European Journal of Pharmacology 620 (2009) 36–41

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European Journal of Pharmacology

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Behavioural Pharmacology

Evaluation of amphetamine-induced hyperlocomotion and catalepsy followinglong-acting risperidone administration in rats

Giorgio Marchese a,b,⁎, Gianluca Casu b, Paola Casti b, Gabriele Pinna Spada b, Luca Pani a,b

a C.N.R., Institute of Biomedical Technology, Sect. Cagliari, Technological Park of Sardinia “Sardegna Ricerche”, Pula, Cagliari, Italyb Pharmaness S.c.a r.l., Technological Park of Sardinia “Sardegna Ricerche”, Pula, Cagliari, Italy

⁎ Corresponding author. C.N.R., Institute of BiomediTechnological Park of Sardinia “Sardegna Ricerche”, BuildinPula, Cagliari, Italy. Tel.: +39 070 9242025; fax: +39 070

E-mail addresses: giorgio.marchese@cnr.it, giorgio.m(G. Marchese).

0014-2999/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.ejphar.2009.07.024

a b s t r a c t

a r t i c l e i n f o

Article history:Received 6 April 2009Received in revised form 6 July 2009Accepted 21 July 2009Available online 5 August 2009

Keywords:AntipsychoticRisperidoneAmphetamineCatalepsyLong-acting

It has been proposed that long-acting risperidone could provide a constant antipsychotic efficacy associatedwith a reduced liability to induce extra-pyramidal symptoms. To ascertain this hypothesis, antagonism ofamphetamine-induced hyperlocomotion and catalepsy were analyzed in rats for a period of 1–6 weeksfollowing long-acting risperidone (20–60 mg/kg) injection. Long-acting risperidone reduced amphetamine-induced hyperlocomotion after 2–5 weeks from drug injection, without producing significant extra-pyramidal symptoms. Following the administration of long-acting risperidone a constant ability toantagonize amphetamine-induced hyperlocomotion was observed during the day, but not when theantipsychotic was chronically administered using a short-acting formulation. The pre-clinical resultsconfirmed that long-acting risperidone may represent an advance in antipsychotic therapy.

© 2009 Elsevier B.V. All rights reserved.

1. Introduction

Recently risperidone has been made available in an injectablelong-acting formulation (long-acting risperidone), that inducessustained drug-plasma levels over a two week period (Eerdekenset al., 2004). The antipsychotic is encapsulated into micrometer-sizedbiodegradable polymeric (poly(D,L-lactide-co-glycolide) micro-spheres which are gradually hydrolyzed following drug injection.The antipsychotic is then released slowly and continuously into theblood over a period of several weeks, avoiding daily fluctuationsbetween peak and trough plasma levels that are characteristic ofshort-acting formulations of risperidone (Mannaert et al., 2005).

It has been proposed that the possibility to reduce drug-plasmafluctuations could provide clinical benefits in terms of constantantipsychotic efficacy and reduction of extra-pyramidal side effects(Ereshefsky and Mannaert, 2005, 2003). Indeed, stable drug-plasmalevels induced by long-acting risperidone could be associated withsmooth fluctuations of dopamine D2 receptor occupancy in the brain(Gefvert et al., 2005; Remington et al., 2006; Medori et al., 2006), soreducing the occurrence of under or over dopamine D2 receptoroccupancy, that might lead to inadequate symptom control or to anincrease of extra-pyramidal symptoms respectively (Kapur et al.,2000).

cal Technology, Sect. Cagliari,g 5, Loc. Piscinamanna, I-090109242206.archese@pharmaness.it

ll rights reserved.

Several clinical trials confirmed that long-acting risperidone is effec-tive in relapse prevention and possesses a reduced liability to induceextra-pyramidal symptoms (Fleischhacker et al., 2003; Kane et al., 2003).Furthermore, a recent clinical study has indicated that an improved anti-psychotic efficacy and tolerability could be observed following the ad-ministration of long-acting risperidone inpatients previously treatedwitha short-acting oral formulation of risperidone (Schmauss et al., 2007).

