The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat

Neuroscience Vol. 58, No. 4, pp. 799-805, 1994 Elsevier Science Ltd Copyright 0 1994 IBRO Printed in Great Britain. All rights reserved 0306-4522194 $6.00 + 0.00

THE ANGIOTENSIN CONVERTING ENZYME INHIBITORS CAPTOPRIL AND ENALAPRIL INHIBIT APOMORPHINE-INDUCED ORAL STEREOTYPY IN THE RAT R. J. A. BANKS,* L. MOZLEY* and C. T. DOURISHt$ *Department of Psychology, University of Sheffield, P.O. Box 603, Sheffield SIO 2UR, U.K. IWyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 OPH, U.K. Abstract-The possible functional interaction between angiotensin and dopamine mechanisms in the rat was investigated by examining the effects of the angiotensin converting enzyme inhibitors captopril and enalapril on apomorphine-induced stereotypy. Apomorphine-induced behaviour was observed, and recorded using a keypad linked to a microcomputer. In agreement with previous findings, low doses of apomorphine induced a syndrome of vacuous mouth movements, penile grooming, yawning and immobility whereas at higher doses the yawning syndrome disappeared to be replaced with sniffing, licking and gnawing. Two antagonism studies were carried out. In the first the effects of captopril on apomorphine-induced behaviour were compared with those of the classical neuroleptic haloperidol, and in the second dose-response curves for the effects of captopril and enalapril on apomorphine-induced behaviour were determined. Captopril had no effect on the apomorphine-induced yawning syndrome whereas this was blocked by haloperidol. In contrast, both captopril and haloperidol blocked oral stereotypy (licking and gnawing) induced by apomorphine but had no effect on sniffing induced by the dopamine agonist. Selective blockade of apomorphine-induced oral stereotypy by angiotensin converting enzyme inhibition was confirmed in the second study in which both captopril and enalapril were observed to antagonize apomorphine-induced gnawing. The inhibition of apomorphine-induced gnawing by enalapril correlated with inhibition of brain angiotensin converting enzyme, but not lung angiotensin converting enzyme, by the drug as assessed by ex uivo penetration studies. These data suggest that angiotensin converting enzyme inhibition modulates the expression of apomorphine-induced oral stereotypy, a response that is thought to be mediated by postsynaptic dopamine receptors. In contrast, the yawning syndrome induced by low doses of apomorphine which is thought to be due to selective stimulation of dopamine autoreceptors is unaffected by the angiotensin converting enzyme inhibitors. Thus the pharmacological interaction between inhibition of brain angiotensin converting enzyme and blockade of apomorphine-induced oral stereotypy probably occurs at postsynaptic dopamine receptors or at downstream sites innervated by striatal neurones (e.g., substantia nigra-or super& colliculusj.

The octapeptide angiotensin II (AII) is a potent vasoconstrictor in animals and humans. Angiotensin converting enzyme (ACE) inhibitors such as captopril and enalapril inhibit the conversion of angiotensin I to AI1 and are widely used in the treatment of hypertension.‘9 AI1 and ACE are found in both the periphery and in the brain. The highest densities of the peptide and enzyme in brain are present in the choroid plexus, subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, striatum and the zona reticulata of the substantia nigra. 34 AI1 can be formed in the brain, but under physiological conditions is rapidly degraded and, therefore, endogenous AI1 is undetectable in rat brain.32 Angiotensin II receptors also exist in the

tTo whom correspondence

should be addressed. ACE, angiotensin converting enzyme; AII, angiotensin II; HEPES, N-2-hydroxyethylpiperazineN’-2-ethanesulphonic acid.

