohimbine, WY 26392 and RS 21361, all selective a2-adrenoceptor antagonists, caused an increase in central excitation, reflected as a decrease in the total time spent immobile after adopting a sleeping posture. The P-adrenoceptor agonist, clenbuterol, also reduced sleeping time. For this drug, a direct stimulation of the postsynaptic P-adrenoceptors would lead to excitation of central NA neurones. It has been shown that electrical stimulation of the LC leads to the release of NA in the cerebral cortex [33], which could then lead to electrocortical and behavioural arousal [34, 35]. The possible correlation between the activity of LC cells and the duration of sleeping time receives support from the action of RX 781094. At low doses it produced an increase in sleeping time, possibly via a presynaptic a2-agonist action. Conversely, higher doses caused a reduction in sleeping time, presumably by autoreceptor block. Both behavioural studies using the thiopentoneinduced sleeping time model [36] and electrophysiological recordings of rate of discharge of LC cells [24] have shown a similar biphasic response with RX 781094. However, the enhancement of sleeping time produced by propranolol, clonidine and ICI 118551 cannot be attributed solely to modulation of coerulear discharge. Many workers have

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SLEEP AND ADRENERGIC RECEPTORS

ACKNOWLEDGEMENT We thank Reckitt & Colman, Syntex, Wyeth and ICI for the generous gifts of the drugs used in this study.

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that P-blockers with a double ring structure on the aromatic moiety of the molecule produce a sedative or depressant action, whereas compounds with a phenyl group such as nifenalol and dichloroisoproterenol cause central excitation. Similarly sotalol, dichloroisoproterenol and Ko 1336 shortened, whereas practolol did not alter, chloral hydrate sleeping time [44]. The significance of structure—activity relationships of a2-adrenoceptor antagonists has been demonstrated [46]. Thus the possibility of a similar structure-dependent action of P-adrenoceptor antagonists cannot be ruled out. The sedative action of clonidine has been attributed to its activation of presynaptic a2adrenoceptors on LC cells causing a decrease in the activity of this ascending NA pathway projecting diffusely to subcortical and cortical areas. However, such a simplistic mechanism of action can, at best, provide only a partial explanation for its wide-ranging central effects. In the present study its action resembled that of an anaesthetic rather than a sleep-inducing agent. Electrophysiological studies [47] have shown that clonidine in high dose (^ 100 (ig kg"1) potentiates the effect of urethane and has an action identical to that of several general anaesthetic agents as measured by electrocortical activity, cerebral evoked responses and its ability to suppress thalamic and cortical, but not cuneate, cellular responsiveness to electrical stimulation of the periphery. The same authors reported a reverse action of clonidine at small doses. Such a biphasic dose-dependent action was seen also in the present study (table I). In support of this suggestion for a separate, non-adrenergic, mechanism of action of clonidine-induced CNS depression, Nassif and colleagues [48] have shown that a neurochemical lesion of the LC system does not suppress its sedative action. Moreover, yohimbine, a specific a2-adrenoceptor antagonist, has no effect on spontaneous electrocortical activity, cerebral evoked responses or cellular responses to peripheral stimulation at cuneate, thalamic or cortical sites [49]. Thus not all of the central actions of clonidine can be ascribed to an otj-agonist action. It may in addition exert a mild anaesthetic-like action. The exact site, or sites, of such action should be determined.

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