Chronic Olanzapine or Sertindole Treatment Results in Reduced Oral Chewing Movements in Rats Compared to Haloperidol Xue-Min Gao, M.D., Kazuo Sakai, M.D., and Carol A. Tamminga, M.D. Chronic haloperidol treatment typically produces late-onset, haloperidol-like chewing in rats, nor did movement ratings purposeless oral chewing movements in laboratory rats with after their chronic administration differ from placebo; a prevalence of 40 to 60%. Chronic clozapine does not whereas, haloperidol produced a 60% prevalence of produce these movements. Based on the phenomenologic purposeless chewing and a prevalence significantly and pharmacologic similarities between these rat chewing increased from placebo. This low rate of oral dyskinesias in movements and human tardive dyskinesia (TD), the animal rats is consistent with several of the preclinical movements are often used as a model of tardive dyskinesia characteristics of the drugs and correlates with their low (TD). Here we report results of the association of oral acute motor side effects in clinical trials. We propose, chewing movements in rats with chronic administration of although have not yet tested in humans, that these animal two new antipsychotic drugs, olanzapine and sertindole. results will predict low TD liability of these drugs. Because each of these antipsychotic drugs has a very low [Neuropsychopharmacology 19:428–433, 1998] incidence of acute Parkinsonism in human studies, they are © 1998 American College of Neuropsychopharmacology. candidates for showing a low tardive dyskinesia risk. Published by Elsevier Science Inc. Neither new drug produced a significant incidence of KEY WORDS: Dyskinesia; Olanzapine; Sertindole; movements parallel certain features (although not all) Haloperidol; Tardive dyskinesia; Chronic neuroleptic of the human neuroleptic-induced dyskinetic syndrome treatment tardive dyskinesia (TD), they are often used in its study. Traditional antipsychotics, such as haloperidol or flu- General criteria for using an animal preparation as a phenazine, induce purposeless oral chewing movements model for a human condition have previously been pro- in rats when they are administered chronically (Clow et posed (McKinney and Bunney 1969) and refined (Weiss al. 1980; Ellison et al. 1987; Waddington 1990; Glenthoj and Kilts 1995). Scientists have stressed that the most and Hemmingsen 1989). These dyskinesias appear critical elements for comparison are similarities in etiol- gradually, and they occur in only some of the animals. ogy, phenomenology, biochemistry, and pharmacol- Because characteristics of these neuroleptic-induced rat ogy between the animal and the human condition. The etiology of these rat oral dyskinesias (i.e., the chronic antipsychotic treatment) matches the etiology of TD, as do some of the demographic aspects of the rat move- From the Maryland Psychiatric Research Center (X-MG, KS, CAT), University of Maryland School of Medicine, UMAB, Balti- ments, such as slow symptom onset, delayed offset, and more, Maryland, USA. jerky quality (Tamminga et al. 1990; Waddington 1990). Address correspondence to: Dr. C.A. Tamminga, University of Moreover, whereas traditional neuroleptics cause these Maryland School of Medicine, Maryland Psychiatric Research Cen- ter, Baltimore, MD 21228, USA. purposeless movements in rats and tardive dyskinesia Received October 6, 1997; accepted April 20, 1998. in humans, clozapine fails to produce dyskinesias in ei- NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 5 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00039-6 NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 5 Chronic Olanzapine or Sertindole in Rats 429 ther rats or humans (Gunne et al. 1982; Kakigi et al. 1986), we hypothesized that their potency in causing 1995). oral dyskinesias in rats with chronic dosing would also The difficulty of distinguishing types of antipsy- be low. chotic-induced movements in rats, along with the lim- ited oral distribution of the movements in rats, and dis- agreements about the anticholinergic suppressability of METHODS the rat movements, have maintained a proper skepti- cism about using this preparation without reservation Male Sprague–Dawley albino rats were divided into six as an animal model of human TD. In this report, we treatment groups: Water ad libitum, n ϭ 10; haloperi- have attempted to expand the pharmacology of these dol, 1.5 mg/kg/day, n ϭ 10; sertindole 0.5 mg/kg/day, rat dyskinesias by testing whether two of the new an- n ϭ 9; sertindole, 2.0 mg/kg/day, n ϭ 10; olanzapine tipsychotic drugs, olanzapine and sertindole, which 0.5 mg/kg/day, n ϭ 10; and olanzapine 2.0 mg/kg/ have known low acute motor side effect profiles in hu- day, n ϭ 10. Because the doses of all the drugs are given mans, would induce purposeless oral chewing in rats. in drinking water, they are administered gradually over Olanzapine is a new antipsychotic drug developed the 24-hour period, not in a