Behavioural assessment in rats of the antipsychotic potential of the potent dopamine D2 receptor antagonist, (-)eticlopride

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BEHAVIOURAL ASSESSMENT IN RATS OF THE ANTIPSYCHOTIC POTENTIAL THE POTENT DOPAMINE Dz RECEPTOR ANTAGONIST, (-)ETICLOPRIDE FRANCESCA Department

of Biomedical

Sciences,

I_

FERRARI

and DANIELA

Division of Pharmacology, 41100 Modena, Italy Accepted

2 February

OF

GIULIANI

University

of Modena,

via G. Campi 287,

1995

The effects of the selective D2 DA receptor antagonist, (-)eticlopride, a drug belonging to the benzamide class, were investigated on the Dz DA agonist SND 919- and CQP 201-403induced stereotyped behaviour and on CQP 201-403-induced shaking, in rats, and on isolation-induced aggression, in mice. (-)Eticlopride was also tested over a wide dose range (5-1200 ,ug kg-‘, s.c.) for sedative and cataleptic activity, in rats. For comparison, some experiments were performed with (-)sulpiride (10 and 40 mg kg-‘, s.c.) The data obtained show that (-)eticlopride differs from (-)sulpiride and potentially modifies animal behaviour, whether spontaneous or induced; moreover, they suggest a potential clinical use for this neuroleptic in the management of psychotic states. KEY WORDS: eticlopride,

aggression,

stereotyped

behaviour,

INTRODUCTION Although there is ample evidence that several transmitters and neuroregulators may take part in the biochemical defects underlying psychoses [l], it is generally recognized that dopamine (DA) plays a key role in these disturbances; inhibition of DA activity by neuroleptics therefore remains the fundamental mode of action of antipsychotics known so far [2]. Accordingly, most preclinical investigations into the mechanism of action of new antipsychotic agents focus attention on the interaction of these drugs with the DA function. In recent years, a number of substituted benzamides have been developed as new antipsychotic agents [3-51 and several of these compounds have been described as being more potent than sulpiride, through belonging to the same class, in their ability to block certain dopamine DA agonistinduced effects [6]. In vivo and in vitro binding studies have shown that the benzamide drug, eticlopride, readily crosses the blood-brain barrier [6,7], unlike sulpiride, and binds with high selectivity to those DA receptors not linked to the adenylcyclase and labelled Dz receptors [8,9]. Subsequently, some behavioural experiments in our laboratory confirmed that high potency of this drug as a DA D2 receptor blocker [lo], since a dose of 10 ,ug kg-’ was able to counteract the stimulation of penile erection and yawning as well as the ‘ejaculatio praecox’ typically

Correspondence to: F. Ferrari, Department of Biomedical Sciences, Division of Pharmacology, University of Modena, Via G. Campi 287, I-41100 Modena MO, Italy. 1043-6618/95/050261-07/$08.00/O

DA Dz receptors,

neuroleptics.

induced in rats by the selective DA D2 agonist, SND 919 [ 1 l-141. In the present study, the action of (-)eticlopride on central DA receptor-mediated behavioural effects in rodents has been further investigated using test procedures that are considered to have predictive value for antipsychotic therapeutic activity. Since, as is known, neuroleptics often induce, as side effects, sedation and extrapyramidal symptoms [ 1.51, and since the latter are felt to be represented by catalepsy in rats [2, 161, preliminary tests evaluated sedation and catalepsy in these animals after (-)eticlopride over a wide dose range. For comparison, some experiments were also performed using (-)sulpiride.

MATERIALS

AND METHODS

Animals The subjects were male Long Evans rats and male albino Swiss mice (Morini, S. Polo d’Enza, Reggio Emilia, Italy) weighing 230-250 and 25-30 g, respectively, at the outset. They were housed in groups of six with food and water ad libitum and on a 12-h light cycle, from 07:OO to 19:00 hrs., for at least 1 week prior to the start of the tests. Behavioural procedures All the tests were performed between 09:OO and 13:00 hrs in a soundproof, airconditioned room (temperature 20+2”C), and the animals were observed by experimenters unaware of the experimental design. Each animal was used only once and the controls were 0 1995 The Italian Pharmacological

Society

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262

handled similarly to the treated for each treatment group). together during the tests were the housed groups and received

ones (no less than five The animals grouped selected a random from the same treatment.