Although the clinical analyses supported the hypothesis that stablerisperidone plasma levels might represent an improvement inantipsychotic therapy, no evidence has yet been provided to ascertainthat long-acting risperidone is able to induce a constant antipsychoticefficacy during the day: furthermore, it should be verified whethershort-acting formulations of risperidone might possess an increasedpropensity to induce extra-pyramidal symptoms and/or sub-optimalantipsychotic efficacy when compared to long-acting risperidone.

The aimof this study is to evaluate the effects induced by long-actingrisperidone in an animal model of therapeutic efficacy (antagonism ofamphetamine-induced hyperlocomotion), and of extra-pyramidalsymptoms liability (catalepsy) in rats: and to investigate the possibilitythat short- and long-acting formulations of risperidone might producedifferent effects in such behavioural tests during the day.

2. Methods

2.1. Animals and treatment

Male Sprague–Dawley albino rats (Charles River, Como, Italy)weighting 200–250 g were kept on a 12 h/12 h dark/light cycle withfood and tap water available ad libitum.

37G. Marchese et al. / European Journal of Pharmacology 620 (2009) 36–41

In order to characterize the behavioral effects induced by long-acting risperidone in laboratory animals, rats (n=14 for eachexperimental group) were injected (s.c.) with three different doses(20, 40, 60 mg/kg) of commercially available long-acting risperidone(Risperdal Consta, 25 mg/ml) using package needles. The antagonismof amphetamine (0.5 mg/kg, s.c., 1 ml/kg) induced hyper-locomotionand the latency on bar test were determined 1, 2, 3, 4, 5 and 6 weeksafter antipsychotic injection. Risperdal Consta vehicle was injected(s.c.) in control animals.

To evaluate whether long-acting formulation of risperidone mightinduce stable pharmacological effects during the day, the antagonism ofamphetamine-induced hyperlocomotion and the latency on bar testwere analyzed in rats (n=14–15 for each experimental group) at threedifferent time points (10:00 a.m., 14:00 p.m., 20:00 p.m.) after 4 weeksfrom the long-acting risperidone (20, 40, 60 mg/kg, s.c. 1 ml/kg)injection. A chronic treatment (2 weeks, twice a day — 08:00 a.m. and20:00 p.m.) with a short-acting risperidone formulation (risperidonefree-base: 2, 4 and 8 mg/kg, 1 ml/kg dissolved in a solution containingsaline, acetic acid and sodium bicarbonate, pH 6.5) was used as acomparator. Vehicles (Risperdal Consta and/or risperidone short-actingvehicle solution) were administered to laboratory animals for a propercomparability of the results.

On the day of the experiment, laboratory animals received only thefirst injection (i.e. 08:00 a.m.) of short-acting risperidone or vehicle,so that rat behavior could be evaluate after 2 h (10:00 a.m.), 6 h(14:00 pm) and 12 h (20:00 p.m.) period from drug/vehicle injection.

Different rats were used at each time point, and dosages refer tothe free-base form of the drugs. All experimental protocols were instrict accordance with the E.C. regulation for care and use ofexperimental animals (CEE No. 86/609).

2.2. Antagonism of D-amphetamine-induced motor behaviors

Rat locomotor activity was assessed in plexiglas cages (area:25×40 cm2; height: 14 cm) equipped with a grid consisting of8 horizontal infra-red beams (two in the frontal side and 6 in thelateral side of the cage) positioned 4 cm above the floor. Infraredbeam breaks were recorded and analyzed using TSE ActMot/Motilmonitoring apparatus (TSE Systems, Bad Homburg, Germany).

Rats were individually placed in the monitoring apparatus for90 min prior to the recording of locomotor activity. Horizontallocomotor activity was measured in meters covered by each individualrat during a 20 minute test period, beginning 20 min after the injectionof D-amphetamine (Sigma-Aldrich, London, UK) dissolved in saline, andadministered (1 ml/kg) at the dose of 0.5 mg/kg. Vertical activity wasevaluated by counting the number of rearings observed during a 10 minperiod starting 30 min after amphetamine administration.

