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J Neuropsychiatry Clin Neurosci 11:1, Winter 1999 79

Received August 11, 1997; revised October 8, 1997; accepted January30, 1998. From the U.S. Department of Veterans Affairs SepulvedaMedical Centers, Los Angeles, California. Address correspondence toDr. Fitten, VAMC 116A-9, 16111 Plummer Street, Sepulveda, CA91343; e-mail: [email protected]

Reduction of Motoric Agitation

and Restlessness by AF102Band Tacrine in the MacaqueL. Jaime Fitten, M.D.Freddy Ortiz, M.A.Douglas W. Siembieda, M.S. Joseph ONeill, Ph.D.Eric Halgren, Ph.D.Abraham Fisher, Ph.D.

The cholinesterase inhibitor tacrine (THA) andthe M1 muscarinic agonist AF102B (cevimeline),both reported to enhance cognition in animals andhumans, were tested in 5 macaques for reductionof spontaneous, random movements. Monkeyswere videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose in-tramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges

counted numbers of spontaneous movementsmade by each monkey over 12 consecutive 15-sec-ond segments for each drug condition. Both THAand AF102B reduced movement signicantly athigh doses without overt side effects, warranting further research on the agitation-reducing poten-tial of cognition-enhancing cholinomimetic drugs.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 1999; 11:7985)

Agitation is a common neuropsychiatric symptomin demented elderly patients. 15 Itis one ofa groupof behavioral complications that often accompany thecore cognitive impairments in Alzheimers disease(AD). Agitation in AD manifests as restlessness, exces-sive and repetitive verbal production, and perseverativelocomotion such as pacing, 1 and it can escalate to noisy,aggressive activity. 6 The management of agitated elderlypatients is a serious clinical issue and a key factor lead-ing to institutionalization, since agitation may have det-rimental effects on the agitated patient, on caretakers,on other patients, and on health care staff.

24,7,8

Mostdemented patients display agitation at some point, andit is amenable to treatment in most, but not all, cases. 4

Pharmacologic strategies for dealing with agitation indementia include both neuroleptic and non-neurolepticagents, but no singularly effective drug has beenfoundperhaps in part because agitation has severaltypes and causes. Neuroleptics offer only moderate ef-cacy in treating agitation, 810 and their extrapyramidaland cognitive side effects are not negligible, makingtheir long-term risk/benet ratio uncertain. 11 Non-neu-roleptic drugs, primarily anticonvulsants and antide-pressants, are also widely used to treat agitation inAD,7,10 but these drugs have been little studied system-atically in this context. 10 Other drugs, such as propran-olol, used to treat aggression in younger psychiatric


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80 J Neuropsychiatry Clin Neurosci 11:1, Winter 1999

AF102B AND TACRINE FOR AGITATION

populations, have been tried in dementia, but thesedrugs may have serious adverse side effects in theaged. 12

There is much evidence that cholinergic decienciesin AD make important contributions to the neuropsy-chiatric dimensions of the disease, including agitation. 13

Demented patients, for example, are highly vulnerableto side effects of anticholinergic psychotropics. 9 In viewof the long-standing interest in cholinergic replacementtherapies for palliating cognitive impairment in AD, 14,15

it will be important to examine the potential of cholin-ergic drugs to alleviate agitation. If cholinomimetics can be identied that lessen agitation signicantly at clinicaldoses and with minimal untoward effects, it is possiblethat such drugs could supplement or reduce neurolepticor non-neuroleptic medications given for this purpose.Further, certain cholinomimetics at appropriate dosesmight offer both agitation reduction and cognitive en-hancement. 16