Abbreviations:

brain and periphery, 24 the highest densities in brain being found in the paraventricular nucleus of the hypothalamus, nucleus tractus solitarius and area postrema. The development and utilization of nonpeptide AI1 antagonists has revealed the presence of multiple AI1 receptors in the peripheral nervous system. 6,8,38At a conference of the American Heart Association it was agreed to designate these subtypes AT, and AT, receptors! Receptors in liver and adrenal gland are of the AT, type and are sensitive to the non-peptide antagonist losartan at nanomolar concentrations. In contrast, receptors in the adrenal medulla and uterus are of the AT, type and are blocked by nanomolar concentrations of the nonpeptide antagonist WL-19.6,‘3 Mapping studies suggest the presence of both receptor subtypes in the brain. Thus, AT, receptors are found in high densities in the nucleus tractus solitarius, area postrema, paraventricular nucleus of the hypothalamus and medial preoptic area, whereas AT, sites are

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most dense in the locus coeruleus, septum and thalamic areas.‘6.29,37A mixed population of AII receptors exists in the superior colliculus and septum.‘6,29 Recent evidence has suggested a functional interaction between brain an~iotens~n mechanisms and dopamine neurons. Thus, AI1 administered intracerebroventricularly (i.c.v.) increased exploratory behaviour in rats and this effect was potentiated by the dopamine uptake blocker, nomifensine, and antagonized by the dopamine receptor antagonist, haloperidol.” Furthermore, AH enhanced stereotypy induced by the dopamine receptor agonist apomorphine, and this effect was blocked by the peptide AI1 receptor antagonist, saralasin.” Similarly, AI1 increased amphetamine-induced stereotypy in rats.3 AI1 has also been suggested to interact with dopaminergic mechanisms involved in learning and memory. Thus, AII injected i.c.v. immediately after training improved retention in active avoidance tasks. The dopamine receptor agonist apomorphine facilitated this effect,” whereas the dopamine antagonist, halope~dol blocked the retention facilitating effects of AII.‘8~39There is also biochemical evidence for an interaction between brain angiotensin and dopamine mechanisms. Thus, AI1 injected i.c.v. increased the levels of the dopamine metabohte dihydroxyphenylacetic acid in the hippocampus.’ Since AI1 has been shown to enhance dopaminergic behaviour (see above) it appeared possible that blockade of AI1 function might produce the opposite effect. In order to test this hypothesis we examined the effects of ACE inhibition on dopamine-mediated behavioural responses. The effects of two ACE inhibitors, captopril and enalapril, on the behavioural syndrome induced by the prototypical dopamine agonist apomorphine were assessed. At low doses, apomorphine induces a syndrome of yawning, immobility and sexual arousal as a result of activation of dopamine autoreceptors.25,‘3 In contrast, high doses of apomorphine induce stereotyped locomotion, sniffing, licking and gnawing due to postsynaptic dopamine receptor activation.‘5 In the present study we compared the effects of ACE inhibitors on apomorphine-induced stereotypy to those of the classical neuroleptic, haloperidol. Furthermore, in order to determine whether the observed behavioural effects were due to peripheral or central actions of the ACE inhibitors, dose-response curves were established for the inhibition of ACE in lung and striatum by enalapril and compared to the doses that were active in the apomorphine model. EXPERIMENTAL

PROCEDURES

Animals Male Sprague-Dawley rats, obtained from Bantin and Kingman, Hull, weighing i80-220g were used. Prior to testing they were housed in groups of six, in plastic cages, with standard chow pellets and tap water constantly available. The rats were maintained on a 07.00-19.00 h light cycle at a constant temperature of 22 i: 2°C.