2.3. Latency on-bar test

Rat forepaws were gently placed over a horizontal bar (diameter0.8 cm) fixed at a height of 10 cm above the working surface. Thelength of time that each rat maintained this position (before removingone or both forepaws from the bar) was recorded by an observer blindto the treatment. Each rat performed three separate consecutive testsand only the longest latency of the three trials was considered forstatistical analysis. No cut-off was applied.

2.4. Statistical analyses

The statistical significance of the effects induced by the com-pounds over-time was evaluated using two-way analysis of variance(ANOVA).When a significant (Pb0.05) interactionwas demonstrated,the Tukey post-hoc test was applied to compare the differentexperimental groups. Statistical analysis was calculated using Sigma-Stat statistical software.

3. Results

3.1. Antagonism of D-amphetamine-induced motor behaviours

The administration of long-acting risperidone produced a dosedependent inhibition of amphetamine-inducedhyperlocomotion in rats(Fig. 1A–B). Two-way ANOVA revealed significant differences depend-ing on the drug administered (horizontal activity Fdrug (4, 390)=79.91,Pb0.01; vertical activity Fdrug (4, 390)=54.94, Pb0.01), on the timeelapsed from drug injection (horizontal activity Ftime (5, 390)=9.55,Pb0.01; vertical activity Ftime (5, 390)=5.84, Pb0.01) as well as whenthe effects of the dosage were analysed in conjunction with the timeelapsed fromdrug injection (horizontal activity Finteract (20, 390)=3.36,Pb0.01; vertical activity Finteract (5, 390)=2. 583, Pb0.05).

A low dosage of long-acting risperidone (20 mg/kg, s.c.) induced asignificant reduction of amphetamine-induced rearing activity after4 weeks from drug injection (Pb0.05 vs. amphetamine+vehicletreated rats), however, this dose of long-acting risperidone did notproduce significant effects on the enhancement of horizontal activityinduced by amphetamine (PN0.05 vs. amphetamine+vehicle treatedrats) (Fig. 1A–B). A significant reduction of amphetamine-inducedhorizontal and vertical activity could be observed after 3 weeks fromlong-acting risperidone 40 mg/kg injection (Pb0.05, vs. amphet-amine+vehicle treated rats) and the pharmacological effects per-sisted until the 4th week (Fig. 1A–B). Long-acting risperidone 60 mg/kg induced an early onset of the antipsychotic-like effect (i.e. 2 weeksafter drug administration) and the statistical analyses indicated thatrats treated with this long-acting risperidone dosage behaveddifferently from amphetamine-injected animals (Pb0.05, Pb0.01)until the 5th week after drug injection (Fig. 1A–B). Significantdifferences could be observed when long-acting risperidone treatedrats were compared with vehicles (vertical and horizontal activityPb0.05, Pb0.01 vs. vehicle treated rats), with the exception of long-acting risperidone (60 mg/kg) treated rats at the 4th week (bothvertical and horizontal activity PN0.05 vs. vehicle treated rats).

When the effects of long-acting risperidone and short actingrisperidone ( or vehicle) on amphetamine induced hyperlocomotionwere analysed during the day, statistical differences could be observeddepending on; the drug injected (horizontal activity Fdrug (7, 324)=26.35, Pb0.01, vertical activity Fdrug (7, 324)=19.55, Pb0.01); the timeelapsed from drug injection (horizontal activity Ftime (2, 324)=19.34,Pb0.01, vertical activity Ftime (2, 324)=19.15, Pb0.01); and when theeffects of the drugs were analysed in conjunction with the time elapsedfrom drug injection, (horizontal activity Finteract (14, 324)=4.382,Pb0.01, vertical activity Finteract (14, 324)=3.154, Pb0.01).

