Psychopharmacology (1992) 107: 18-22 Psychopharmacology © Springer-Verlag 1992

Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys Daniel E. Casey

Chief, Psychiatry Research and Psychopharmacology, VA Medical Center, 3710 S.W. US Veterans Hospital Road, Portland, OR 97207, USA

Received August 28, 1991 / Final version September 24, 1991

Abstract. The ability of dopamine D~ antagonists to produce acute extrapyramidal syndromes (EPS) in nonhuman primates is unclear. Some studies in monkeys show that Dt antagonists produce acute dystonia, where- as other studies do not report these effects. The central issues that have yielded conflicting results revolve around prior treatment status (neuroleptic-naive versus neu- roleptic sensitized) and route of administration (oral versus parenteral). In this study, separate groups of neu- roleptic drug-naive cebus monkeys were tested once weekly with intramuscularly administered SCH 23390, a D1 antagonist, or haloperidol, a D2 antagonist, across a dose range of 0.01-0.25 mg/kg, and a saline control. Both active drugs, but not saline, produced clinically identical syndromes of acute dystonia and bradykinesia, though haloperidol induced higher symptom scores over a longer duration. Sedation and locomotor activity were un- changed by SCH 23390, but decreased with haloperidol. Factors regarding acute EPS liability in nonhuman primate models and clinical implications in man are discussed.

Key words: Neuroleptics - Dopamine receptor subtypes - SCH 23390 - Haloperidol - Extrapyramidal syndromes - Nonhuman primates

Neuroleptic drugs have become the mainstay for treating both acute and chronic psychoses. Unfortunately, there is a very narrow therapeutic index between the desirable antipsychotic effects and the undesirable acute ex- trapyramidal syndromes (EPS). These acute EPS of dys- tonia, akathisia and parkinsonism can occur in up to 75 % of patients taking these drugs, and are a major reason for treatment noncompliance (Casey and Keepers 1988). Therefore, any drug with the potential for antipsychotic benefits with no or greatly reduced acute EPS liability is a substantial treatment advancement.

The currently available neuroleptic drugs are thought to have both their antipsychotic and acute EPS effects

mediated by blockade of dopamine Dz receptors. This property is common to all commercially available and effective antipsychotic drugs (Seeman et al. 1976; Farde et al. 1988). With the identification of behavioral (Iorio et al. 1983; Christensen et al. 1984; Waddington 1986) and biochemical (Hyttel 1983) characteristics of com- pounds that block dopamine D1 receptors there is much hope that these compounds might have antipsychotic efficacy but be free of acute EPS, much like clozapine, a mixed D1/D2 antagonist (Meltzer et al. 1989) with mini- mal EPS liability in man (Casey 1989a) and no acute dystonia produced in monkeys (Casey 1991a). D~ re- ceptors have been identified in the human brain with SCH 23390 (Farde et al. 1987), but this and other Dt antagonists have not been adequately tested in the clinic (Casey 1991b; Gessa et al. 1991a, b). However, they have been extensively studied in animal models.

Behavioral data from studies with SCH 23390 have been somewhat conflicting. Initially this compound was thought not to produce catalepsy in rodents, a commonly used model for acute EPS (Iorio 1983). Yet others have demonstrated that SCH 23390 does produce catalepsy (Christensen et al. 1984; Waddington and O'Boyle 1989).

This compound has also been actively studied in nonhuman primates. When parenterally administered in acute studies to cebus monkeys that had previously re- ceived other neuroleptics, SCH 23390 induced dystonic symptoms that are typically seen with other traditional neuroleptics from several different classes, such as phenothiazines, butyrophenones, thioxanthenes, and substituted benzamides (Gerlach et al. 1987; Casey 1988; Gerlach and Lublin 1988; Christensen 1990; Peacock et al. 1990; Hansen and Gerlach 1991). In contrast, when SCH 23390 was given orally to neuroleptic-naive cebus monkeys no EPS developed (Coffin et al. 1989). These investigators attributed the EPS seen in other studies to the sensitized state of the central nervous system that developed from prior neuroleptic treatment, which consequently produced a qualitatively different response to SCH 23390 than that seen in neuroleptic drug-naive animals. However, these studies differed in the two criti-

cal parameters o f route o f adminis t ra t ion (oral vs. paren- teral) and pr ior t rea tment status (neuroleptic-naive ver- sus neuroleptic-experienced). Thus, it is unclear which o f these two factors could explain the different results with SCH 23390 In yet another research design using gradu- ally increasing doses over 4 months , the D~ antagonis t N O 01-756 p roduced catalepsy, but no t dys tonia (Han- sen and Ger lach 1991).