In the first experiment the effect of the ACE inhibitor captopril on apomorphine-induced behaviour was compared with that of haloperidol. Rats were allowed to habituate to Perspex observation boxes (20.5 x 30.5 x 30 cm) with grid floors for 4.5 min and injected with captopril (10 mg/kg iv.), haloperidol (0.2 mg/kg i.p.) or 0.9% saline (I ml/kg i.v. or i.p. as appropriate). The animals were returned to the observation boxes for 50 min (captopril) or 20 min (haloperidol) and injected with apomorphine (0.03,0.3, I or 3 mg/kg s.c.) or vehicle (0.5 mgjml ascorbate in saline). Six rats received each combination of drugs. The rats were observed for a period of 30 min (starting immediately after the second injection). The duration and frequency of cage-crossing, penile grooming, vacuous mouth movements, yawning, rearing, snifFmg, immobility, and licking/gnawing were recorded using a keypad linked to a BBC microcomputer. In the second experiment, dose-response curves for the effects of enalapril and captopril on apomorphine-induced stereotypy were established. Rats were allowed to habituate to observation boxes for 45 min and injected with 1, 3, 10 or 30mg/kg captopril i.v. or 1, 3, 10, 30, or 100 mg/kg enalapril i.v. or s.c., or saline vehicle. The animals were returned to the boxes for SOmin and then injected with 1mg/kg a~omorphine or vehicle S.C. Twelve rats received each combination of drug. The duration of licking and gnawing (considered separately in this experiment as it was apparent in the first experiment that the principal effect was on gnawing), and the frequency of cage crosses were recorded for 10 min (as the most pronounced stereotypy was observed lo-20min after apomorphine in the first experiment), beginning 10 min after the second injection, as described above.

Rats were allowed to habituate to observation boxes for 45 min and injected with 1, 3, 10 or 30mg/kg enalapril i.v. or saline vehicle. The animals were returned to boxes for 50min and injected with I mg/kg apomorphine or vehicle S.C. Twenty minutes after the second injection (the time of peak behavioural responses), rats were killed by decapitation and samples of lung and striatum removed for determination of ACE inhibition (using the method of Ryan et ai.‘“). Tissues were homogenized in HEPES buffer (50 mM HEPES: 50 mM NaCl: 500 mM NaSO,: aH 7.4: iung 100 volumes, striatum 2O’volumes) and an$sed for ACE inhibition following incubation with a radiolabelled substrate. One-hundred-microlitre aliquots were incubated with 1.2 Ci/ml~‘4Clhippuryl-L-histidine-L-l~ucine 5Ofik __ (specific activity 3 mCi/m~oi) for 1Ii at room temperature. Non-specific formation of f’4Clhiuouric acid was determined from samples incubated Gith 50,l of 1pM lisinopril. The reaction was terminated with 0.2ml 1 N HCl and the [‘Qhippuric acid extracted with 2 ml ethylacetate. Counts were estimated with a program corrected for quench and background and the results expressed as percentage ACE inhibition. Drugs

Apomorphine hydrochloride (Sigma) was dissolved in 0.9% saline containing 0.5 mg/ml ascorbate and injected S.C. Haloperidol (obtained as Haldol ampoules, Janssen Pharmaceuticals, Oxford) was diluted to the required concentration in 0.9% saline, and injected i.p. Enalapril maieate (Merck Sharp and Dohme, Rahway, U.S.A.) and captoprii (Sigma) were dissolved in saline, and the pH brought back to 7.4 using 1 M NaOH and injected i.v. or S.C. All drugs were injected in a volume of 1 ml/kg body weight. Doses refer to the respective salt (apomorphine and enalapril) or base (halo~ridol and captopril).

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mouth movements and potentiated the duration of immobility induced by 0.3 mg/kg apomorphine (data not shown). Captopril and haloperidol had no significant effect on sniffing or rearing induced by 1 mg/kg of apomorphine (see Fig. 2). However, licking/ gnawing induced by 1 mg/kg apomorphine was blocked by captopril (F(l,25) = 19.67, P < 0.0005) and haloperidol (F(1,lO) = 906.72, P < 0.00001) [see Fig. 21. In addition, captopril enhanced locomotion in apomo~hine treated rats (F(3,39) = 8.53, P -C0.001) [see Fig. 21.