bolus. The dose of haloperi- by Lilly Laboratories, Inc., a thio[1,5]benzo-diazepine dol was selected, because it has previously been used in (Bymaster et al. 1996). It has potent antipsychotic ac- our studies and reliably produces purposeless chewing tions in schizophrenic psychosis, comparable to tradi- movements (CMs). Moreover, we have previously dem- tional neuroleptics, and is active against both positive onstrated that this dose of haloperidol (1.5 mg/kg/day) and negative symptoms (Beasley et al. 1996). One of the produces rat drug plasma levels of 6.8 Ϯ 1.1 ng/ml, unusual characteristics of olanzapine is its low potency which are in the clinical antipsychotic range (Gao et al. in producing Parkinsonian side effects and akathisia in 1997). Plasma levels in this range in humans are associ- humans. Olanzapine is a clozapine-like drug with re- ated with an incidence of TD of 5% per treatment year spect to its chemical structure, its broad receptor affin- (Kane et al. 1986). ity profile (dopamine D1-D5, serotonin 5HT2A, 5HT2C, For the new neuroleptics, we attempted to pick two ␣ 5HT6,1 noradrenergic, muscarinic cholinergic, and his- doses of each that were in the range of this dose of halo- tamine H1); moreover, it shows selective action on the peridol based on clinical potency and animal pharma- mesolimbic (A10) versus the nigrostriatal (A9) dopa- cology. The recommended clinical dose ranges of halo- mine neurons, with chronic dosing (Skarsfeldt 1995), peridol, olanzapine, and sertindole for schizophrenic fails to stimulate Fos protein in dorsal striatum (Robert- psychosis are 8 to 16 mg (VanPutten et al. 1991), 10 to 20 son and Fibiger 1996), and does not cause catalepsy. mg (Beasley et al. 1996), and 12 to 24 mg (Zimbroff et al. Sertindole is a new antipsychotic drug jointly devel- 1997), respectively, with more uncertainty about the lat- oped by Abbott Laboratories and Lundbeck A/S, a phe- ter two dose ranges than that for haloperidol. Oral bio- nyl indole derivative (Sanchez et al. 1991). Like olanza- availability in rat is substantial for all three drugs. The pine, it has potent antipsychotic actions in schizophrenic dose range selected for the new antipsychotics (0.5 and psychosis, on both positive and negative symptoms 2.0 mg/kg/day) spanned this range relative to halo- (Zimbroff et al. 1997). Similarly, one of the unusual peridol; moreover, plasma drug levels of all three drugs characteristics of sertindole is its low potency in produc- were analyzed in rat trunk blood. ing Parkinsonian side effects and akathisia in humans. Each drug was administered in drinking water con- The drugs is clozapine-like in its selective action on A10 tinuously for 6 months. The two test drugs, sertindole (mesolimbic), compared to A9 (nigrostriatal) dopamine and olanzapine, were separately dissolved in a mini- neurons (Skarsfeldt 1992); indeed, this was the selection mum volume of glacial acetic acid. Each solution was principle used prospectively in its design. Consistent diluted with distilled water and adjusted to pH 5.5 to with this anatomic selectivity, sertindole fails to stimu- 6.0, using 10 N sodium hydroxide, to give stock solu- late Fos protein in dorsal striatum (Fink-Jensen and tions of 33.3 mg/100 ml. The stocks were diluted every Kristensen 1994), and does not cause catalepsy at rele- 7 days to 3.3 mg/100 ml drug solution for the high-dose vant doses (Sanchez et al. 1991). Despite this, its chemi- groups, and to 0.833 mg/100 ml drug solution for the cal structure and receptor profile differ from that of low-dose groups. Rats were housed two per cage; drug clozapine, with a considerably narrower receptor affin- dosage was calculated (weekly initially; monthly in last ity profile (the dopamine D2 family, serotonin 5HT2A, months) by the amount of water drunk, assuming equal ␣ 5HT2C, and 1 noradrenergic receptors). drinking between the two animals. Body weight was Based on the low incidence of Parkinsonism and monitored. Haloperidol dosing in this strategy has been akathisia with each of these antipsychotic drugs in clin- previously verified by us (Gao et al. 1997); preclinical ical trials (Beasley et al. 1996; Zimbroff et al. 1997), and scientists familiar with the pharmacology of olanzapine therefore, the potential that either drug might have a and sertindole verified the dosing strategy for the two low incidence of TD with long-term use (Kane et al. new drugs (J. Arnt, personal communication; R. Lahti, 430 X-M. Gao et al. NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 5 personal communication). Drug concentration in the Table 1. Characteristics of Haloperidol (Hal)-Induced CMs drinking water was adjusted as needed, through moni- (# per 2 min): Time to Onset, Offset; Atropine Effect toring water intake, to maintain the target daily dose. (Tamminga et al. 1990) After 6 months of continuous drug administration, rats CM onset time 1 Week 4 Weeks 8 Weeks 12 Weeks were sacrificed by decapitation.