Experiments in rats Twenty-five minutes after Evaluation of sedation (-)eticlopride and 40 min after (-)sulpiride, the rats were transferred in groups of 3-4 to glass observation cages (40x30~34 cm) where they were continuously observed for 40 min. Sedation was evaluated as elsewhere [ 10, 131. In brief, every 5 min, starting immediately in the test period, each animal was observed for 30 s and rated on a scale of O-2, where: O=absent; l=immobility of the animal, for at least 25 s, with open eyes; 2=immobility of the animal, for at least 2.5 s, with closed eyes. The sedation value for each rat was the sum of all the scores attributed to the animal during the test period. This rating scale, although simple, gives data in line with those obtained from actimeters; also, it affords a more precise evaluation of behaviour since it enables the observer to record phenomena that cannot be detected automatically, such as open or closed eyes, and which probably indicate quite different physiological states. Evaluation of mator activity The rats were S.C. injected with saline, (-)eticlopride or (-)sulpiride and, after 30 min, placed in pairs in special motility cages (Cibertec, Spain) where their motor activity was automatically recorded for 30 min. The apparatus records any movement made by the animals in the cage and provides the data in the form of a printout, each movement corresponding to a single count. Evaluation of catalepsy Thirty, 60 and 120 min after treatments each rat was placed with its front paws over a 10 cm high horizontal bar. The intensity of catalepsy was measured by the length of time it took the animal to move both forelegs to the table. A time of 20 s was considered maximum catalepsy. Evaluation of SND 919- and C&P 201-403-induced stereotyped be,haviour (SB) and C&P 201-403induced shaking behaviour Twenty-five minutes after (-)eticlopride and 40 min after (-)sulpiride the rats were treated with the DA agonists and immediately transferred in groups of three or four to glass observation cages (40~30x34 cm) where they were continuously observed for 30 min. SB was evaluated as elsewhere [ 131: in brief, every 5 min, each animal was observed for 30 s and rated on a scale of O-2, where: O=absent; l=low stereotyped behaviour sniffing; 2=high as intermittent or continuous stereotyped behaviour as continuous sniffing and/or intermittent or continuous licking and biting; all for at least 25 s. Each episode of shaking, as a rapid rotational movement of the head, neck and/or entire body around

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Fig. 1.

Effect of (-)eticlopride and (-)sulpiride on sedation and catalepsy in male rats. Each histogram represents the meat&EM of the score of sedation (a) and of the cataleptic time (b) of the animals for each treatment group: Saline (Sal.)=S; (-)eticlopride (E) 10=8; E 20=6; E 40=6; E 80=6; E 120=6; E1200=8; (-)sulpiride (S) 10=6; S 40=6. ?? , Sal; a, E 120 pg; 0, E 1200 pg; S 40 mg. *Significantly different from Sal. (Kruskal Wallis followed by Mann-Whitney Utest.)

the spinal axis, was scored for each animal presenting the phenomenon during the test period. SB and shaking values were represented by the sum of all the scores attributed to the animal during the test for the signs in question. Experiments in mice Evaluation of isolation-induced aggression The mice were isolated for 30 days in individual cages (24 ~14x15 cm) with no visual contact with other animals, the cages being situated in a quiet, air conditioned room with a natural light-dark cycle. Their aggression was measured according to Valzelli [17], with some modifications. In brief, at the end of the isolation period, and after the treatments with saline or (-)eticlopride, an ‘intruder’ (previously housed in a group) was introduced into the cage and the general behaviour as well as the fighting episodes exhibited by the isolated mice were monitored for 5 min. The parameters considered were the following: (1) latency to the first attack, as the time elapsing from the introduction of the intruder to the first attack by the isolated mouse; (2) aggression, as the score attributed to each mouse on a scale from 0 to 4,

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si

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si

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E 20

E 40

E 60 yg kg-l, S.C.

S’lO

S’lO

S’lO

S’lO

S’lO mgkg-‘, i.p.

Fig. 2. Effect of (-)eticlopride on stereotyped behaviour (SB) induced in rats by SND 919. The test was performed immediately after the injection of SND 919 (S) at 1 mg kg-’ (a) and 10 mg kg-’ (b). Saline (Sal) and (-)eticlopride (E) were administered 25 min before the DA agonist. Each histogram is the meanfsEM of the values of the animals for each treatment group: six rats for all groups apart from Sal+S 10=8. *Significantly different from respective controls (Sal+S 1 and Sal+S 10) (Kruskal-Wallis followed by Mann-Whitney U-test.)