Data were analysed by ANOVA followed by posr hoc Newman-Keuls or Tukey tests. Correlations between behavioural and biochemical data were calculated using the Spearman test. RESULTS

Effects of captopril induced behaviour

and haloperidol on apomorphine-

Low doses of apomo~hine (0.03.-0.3 mg/kg) induced penile grooming (F(3,25) = 3.32, P < 0.05), vacuous mouth movements (F(3,25) = 9.91, P < 0.0002), yawning (F(3,25) = 6.83, P < 0.002) and immobility (F(3,25) = 142.98, P < 0.0001) and suppressed locomotor activity (F(3,25) = 7.93, P < 0.001) and sniffing (F(3,25) = 142.98, P < 0.0~1). Higher doses of apomorphine (0.3-3 mg/kg) increased sniffing (F(3,25) = 142.98, P < 0.0001) and induced licking and gnawing (F(3,25) = 50.12, P < 0.0001). These high doses of apomorphine suppressed rearing, locomotor activity, penile grooming, yawning and immobility (see Fig. 1). Captoprii had no effect on behaviour induced by low doses of apomorphine. However, haloperidol blocked yawning, penile grooming, and vacuous

Dose-response curves for inhibition of apomorphineinduced behaviour by the angiotensin converting enzyme inhibitors captopril and enalapril

The gnawing response induced by 1 mg/kg apomorphine was blocked by both of the ACE inhibitors. Thus, apomorphine-induced gnawing was blocked by 10 mg/kg captopril (F(3,25) = 42.9, P < 0.01) injected i.v., replicating the effect observed in the first study, but not by doses of 1, 3, and 30 mg/kg. Captopril also tended to increase the licking response but this effect did not achieve statistical significance. It is possible that the decrease in gnawing induced by captopril may be partially accounted for by a concomitant increase in licking. 90

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Fig. I. Effect of apomorphine on the frequency of yawning and locomotion (cage crossing), and the duration of vacuous mouth movements, penile grooming, immobility, sniffing, rearing and licking/gnawing. The data are mean (+S.E.) of six rats per group. Significant differences between drug treated groups and controls were determined by ANOVA and Tukey test (*P -c 0.05).

R. J. A. BANKSet al.

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Fig. 2. Comparative effects of 10 mg/kg captopril injected i.v. (upper panel) and 0.2 mg/kg haloperidol injected i.p. (lower panel) on the frequency of locomotor activity and the duration of sniffing, rearing and licking/gnawing induced by 1 mg/kg apomorphine injected s.c. The data are the mean (+S.E.) of six rats per group. Plain bars are saline/ apomorphine treated rats. Hatched bars are captopril/apomorphine treated rats or haloperidol/apomorphine treated rats. Stars above the vertical bar indicate that this group differs significantly from saline/apomorphine treated rats (P < 0.01).

Similarly, enalapril injected i.v. attenuated apomorphine-induced gnawing at 3 mg/kg (F(1,21)= 3.14, P < 0.01) and 10 mg/kg (F(1,20) = 5.54, P < 0.05), and abolished the response at 30 mg/kg (see Fig. 3). However, when the dose of enalapril was increased to 100 mg/kg i.v. the apomorphine antagonist action disappeared. Enalapril injected s.c. also blocked apomorphine-induced gnawing at doses of 10 mg/kg (F(1,20) = 5.09, e < 0.05) and 30 mg/kg (F(1,21) = 6.38, P < 0.02) [data not shown]. Enalapril had no significant effect on apomorphine-induced licking or locomotor activity at any dose (see Fig. 3). The dose of captopril and enalapril that blocked apomorphine-induced gnawing had no effect on the behaviour of rats not treated with apomorphine (data not shown). Ex vivo penetration of enalapril Enalapril injected i.v. inhibited A C E in both the lung and striatum. All doses of enalapril tested inhibited the lung enzyme to a similar extent ( > 90% inhibition of lung ACE; see Fig. 4). In contrast, striatal A C E inhibition increased dose dependently over the dose range tested, being inhibited by 20% at a dose of 1 mg/kg enalapril and reaching maximal inhibition ( > 90%) at the 30 mg/kg dose (see Fig. 4).