Sedative effects o f SCH 23390 have also been studied. Initial doses p roduced minimal sedation, but sedative effects increased with chronic t rea tment (Gerlach and Lubl in 1988; Coffin et al. 1989; Christensen 1990; Pea- cock et al. 1990).

The aim o f this s tudy was to evaluate the effects o f the D~ antagonis t SCH 23390 and the t radi t ional D2 an- tagonis t haloper idol in drug-naive cebus monkeys . Acute dys tonia and sedat ion were selected as the p r imary s tudy behaviors because they have been the ou tcome measures in earlier studies, though other behaviors were also eval- ua ted in this investigation. The dys tonia model has the benefit tha t the EPS symptoms, which can be reliably induced in monkeys , are identical to those seen in pa- tients (Casey et al. 1980; Casey 1989b).

Materials and methods

Subjects. Drug-naive cebus albifrons monkeys (12-20 years old) were tested. Two separate groups of n = 11 (10 female, 1 male) for SCH 23390 and n = 8 (5 female, 3 male) for haloperidol were tested in their home cages. The environment was temperature and light- controlled (12-h light/dark cycle).

Drugs. Both SCH 23390 and haloperidol were tested at the doses of 0.01, 0.025, 0.05, 0.01, and 0.25 mg/kg. Saline 0.25 ml was also given as a control to each group. Drugs were prepared fresh each day and administered within 1 h of preparation. They were adminis- tered intramuscularly (IM) in equal volumes for each dose in the external thigh. Each group received randomly sequenced single doses at 7-day intervals.

Scoring. Behaviors were scored by an experienced rater blind to drug dose. Observations were scored before and at 15, 30, 45, 60, 90, and 120 min after SCH 23390 and saline. The scoring timetable for haloperidol and saline was before, and at 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 rain after injection. Both groups were also scored 24 h after drug treatment. Acute dystonia total score was the sum of symptoms in four body regions (head and neck, trunk, upper limbs, lower limbs), whereas bradykinesia scores de- rived from three items (slow movement, tremor, salivation) on a scale of 0 to +3. Sedation (0 to -3)/arousal (0 to +3) and loco- motor decrease (0 to -3)/increase (0 to + 3) were scored along a continuum ( - 3 to + 3). Score values assigned were 0 = normal, + or - 1 = mild, + or - 2 = moderate, + or - 3 = severe. Eye blink rates were the average of the number of blinks per 30 s from three consecutive 30 s periods at each observation time. Oral dys- kinesias of tongue protrusion and licking were also counted over three consecutive 30 s periods at each observation time. Data are presented as group mean total scores i standard error summed from all observation periods. Statistical evaluation was with a repeated measures analysis of variance.

Results

Both S C H 23390 and haloper idol p roduced dystonia tha t significantly ( P < 0 . 0 5 ) increased with higher doses, be-

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Fig. la, b The effect of SCH 23390 and haloperidol on dystonia time course in neuroleptic-naive monkeys

ginning at a threshold dose o f 0.10 mg/kg I M (Figs. la, b, 2a, b). All animals were affected by the dystonia- induc- ing doses o f 0.10 and 0.25 mg/kg. The dystonia syn- dromes p roduced by the drugs were clinically indistin- guishable. Identical symptoms in the same b o d y regions occurred with bo th drugs. Peak scores were higher for haloperidol , and the drugs differed in dys tonia time course. SCH 23390 effects peaked at 30 min and resolved by 2 h (Fig. la). Haloper idol peaked at 90-120 min, but persisted for 6 hours (Fig. lb). T h o u g h bradykinesia scores were lower than dystonia scores for the respective drugs, their course closely paralleled those o f dystonia. Oral dyskinesias occurred inconsistently at low levels and varied f rom m o n k e y to m o n k e y with bo th drugs. N o consistent pa t tern evolved.