Drugs and treatments

(Boehringer Ingelheim, Ingelheim am Rhein, Germany) and CQP 201-403 (Sandoz, Basel, Switzerland). All the drugs were freshly dissolved in distilled water apart from (-)sulpiride, which was dissolved in a drop of HCL, and diluted in distilled water, its pH being adjusted to 7.4 with NAOH; all were administered at 1 ml kg-‘. The routes of administration were subcutaneous (KC.) for (-)eticlopride and (-)sulpiride and intraperitoneal (i.p.) for the DA agonists. The dose-rates, which are reported in the figures, and the pretreatment times were chosen on the basis of previous experiments.

The following substances were used: (-)eticlopride (RBI, USA), (-)sulpiride (Ravizza, Italy), SND 919

Statistical

where: O=no interest in the intruder; l=interest in the intruder; 2=adoption of fighting stance and occasional attacks on the intruder (no more than three or four during the observation period); 3=powerful attacks (no more that 10 or 11 during the observation period); 4=fierce wrestling, with savage biting hard enough to draw blood, the attacks covering practically the entire period of observation. The same animals were tested twice for their behaviour, 20 min (first test) and 60 min (second test) after the treatments with (-)eticlopride or saline.

Effect of (-)eticlopride activity Treatment + Sal.

Eti. 10 pg kg-’ Eti. 20 pg kg-’ Eti. 40 pugkg-’ Eti. 80 pg kg-’ Sul. 10 mg kg-’ Sul. 40 mg kg-’

Table I and (-)sulpiride in male rats.

on motor

Motor activity (counts)

6950&303 6397+290 5195+180* 4530+210* 2280t114* 7120+315 5980+370

Saline (Sal.), (-)eticlopride (Eti.) and (-)sulpiride (Sul.) were S.C. injected 30 min before the experiments. Each value for motor activity is the mean+sEM of three experiments. *Significantly different from Sal. (ANOVA followed by SNK test).

evaluation

Data are expressed as means (+SEM) of the values for the animals, whose number is presented in the legends of the figures, and were analysed using Kruskal Wallis followed by Mann-Whitney U-test and ANOVA followed by Student-Newman-Keuls test (SNK test), where appropriate, with the level of significance set at PcO.05.

RESULTS

Experiments

in rats

Figure la shows that, unlike (-)sulpiride at 10 and 40 mg kg-‘, (-)eticlopride enhanced rat sedation in a dose-dependent manner from 20 to 120 ,ug kg-’ during the 40-min observation period. However, the animals appeared to be sensitive to external stimuli at all doses, and even at the highest dose sedation was not

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Fig. 3.

Effect of (-)eticlopride and (-)sulpiride on stereotyped behaviour (a and c) and shaking (b and d) induced by rats by CQP 201-403. The test was performed immediately after the injection of CQP 201-403 (CQP) at 500 pg kg-‘; saline (Sal) and (-)eticlopride (E) were ‘admjnistered 25 min before the DA agonist, while (-)sulpiride (S) 40 min before. Each histogram is the mean+servr of the values of the animals for each treatment group: eight rats for all groups apart from Sal+CQP 500 (a)=l6, S lO+CQP 500=6 and S 4O+CQP 500=6. *Significantly different from Sal+CQP 500 (Kruskal-Wallis followed by Mann-Whitney U-test). tsignificantly different from Sal+CQP 500 (ANOVA followed by SNK test).

accompanied by a cataleptic state, as demonstrated by the fact that this sign, recorded at 30, 60 and 120 min after the treatments with (-)eticlopride (120 and 1200 ,ug kg-‘) was always quite similar to that of the controls. occurred for (-)sulpiride The same (40 mg kg-‘) (Fig. lb). Table I reports the motility counts automatically recorded after treatments with (-)eticlopride (10, 20, 40 and 80 ,ug kg-‘) and (-)sulpiride (10 and 40 mg kg-‘). In accordance with sedation experiments, (-)eticlopride dose-dependently diminished motor activity from 20 ,ug kg-’ upwards, while (-)sulpiride was ineffective with respect to controls. When (-)ecticlopride was administered before the selective DA Dz agonist, SND 919, the behavioural effects observed were quite similar to those already obtained with Wistar rats [12, 131, namely: in our saline-pretreated animals, SND 919 at 1 mg kg-’ (Fig. 2a) elicited a certain degree of SB, mainly consisting of sniffing, which was potently antagonized by (-)eticlopride at 10 and 20 pg kg-‘. A higher SB (with sniffing and licking episodes), induced by SND 919 at 10 mg kg-’ (Fig. 2b), was significantly counteracted by (-)eticlopride at 20 and 40 ,ug kg-i and practically abolished at 60 ,ug kg-‘. The ability of (-)eticlopride to antagonize SB was