1

Licking gehaviour

Gnawing

Fig. 3. Dose-response curve for blockade of apomorphineinduced gnawing by enalapril injected i.v. The top panel represents rats treated with 3 mg/kg, the middle panel 10 mg/kg i.v., and the lower panel 30 mg/kg enalapril i.v. Note the lack of effect of enalapril on apomorphine-induced licking or locomotion. The data are mean (± S.E.) of 12 rats per group. Plain bars are saline/apomorphine treated rats. Hatched bars are enalapril/apomorphine treated rats. Stars above the vertical bar indicate a significant difference from saline/apomorphine treated rats (P < 0.05). Other details are as in Fig. 2.

100 80 A

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Fig. 4. Dose-response curve for the inhibition of apomorphine-induced gnawing and inhibition of brain (striatal) and peripheral (lung) ACE by enalapril administered i.v. Note the correlation between inhibition of apomorphine-induced gnawing and inhibition of striatal ACE, and lack of correlation with inhibition of lung ACE. The data are the mean of six to 12 rats per group.

Angiotensin-dopamine

There was a significant correlation between percentage inhibition of striatal ACE and percentage inhibition of apomorphine-induced gnawing by enalapril (Spearman r, = 1, n = 4, P < 0.05; see Fig. 4). No correlation was apparent between inhibition of lung ACE and inhibition of apomorphine-induced gnawing by enalapril. DISCUSSION

Apomorphine produced two distinct behavioural syndromes when injected S.C. in rats, the presence of which was dependent on the dose used. Low doses produced immobility, yawning, penile grooming, and chewing mouth movements. In the present study, these behaviours were maximal at 0.3 mg/kg. Higher doses induced stereotyped sniffing, licking and gnawing. The yawning and associated behaviours were probably masked at higher doses of apomorphine by response competition. Apomorphine-induced yawning, penile grooming and chewing mouth movements are thought to be due to selective activation of dopamine autoreceptors and are dependent on the integrity of the nigrostriatal dopamine neurones. Thus, lesions of the striatum or substantia nigra by the selective dopamine neurotoxin 6-hydroxydopamine block the apomorphine syndrome. “.33 Dopamine autoreceptor stimulation is thought to disinhibit striatal cholinergic activity and thereby allow expression of the yawning syndrome.‘* Blockade of autoreceptors with haloperidol prevents the expression of these behaviours. The lack of effect of captopril on apomorphine-induced yawning and associated behaviours suggests that ACE inhibition does not modulate presynaptic dopaminergic function. In contrast, captopril and enalapril dose-dependently blocked oral stereotypy (but spared sniffing) induced by apomorphine, indicating that ACE inhibition can modify certain aspects of postsynaptic dopamine receptor output. These data are consistent with results published in a meeting report suggesting that captopril blocks apomorphine-induced stereo35 The profile of the ACE inhibitors in our tYPY. experiments was similar to that of 0.2mg/kg haloperidol which selectively blocked apomorphineinduced oral stereotypy. These data are consistent with a previous report that a low dose of haloperidol selectively blocked oral stereotypy induced by apamorphine whereas a high dose of the neuroleptic abolished all components of the apomorphine response.23 Captopril at a dose of 10 mg/kg blocked apomorphine-induced suppression of locomotor activity and caused hyperactivity. This effect was not evident at other doses of the drug or with haloperidol. There was also a trend towards increased locomotion in rats treated with enalapril and apomorphine, although in no case did this effect reach statistical significance. It is possible that blockade of focused