Sedative effects for the two drugs were different. SCH 23390 did not p roduce sedation that was quanti- tatively different f rom saline (Fig. 2c). However , haloper- idol p roduced a significant ( P < 0.01) dose-related seda- tive effect (Fig. 2d). The sedative effects were expressed by the animals closing their eyes and sleeping. There were

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Fig. 2a-d. The effect of SCH 23390 and haloperido! on dystonia and sedation in neuroleptic-naive monkeys

no arousal effects from either drug. SCH 23390 had no consistent effect on locomotion, whereas haloperidol produced a significant (P<0.05) decrease in locomotor activity that paralleled sedation. Eye blink rates were unchanged by either drug. No drug effects were observed in either group 24 h after receiving the test compounds. Saline produced no abnormal behaviors.

D i s c u s s i o n

These data demonstrate that acutely administered SCH 23390, and possibly other D1 antagonists, has cen- tral nervous system-mediated behavioral effects in neuro- leptic-naive nonhuman primates that extend beyond the previously reported sedative effects noted in a different experimental paradigm (Coffin et al. 1989). The SCH 23390-induced dystonia and bradykinesia in neuroleptic drug-naive monkeys is consistent with reports of SCH 23390-induced catalepsy in neuroleptic-naive rodents, which is another purported model of neuroleptic drug- induced acute EPS (Christensen et al. 1984; Wad-

dington and O'Boyle 1989). These data are also con- sistent with prior results of acutely administered SCH 23390-induced dystonia in monkeys previously treated, or sensitized, with neuroleptics (Gerlach et al. 1987; Casey 1988; Gerlach and Lublin 1989; Christensen 1990; Peacock et al. 1990), and conflict with the proposal that the lack of dystonia with oral SCH 23390 was due to a qualitatively different response in neuroleptic-naive monkeys (Coffin et al. 1989).

This current study addresses the alternate hypothesis that the apparent qualitative differences are better ex- plained by quantitative differences in bioavailability that are due to the critically important factor of different routes of drug administration. SCH 23390 is rapidly metabolized in man, with only 15 % of [11C] SCH 23390 remaining unchanged in blood 42 min after IV injection (Farde et al. 1987). It may be that oral administration produces substantially different, and probably lower, blood and brain levels than parenteral administration. With a very short duration of action of approximately 30-60 min, coupled with low tissue drug levels, the doses administered in studies using the oral route may not have produced sufficient drug in the brain to elicit acute dys- tonia or other neurological effects such as akathisia (Farde 1991). Studies with a wider dose range of oral SCH 23390 than the 30 mg/kg dose used in the earlier study (Coffin et al. 1989) are needed to more fully charac- terize a dose-response curve, as higher doses may have the capacity to produce EPS.

The dystonia syndromes produced by the D1 antago- nist SCH 23390 and the D 2 antagonist haloperidol were clinically the same, except for differences in duration and severity. This may be due to several factors. The doses selected for testing may not be clinically equipotent, and thus are not quantitatively comparable. Also, the rapid metabolism of SCH 23390, characterized by the rapid onset and resolution of dystonia symptoms, may have prevented the full expression of drug effects that might be seen with a longer acting compound like haloperidol.

The study with oral administration noted seda- tive effects from SCH 23390 and haloperidol with the initial doses of these drugs, indicating that both agents entered the central nervous system (Coffin et al. 1989). In contrast, this study observed sedation with halo- peridol, but not SCH 23390. Yet, sedation does not directly address the issue of acute dystonia liability be- cause the dose-response curves for sedation and acute dystonia may not have the same shape and/or could be shifted to the left or right of one another. In addition, dystonia might be masked by sedation, or sedation may be reversed by dystonia, though this was not the case for haloperidol. The absence of arousal is consistent with the dopamine antagonistic activity of these drugs.

Since locomotor activity measures in response to SCH 23390 were not emphasized in previous nonhu- man primate studies, it is difficult to compare and con- trast the absence of locomotor effects in this investiga- tion. The haloperidol-related locomotor decrease paral- leled sedation. Thus, it is not possible to separate the nonspecific sedative effect from a specific anti-locomotor effect. The lack of effect of either the D 1 or Dz antagonist

21

on eye blink rates has been previously observed (Peacock et al. 1990).