There is reason to suspect that some cholinergics mayact to abate agitation. It has long been postulated that afunctional equilibrium exists in the normal striatum be-tween cholinergic excitation and dopaminergic inhibi-tion, and that when this equilibrium is disrupted by aloss of dopamine (DA) input, the motoric symptomcomplex of Parkinsons disease (PD), dominated by hy-pokinesia, tremor, rigidity, and abnormal posture,emerges. 17 More recently, it was proposed that DA neu-rons synapse on cholinergic interneurons in the stria-tum, inhibiting them, and that the acetylcholinereleased by these large interneurons is excitatory to striatal out-put neurons. 18 Studies in nonhuman primates havedemonstrated that parkinsonian symptoms can resultfrom pathologically decreased activity of the direct(pallidal-nigral-thalamocortical) and/or increased ac-tivity of the indirect (pallidal-subthalamic nuclear-thalamocortical) striatal output pathway. 19 Despite theuse of anticholinergics to treat PD since the time of Char-cot and the probable inhibitory action of DA on cholin-ergic interneurons, the action of cholinomimetics onstriatal neurons has not received broad attention fromneuropharmacologists. Although cognitive, presumablycortically mediated, effects of cholinergic agonism have been demonstrated in primate models, 14,2022 the poten-

tial behavioral effects of newer, better tolerated choli-nomimetics uponstriatal neurons, particularly in the ab-sence of DA deciency, have not been evidenced. In ourwork with this class of cholinomimetic, we have noticedthat high doses given to primates tend to quiet the ani-mals down, an action that may occur through cholin-ergic modulation of the output to frontal cortex of theindirect circuit. Modulation of this circuit, moreover,would not be likely to lead to sedation. Since the various

motor symptoms of PD result both from cholinergic ex-cess and from DA depletion, it is also possible thatproper cholinergic agents given to normodopaminergicsubjects would reduce agitation without the emergenceof other, undesired, parkinsonian symptoms.

The present pilot study tests, in a small number of

subjects, the hypothesis that centrally active cholinom-imetic drugs reduce motoric agitation in nonhuman pri-mates. At present there is no generally accepted animalmodel of AD, and so our investigation was restricted tonormal-young and normal-aged primates. It is, as such,intended only as groundwork for future approaches toevaluating pharmacotherapies for agitation in AD, based on the notion that a drug that reduces agitationin normal subjects may, but need not necessarily, alsoreduce agitation in AD. In this monkey behavioralmodel of agitation, one agent from each of the two majorclasses of therapeutic cholinomimetics was comparedwith vehicle-only. We examined tacrine (tetrahydroam-inoacridine; THA), a reversible cholinesterase inhibi-tor, 23 and AF102B (cevimeline), a rigid acetylcholineanalogue that acts as a partial selective direct M 1 mus-carinic agonist in nervous tissue. 24 Both AF102B2427 andTHA 2022,2833 have yielded cognitive improvement inanimal models and in AD patients. Whereas THA ishepatotoxic, 31,34 known side effects of AF102B are minorat therapeutic doses. 35 AF102B also has certain in vitroproperties that may offer additional benets in treatingAD.36,37 To our knowledge, effects of THA and AF102Bon agitation have not been studied previously.

METHODS

One male (age 7 years) and 4 female (16, 26, 28, and 33years) Macaca radiata (bonnet) monkeys in good healthweighing 49 kg took part. Ages were taken from birthrecords. All monkeys were kept under controlled con-ditions and had received cognitive training prior to thepresent study. The same dark/light cycle, feeding time,and behavioral testing time (11:00 A.M.) were kept for allsubjects. Senescence begins near age 20 years in the ma-caque; 3840 thus, our population comprised 2 youngand 3 old monkeys.

We developed the behavioral model of restlessnessand agitation as follows: For earlier studies, 41 we hadtrained monkeys to execute computer tasks on a touch-screen monitor. Subjects habitually performed thesetasks in exchange for fruit juice reward while sittingalone in a primate restraint chair inside a behavioral re-cording chamber. Ordinarily, after placement in thechamber, monkeys sat quietly awaiting the rst com-puter task. When, however, subjects were left sitting


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without computer activity for more than 3 min, they became restless and agitated, with a marked increase inrandom, often repetitive, movements rather than anyspecic attempt to escape from the chair. This agitatedstate could persist for 15 min or longer. Informally, wehave noticed this behavior repeatedly over months of

working with the monkeys and have observed no ap-parent habituation or other change in its character overtime.