A stable antagonism of amphetamine-induced horizontal andvertical activity could be observed following long-acting risperidoneinjection at the different time points. Conversely, the chronicadministration with short-acting risperidone (2, 4, and 8 mg/kg, s.c.,twice a day) induced pharmacological effects that declined dependingon the time after injection and on the dose administered (Fig. 2A–B).

3.2. Latency on bar test

Administration of long-acting risperidone (20, 40, and 60 mg/kg)did not induce a significant increase in the latency on bar test whencompared with vehicle during the six week period of behaviouralobservation (PN0.05 vs. vehicles treated rats — data not shown).

When the effects of long-acting risperidone and short-actingrisperidone (or vehicle) on rat catalepsywere analysed during the day(Fig. 3) two-way ANOVA statistical analysis indicated that significantdifferences exist depending on; the drug injected (Fdrug (6, 279)=10.06, Pb0.01); on the time elapsed from drug injection (Ftime

(2, 279)=22.04, Pb0.01); and when the effects of the drugs wereanalysed in conjunction with the time elapsed from drug injection(Finteract (12, 279)=7.57, Pb0.01).

Fig. 1. Histograms showing the effect induced by long-acting risperidone (20, 40, and 60 mg/kg, s.c.) or vehicle administration on rat amphetamine-induced horizontal (A) andrearing activity (B). Behavioural testing was carried out 1, 2, 3, 4, 5 and 6 weeks after long-acting risperidone injection (n=14). Statistical analyses were carried out using two-wayANOVA followed by Tukey post-hoc test (*Pb0.05, **Pb0.01 vs. amphetamine+vehicle treated rats).

38 G. Marchese et al. / European Journal of Pharmacology 620 (2009) 36–41

Latencies on bar test resembling those of vehicle treated rats couldalso be observed when the effects of different doses of long-actingrisperidone were analysed during the day (PN0.05 vs. vehicles treatedrats). Conversely, a significant increase of the latency on bar test wasinduced by the short-acting formulation of risperidone (2, 4, and8 mg/kg) after 2 h (10:00 p.m.) from drug injection (Pb0.05, Pb0.01vs. vehicles treated rats) (Fig. 3)

4. Discussion

Clinical pharmacokinetic analyses indicated that the drug releaseof long-acting risperidone starts about 3 weeks after drug injection,providing sustained drug plasma levels approximately until the 7thweek (Eerdekens et al., 2004; Mannaert et al., 2005). This finding

correlated with dopamine D2 receptors occupancy studies (Gefvertet al., 2005), suggesting that the drug should be administered everytwo weeks.

The time course of long-acting risperidone in laboratory animals,based on behavioural analyses, was in line with that described inhumans: long-acting risperidone (40–60 mg/kg) was effective inreducing amphetamine-induced hyper-locomotion after 2–3 weeksfollowing drug injection and this antipsychotic-like effect lasted for atleast 2–3 weeks, thus supporting the use of rodents in the pre-clinicalresearch of long-acting risperidone.

The present study highlights that the time course of long-actingrisperidone mediated effects might differ depending on the doseadministered. Only a transient antagonism of amphetamine-inducedhyperlocomotion was observed in laboratory animals following the

Fig. 2. Histograms showing the antagonism of amphetamine-induced horizontal activity (A) and rearing activity (B) observed during the day (h 10:00 a.m.; h 14:00 p.m., h 20:00p.m.) following chronic exposure to long-acting risperidone, short-acting risperidone or vehicle (n=14–15). Behavioural testing was carried out after 4 weeks from long-actingrisperidone injection (20, 40, 60 mg/kg, s.c.) or following a twoweek sub-chronic treatment with short-acting risperidone (2, 4 and 8 mg/kg, s.c. injected twice a day— 08:00 a.m.and 20:00 p.m.). Statistical analysis was carried out using two-way ANOVA, followed by Tukey post-hoc test (*Pb0.05, **Pb0.01 vs. amphetamine+vehicle treated rats; °Pb0.05,°°Pb0.01 vs. vehicle+vehicle treated rats).