In contrast to the effects of acute drug administration evaluated in this study, the effects of chronic treatment in other reports have been quite different. In neuroleptic- naive monkeys, oral SCH 23390 did not produce EPS, but caused increasing sedation (Coffin et al. 1989) as did the other DI antagonist NO 01-756 when parenterally administered (Hansen and Gerlach 1991), whereas the D 2 antagonists haloperidol (Coffin et al. 1989) or raclo- pride (Hansen and Gerlach 1991) progressively elicited dystonia. Neuroleptic Dz-sensitized monkeys gradually desensitized to the dystonia effects with repeated D~ antagonist treatment (Gerlach and Lubling 1988; Chris- tensen 1990; Peacock et al. 1990; Hansen and Gerlach 1991). These data indicate that D1 and D2 antagonist effects may be quite different in different experimental paradigms and emphasize the importance of characteriz- ing drug effects in both acute and chronic studies.

Clinical implications are that acutely administered D1 antagonists may produce acute dystonia, and by implica- tion, the other acute EPS of akathisia and drug-induced parkinsonism in man that are seen with Dz antagonists in man and monkey (Casey et al. 1980; Gerlach et al. 1987; Casey 1988, 1989b, 1991a, c; Gerlach and Lublin 1988; Christensen 1990; Peacock et al. 1990; Hansen and Gerlach 1991). Support for this proposal comes from the observation of akathisia in healthy volunteers receiving SCH 23390 and schizophrenic patients receiving the Dz antagonist raclopride during a positron emission tomo- graphy study (Farde 1991). This further corroborates the model of drug-induced dystonia in monkeys as a predic- tor of EPS in man (Casey et al. 1980; Liebman and Neale 1980; Casey 1989b, 1991 a, c). I f D1 antagonists produce acute EPS in both neuroleptic-naive and neuroleptic- sensitized nonhuman primates, as has now been shown, then it is possible that acute administration of these drugs will produce similar syndromes in patients that have or have not been previously treated with neuroleptics.

It is not possible to draw any firm conclusions about the antipsychotic efficacy of the D1 antagonists as there are not yet direct, reliable and valid nonhuman primate models of schizophrenia or other psychoses. However, neuroleptics that produce EPS in monkeys are also ef- fective antipsychotic agents (Liebman and Neale 1980; Casey 1989b, 1991a, c). Thus D~ antagonists should also have antipsychotic properties. Additionally, indirect models of purported antipsychotic drug action in which SCH 23390 has activity include antagonizing am- phetamine-induced stereotyped behavior and blockade of conditioned avoidance responses.

While these data have important clinical and preclini- cal implications, it is necessary to consider several ca- veats. The relative position of the dose-response curves for the antipsychotic and acute EPS characteristics is critically important. If the antipsychotic curve is to the left of the EPS curve, it may be possible to achieve antipsychotic efficacy with doses that are below the EPS dose threshold. On the other hand, if the antipsychotic dose curve is similar to or shifted to the right of the EPS response, EPS will possibly be a clinical feature of D1

antagonist doses that are antipsychotic. It is also possible that pharmacokinetic parameters are different in man and monkey or that important differences in drug me- tabolism may occur across species. The potential differ- ences between acute and chronic treatment are further considerations. Finally, and most importantly, one must note that only SCH 23390 was tested. Since it is the prototypical drug in the D1 antagonist class, it is tempt- ing to conclude that all drugs in the class will share the same characteristics. However, this may be a very risky assumption. Many more D 1 antagonists need to be tested before it is possible to conclude what properties are common to the class and what characteristics are specific to SCH 23390. When several of these compounds are further tested in nonhuman primates and man, we will substantially increase our knowledge of the pathophys- iology and treatment of schizophrenia, other psychoses and movement disorders.

Acknowledgements. This work was supported in part by funds from the Veterans Administration Research Program and by NIMH grant MH36657. SCH 23390 was generously donated by the Scher- ing Corporation, Bloomfield, New Jersey. Kristina Wells prepared the typescript.

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