confirmed in a second series of experiments using a DA agonist belonging to the ergot derivative class (CQP 201-403) [18, 191 (Fig. 3a). In fact, (-)eticlopride (20, 40 and 60 ,ug kg-‘) dosedependently antagonized SB induced by CQP 201-403 at 500 pug kg-‘. However, shaking behaviour, which was visible in the rats injected with CQP 201-403 at the same dose (Fig. 3b), was only significantly reduced by pretreatment with (-)eticlopride at 120 y g kg-i. (-)Sulpiride (10 and 40 mg kg-‘) comparatively tested, did not modify CQP 201-403induced SB (Fig. 3c) and, at the higher dose, potentiated shaking (Fig. 3d).

Experiments

in mice

In the isolation-induced administered

at

fighting

test, (-)eticlopride,

20, 80 and 120 ,ug kg-‘, 20 min before

the first test (Fig. 4), significantly reduced the aggression score only at the highest dose, although a tendency to increase the latency to the first attack was observed. When the test was repeated in the same animals 60 min after the treatments (Fig. 4, second test) the aggression score of the isolated mice was reduced by (-)eticlopride at 80 and abolished at

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Effect of (-)eticlopride on isolation-induced aggression in mice. Saline (Sal) and (-)eticlopride (E) were S.C. injected 20 min (first test, upper panels) and 60 min (second test, lower panels) before the observation period (5 min). For details see Methods. Each histogram represents the mean+sEM of the latency to the first attack by the isolated mice and of the score of aggression of the animals for each treatment group: Sal=12; E 20=10; E 80=10; E 120=6. *Significantly different from Sal (Kruskal Wallis followed by Mann Whitney U-test). TSignificantly different from Sal (ANOVA followed by SNK test).

120 pg kg-‘, doses that also increased the first attack.

the latency

to

DISCUSSION Although it is extremely doubtful whether human mental diseases can be reproduced in animals, many psychiatrically-useful compounds have been discovered by means of animal behavioural screening tests. Pharmacological manipulations of DA neurotransmission alter both the aggressive [20,21] and motor components [22] of rat behaviour and antagonism of DA agonist-induced SB and isolationinduced aggression are two procedures sensitive to all known clinically-useful agents [23,24]. Overall, our results show that, from a behavioural point of view, (-)eticlopride, is extremely active since, at very low doses, it potently counteracted SND 919- and CQP 201-403-induced SB in rats and was also able to diminish the aggressive behaviour of isolated mice. As regards the antiaggression activity of (-)eticlopride, although it is probable that it is not a specific effect, since inhibition of aggression was obtained at sedative doses, the possibility of its being ascribable to a general motor impairment produced by the drug be excluded (see also catalepsy experiments). (-)Eticlopride, on the other hand, did not seem to be very active in suppressing CQP 201-403-induced shaking [18, 191. The documented high selectivity of

(-)eticlopride for DA receptors [6,7] is likely to be responsible for the phenomenon, since shaking has been attributed to serotonin receptors [ 181. (-)Eticlopride differed from (-)sulpiride, the bestknown benzamide derivative, which has a relatively low activity owing to its poor penetration of the blood-brain barrier and low lipid solubility [7]. It has been reported that in animal models, (-)sulpiride only exerts some of the effects of the more typical neuroleptics [3,25]; for example, it is unable to antagonize apomorphine-induced SB [26] and it actually exacerbates this sign when elicited by amphetamine [27]. In the present study, (-)sulpiride completely failed to antagonize CQP 201-403-induced SB and at 40 mg kg-’ potentiated the shakings elicited by the ergot-derivatives. Interestingly, (-)sulpiride has already been seen to exacerbate imidazoleinduced shaking, unlike haloperidol, which potentially reduces it [28]. Our behavioural findings, therefore, are in good agreement with binding studies in vitro and in vivo, which have demonstrated that [3H]eticlopride binds with very high affinity and selectivity to DA or neuroleptic receptors in DA-rich brain areas, as distinct from [3H]sulpiride, whose non-specific binding is marked [6]. Studies on DA-receptor binding in brain membrane preparations have shown a very close correlation between the ability of antipsychotic drugs to inhibit the [3H]DA and [3H]haloperidol and their clinical potency [29]. Another behavioural result