39G. Marchese et al. / European Journal of Pharmacology 620 (2009) 36–41

administration of a low dosage of long-acting risperidone (20 mg/kg),while an anticipated and long-lasting appearance of this pharmaco-logical effect could be observed when higher dosages (40–60 mg/kg, s.c.) of the drug were injected. Based on this evidence it can behypothesized that the frequency of long-acting risperidone adminis-tration might be varied depending on the dosage adopted in drug

therapy. In line with this hypothesis, recent clinical studies haveshown that long-acting risperidone (50 mg) induced sustaineddopamine D2 receptor occupancy and an efficacious relapse controleven when the drug was administered using a once monthly regimen(Gharabawi et al., 2007; Uchida et al., 2008), producing pharmaco-logical effects that were comparable to those induced by biweekly

Fig. 3. Histograms showing the latency on bar test showed by rats (n=14–15) that received a constant exposure to long-acting risperidone (20, 40, and 60 mg/kg, s.c.) or a chronictreatment with short-acting risperidone (2, 4, and 8 mg/kg, s.c. twice a day) or vehicle. Cataleptic scores was evaluated at different time points (h 10:00 a.m.; h 14:00 p.m., h 20:00p.m.) during the day. Behavioural testing was carried out after 4 weeks from long-acting risperidone injection or following a two weeks sub-chronic treatment with short-actingrisperidone. Statistical analysis was carried out using two-way ANOVA followed by Tukey post-hoc test (°Pb0.05, °°Pb0.01 vs. vehicle+vehicle treated rats).

40 G. Marchese et al. / European Journal of Pharmacology 620 (2009) 36–41

injections of long-acting risperidone at 25 mg dosage (Gharabawiet al., 2007).

The analyses of the antagonism of amphetamine-induced hyper-locomotion and of rat catalepsy observed during the day support thehypothesis that long-acting risperidone might induce a constantantipsychotic efficacy associated with a low propensity to induceextrapyramidal symptoms (Eerdekens et al., 2004; Ereshefsky andMannaert, 2005, 2003). These pharmacological properties of the drugmight possibly account for the improved relapse control and drugcompliance observed among patients treated with long-actingrisperidone (Fleischhacker et al., 2005; Simpson et al., 2006; Mariniset al., 2007).

The constant antipsychotic efficacy and the low propensity toinduce extrapyramidal effects of long-acting risperidone are possiblyrelated to the delivery system of the drug, since significant fluctua-tions of amphetamine-induced hyperlocomotion and increasedincidence of extrapyramidal side-effects could be observed when ashort-acting formulation of risperidonewas chronically injected twicea day. Possibly, short acting formulations of risperidone might bemore susceptible to induce under- and/or over-dosage during the daythan long-acting risperidone.

However, it should be noted that even if the doses of risperidoneadopted in the present study reflect a correspondence between thedosages of short and long-acting risperidone formulations used in clinic(Bai et al., 2006, 2007), recent pre-clinical studies have questioned thatdaily antipsychotic administrations might fulfil the criteria to definetherapeutic effectiveness as observed in humans (Kapur et al., 2003).Moreover, further studies are required to fully characterize thepharmacological effects induced by long-acting risperidone in rodents,therefore caution should be taken in extrapolating the present results atclinical level. To this respect, thepresent results indicated that that long-

acting risperidone may turn out to be as interesting as mini-pumpsdelivery in animal models of atypical antipsychotic efficacy.

In conclusion, the behavioural analyses of the present studyindicates that long-acting risperidone induces a stable antagonism ofamphetamine-induced hyperlocomotion in rats during the day whichis associated with a reducedmotor side effect liability, suggesting thatthis drug might represent an improvement in schizophrenia drugtherapy when compared to short-acting formulations of risperidone.

Acknowledgments

The study has been partially supported by an unrestricted grantthat was generously provided by Janssen-Cilag.

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