interactions

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stereotypy by ACE inhibitors releases locomotor activity which is normally suppressed by response competition. Increasing the dose of captopril to 30mg/kg i.v. and enalapril to lOOmg/kg i.v. caused a disappearance of their apomorphine antagonist action. The explanation for this may be related to the effect of the drugs on other peptide and hormone systems.i4 Enalapril was effective in blocking apomorphineinduced oral stereotypy at a lower dose when administered i.v. than when injected S.C. This may be explained by increased bioavailability of the drug when given iv. and/or the effectiveness of a bolus injection leading to greater penetration of the ACE inhibitor across the blood-brain barrier. N.B. penetration appears to be the limiting factor for inhibition of brain ACE by captopril and enalapril.9 The ex uivo penetration data revealed a significant correlation between inhibition of apomorphine-induced gnawing and inhibition of striatal ACE. In contrast, no correlation was apparent between inhibition ofperipheral(lung) ACE, and the blockade of the gnawing response. These results suggest that blockade of apomorphine-induced gnawing by enalapril and captopril is due to inhibition of brain ACE. The inhibition of apomorphine-induced oral stereotypy and the sparing of the sniffing response by the ACE inhibitors may provide a clue to the neuroanatomical site of the drug interaction. Oral stereotypy induced by dopamine agonists has been thought for many years to be critically dependent on striatal dopaminergic mechanisms.*’ Apomorphineinduced sniffing is less dependent on the striatum*’ and microinjections of N-propyl norapomorphine into areas such as the nucleus accumbens produces a much stronger sniffing response than intrastriatal injections.* Similarly, dopamine agonist-induced locomotion is thought to be controlled predominantly by the nucleus accumbens.20*26~36Recent studies have shown that intense oral stereotypy can be induced by microinjection of amphetamine,*’ dopamine” and N-propyl-norapomorphine’ into the ventrolateral region of the striatum. Therefore, the ventrolateral striatum has been proposed to play a crucial role in the control of oral motor behaviour’0,3’ and hence is a possible site at which ACE inhibition may modify apomorphine-induced gnawing. Alternatively, this interaction may occur downstream of the striatal dopamine receptor at one or more points along its output pathway. Stimulation of postsynaptic dopamine receptors in striatum stimulates the firing of GABAergic neurons that descend to substantia nigra.** This inhibits GABAergic nigrotectal fibres projecting to the superior colliculus.’ The superior colliculus has been strongly implicated in the control of stereotypy as collicular lesions abolish apomorphine-induced oral stereotypy.27 The nigrotectal fibres have a high tonic firing rate and are thought to inhibit the expression of collicular functions such as eye and head orienting in rats.’ Thus, stimulation of

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striatonigral neurons may disinhibit collicular control and result in oral stereotyped behaviour. ACE has been localized throughout the brains~24 and importantly, with regard to the current data is found in neurons of the striatonigral tract.34 Inhibition of ACE in the striatum, the proposed site of initiation of oral stereotypy,*“,*’ would decrease formation of AI1 in this region and could thereby block striatonigral output. The majority of fibres in the striatonigral tract contain either substance P or GABA** and it is possible that AI1 may act as a co-transmitter in these neurons. The development of the selective AI1 receptor antagonists losartan (AT,) and WL-19 (AT,), has led to the identification of two AI1 receptor subtypes in the brain (see Introduction). The receptor subtypes are heterogenously localized throughout the brain

and both are present in the superior colliculus.“‘~“’ Therefore it is possible that the superior colliculus may be another site at which AI1 could act to decrease the oral component of apomorphine-induced stereotypy. Further studies are clearly necessary to characterize the interaction of ACE inhibition with apomorphine-induced oral stereotypy. ACE is not a specific enzyme for AI1 and is involved in the catabolism of other peptides, specifically bradykinins. I4 Thus , it is possible that a substrate other than AI1 may be involved in mediating the interaction observed. Further studies that are currently underway in our laboratory using selective AI1 antagonists may help to resolve this issue and could also be useful in probing the neuronal pathways involved.

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”

(First accepted 27 January 1992; finally accepted 1 December

1993)