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points to a qualitative difference between (-)eticlopride and (-)sulpiride is their influence on animal motor activity. Only (-)eticlopride dosedependently induced sedation; it has also been reported that (-)sulpiride can enhance locomotion in rodents [30] and that it increases cocaine-induced hyperactivity, which has been related to the activation of brain DA systems [31]; accordingly, several clinical studies have remarked on the low incidence of sedative-side effects after the drug [ 151. An activity shared by the two benzamides is their inability to provoke catalepsy [3, 4, 321, which is felt to reflect some of the Parkinson-like side effects seen in patients treated with neuroleptics [16]. It should, however, be pointed out that, while some clinical studies report low extrapyramidal symptoms after (-)sulpiride [ 151, others report an incidence quite similar to that recorded after haloperidol, which, as is known, is a potent inducer of catalepsy in the rat [25, 321. -.In conclusion, our data show that (-)eticlopride actively antagonizes DA-mediated behaviour and suggest its potential therapeutic efficacy in the treatment of human psychosis. Although Kebabian and Came have classified DA receptors into two types, based on their functional linkage to the adenylcyclase, and while it has been proposed that benzamides may behave as selective Dz receptor antagonists [6-91, some authors have presented data suggesting the existence of more than two types of DA receptor [22,23]. The lack of a clear correlation between the blockade of D2 receptors and antipsychotic activity or induction of extrapyramidal syndromes [25] indicates that the precise neurochemical mechanisms of benzamides are far from being completely understood. In view of the considerable interest in this class of drugs [3,4,6] it is possible that future studies on (-)eticlopride, which differs from other benzamides by virtue of its powerful effects, will afford insight into the DA receptor subtypes involved in the neuropharmacological and neurochemical effects of antipsychotic agents. which

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ACKNOWLEDGEMENTS 17.

This work was supported in part by grants from Minister0 della Pubblica Istruzione (60%) and CNR.

REFERENCES 1. Berger PA, Elliott GR, Barchas JD. Neuroregulators and schizophrenia. In: Lipton MA, DiMascio A, Killam KF eds. Psychopharmacology: a generation ef progress. Raven Press, New York, 1978: 1070-82. 2. Carlsson A. Mechanism of action of neuroleptic drugs. In: Lipton MA, DiMascio A, Killam KF eds.

18.

19.

20.

21.

Psychophurmulogy: a generation of progress. Raven Press, New York, 1978: 1057-70. Jenner P, Marsden CD. Substituted benzamide drugs as selective neuroleptic agents. Neuropharmacology 1981; 20: 1285-93. Ogren SO, Hall H, Kohler Ch, Magnusson 0, Florvall L. Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain. Eur J Pharmucol 1984; 102: 459-74. De Paulis T, Hall H, Ogren SO, Wagner A, Stensand B, Csoregh I. Synthesis, crystal structure and antidopaminergic properties of eticlopride (FLB 131). Eur J Med Chem 1985; 20: 273-9. Hall H, Kohler C, Gawell L. Some in vitro receptor binding properties of [3H] eticlopride, a novel substituted benzamide, selective for dopamine D2 receptors in the rat brain. Eur J Phurmucol 1985; 111: 191-9. Kohler C, Hall H, Gawell L. Regional in vivo binding of the substituted benzamide [3H] eticlopride in the rat brain: evidence for selective labelling of dopamine receptors. Eur J Pharmacol 1986; 120: 217-26. Trabucchi M, Longoni R, Fresia P, Spano PF. Sulpiride: a study of the effects of dopamine receptors in rat neostriatum and limbic forebrain. Life Sci 1975; 17: 1551-6. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature 1979; 277: 93-6. Ferrari F, Giuliani D. The selective D2 dopamine the receptor antagonist eticlopride counteracts ejaculatio praecox induced by the selective Dz dopamine agonist SND 919 in the rat. Life Sci 1994; 55: 1155-62. Matsumoto S, Yamada K, Domae M, Shirakawa K, Furukawa T. Occurrence of yawning and decrease of prolacting levels via stimulation of dopamine D2 receptors after administration of SND 919 in rats. Nuunyn-Schmied Arch Phurmucol 1989; 340: 21-5. Ferrari F, Pelloni F, Giuliani D. Behavioural evidence that different neurochemical mechanisms underly stretching-yawning and penile erection induced in male rats by SND 919, a new selective Dz dopamine receptor agonist. Pyschopharmacology 1993; 113: 172-6. Ferrari F, Giuliani D. Influence of idazoxan on the dopamine Dz receptor agonist-induced behavioural effects in rats. Eur J Pharmucol 1993; 250: 51-7. Ferrari F, Giuliani D. Sexual attraction and copulation in male rats: effects of the dopamine agonist SND 919. Phurmacol Biochem Behav 1994 (in press). Peselow ER, Stanley M. Clinical trials of benzamides in psychiatry. In: Rotrosen J, Stanley M, eds. Benzumides: pharmacology neurobiology and clinical aspects. Raven Press, New York, 1982: 163-94. Fielding S, La1 H. Preclinical neuropharmacology of neuroleptics. In: Fielding S, La1 H. eds. Neuroleptics, Futura Press, New York 1974: 64-65. Valzelli L. Aggressive behaviour induced by isolation. In: Garattini S, Sigg EB, eds. Aggressive behuviour. Amsterdam: Excerpta Medica, 1969: 70-6. Fluckiger E, Briner U, Clark B, Closse A, Enz A, Gull P, Hofmann A, Markstein R, Tolcsvai L, Wagner HR. Pharmacodyne profile of CQP 201-403 a novel 8amino-ergoline. Experientia 1988; 44: 43 1-6. Ferrari F. Behavioural effects induced in male rats by CQP 201-403 and CQ-32 084, two novel ergotderivatives. Phurmacol. (Life Sci. Adv.) 1990; 9: 21-6. Baggio G, Ferrari F. Role of brain dopaminergic mechanisms in rodent aggressive behavior: influence of fN-n-propyl-norapomorphine on three experimental models. Psychopharmacology 1980; 70: 63-8. Miczek KA, Weerts E, Haney M, Tidey J.

Pharmacological Research, Vol. 31, No. 5,1995

22. 23.

24.

25.

26.

27.

Neurobiological mechanisms controlling aggression: preclinical developments for pharmacotherapeutic interventions. Neuvosci Biobehav Rev 1994; 18: 97-l 10. Seeman P. Brain dopamine receptors. Phavmacol Rev 1980; 32: 229-313. Janssen PAJ, Jageneau AH, Niemegeers CJE. Effects of various drugs on isolation-induced fighting behavior in male mice. J Pharmacol Exp Ther 1960; 129: 471-5. Cook L, Tam SW, Rohrbach KW. DuP 734 [l(cyclopropylmethyl)-4-(2’(4”-fluorphenyl)-2’oxoethyl)piperidine HBr], a potential antipsychotic agent: preclinical behavioral effects. J Pharmacol Exp Ther 1992; 263: 1159-66. Worms P. Behavioral pharmacology of the benzamides as compared to standard neuroleptics. In: Rotrosen .I, Stanley M, eds. Benzamides: pharmacology neurobiology and clinical aspects. Raven Press, New York: 1982: 7-16. Costa11 B, Naylor RJ. Detection of the neuroleptic sulpiride and thioridazine. properties of clozapine, Psychopharmacologia 197.5; 43: 69-74. Robertson A, Macdonald C. Opposite effects of sulpiride and metoclopramide on amphetamine-induced stereotypy. Eur J Pharmacol 1985; 109: 81-9.

267 28. Ferrari F, Ferrarti P, Baggio G, Mangiafico V. Antagonism of imidazole-induced shaking in the rat: a behavioral tool predictive of antidyskinetic activity. Arch Int Pharmacodyn Therap 1986; 283: 209-21. 29. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-3. 30. Costa11 B, Domency AM, Naylor RJ. Stimulation of rat spontaneous locomotion by low doses of haloperidol and (-)sulpiride: importance of animal selection and measurement technique. Eur J Pharmacol 1983; 90: 307-14. 31. Cabib S, Castellano C, Cestari V, Filibeck U, PuglisiAllegra S. D, and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the 1991; 105: 335-9. mouse. Psychopharmacology Costa11 B, Funderburk WH, Leonard CA, Naylor RJ. Assessment of the neuroleptic potential of some novel benzamide, butyrophenone, phenotiazine and indole derivatives. J Pharm Pharmacol 1978; 30: 771-8. ML, 33. Sokoloff P, Giros B, Martres MP, Bouthenet Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 1990; 347: 146-51.