We videotaped subjects during the rst 5 min of theserestless periods, starting 1 hour after administration of normal saline vehicle-only (control) and of each of fourcholinomimetic drug-dose combinations. No systematicminute-to-minute variation in agitation was evidentover this 5-min period. Nor were any time-dependenteffects in drug response anticipated in this timeframe,as the cholinomimetics selected (AF102B and THA), inour experience, exert their behavioral effects on thetimescale of hours rather than minutes. Therefore, foreach monkey and each condition, a 3-min length of vid-eotape was chosen at random out of the 5 min recordedand divided into 12 consecutive 15-s segments for view-ing. Two judges watched each segment independentlyon a 21 monitor at a distance of 1 m and counted everyspontaneous movement made by the monkey duringthe segment. Judges were independent and blind to thedrug conditions pertaining in each segment. Judgesdid,however, take part in a practice session, prior to formal judging, using an additional length of videotape, to es-tablish protocol agreement on counting procedures. Foreach judge, monkey, and drug condition, a mean was

taken across the twelve 15-s segments. We chose 15 s assegment length and 3 min as overall length because thisminimized monitor viewer fatigue, a possible source of inaccuracy.

Videotaping began 60 5 min after administration of vehicle or drug, including a nal 3-min wait duringwhich the monkey sat alone before the inactive touch-screen. The variation in postadministration time wasdue to the usual small differences in the exact time re-quired to chair the animal, to place the chair in thechamber, and so on, commonplace in monkey behav-ioral work.

Drugs were given in ve separate regimens, each oc-

curring 2 weeks apart and in the following order for allsubjects:

1. 1 cc intramuscular (IM) normal saline (vehicle-only).2. 0.5 mg/kg IM AF102B (young monkeys) or 0.2 mg/

kg IM AF102B (old monkeys) (Lo-AF102B).3. 3.5 mg/kg IM AF102B (young) or 2.0 mg/kg IM

AF102B (old) (Hi-AF102B).

4. Oral THA mixed in with 2 cc peanut butter vehicle:1.0 mg/kg (young) or 0.5 mg/kg (old) (Lo-THA).

5. 3.0 mg/kg (young) or 2.0 mg/kg (old) oral THA in2 cc peanut butter (Hi-THA).

In our previous published 4143 and unpublished ex-

perience, we have seen AF102B yield cognitive enhance-ment in the 0.14.5 mg/kg dose range for young mon-keys, with best enhancement around 1.1 mg/kg,whereby both the dose ranges and the best doses varyfor individual subjects. For old monkeys on AF102B, therange has been 0.10.6 mg/kg (best dose near 0.3 mg/kg). For THA, the ranges have been 0.52.5 mg/kg (bestdose near 1.3 mg/kg) for young monkeys and 0.52.0mg/kg (best dose near 1.0 mg/kg) for old monkeys. Forcomparison, daily oral doses of THA ranging from 0.5to 2.3 mg/kg are recommended for AD patients. 44 Com-parable human dosage data are not available forAF102B. Cognitive enhancement in monkeys was pre-viously assessed as improvements in behavioral perfor-mance, including increases in accuracy and decreases inreaction time in object working memory 41,43 and visualfocused attention 42 tasks.

We used the Pearson correlation coefcient ( r) tocom-pare the results of the two judges. Drug effects weretested in separate repeated-measures analyses of vari-ance (R-ANOVA) for each agent, using differences be-tween movement rates on drug and on vehicle-onlyacross all 5 subjects, with dose (Lo vs. Hi) as a factor. R-ANOVAs were done both for differences in absolutemovement rates and for percentage differences in move-ment rates normalized to rates on vehicle-only. One-wayanalyses of variance (1-ANOVA) were used for directcomparisons between the young and the old monkeys.Absolute and percentage differences between drug andvehicle were also examined for both drugs at both doseswith one-sided t-tests to see if means across monkeyswere signicantly below zero. Criterion for statisticalsignicance was P 0.05 in this exploratory, pilot study.

RESULTS

For most subjects, reduced restlessness and motoric ag-

itation were readily apparent on segments taped aftercholinergic administrations relative to segments tapedafter vehicle administrations. Both frequency and am-plitude of spontaneous movements were clearly de-creased even on supercial inspection. Movement am-plitude was not further investigated, but the nding of reduced frequency was tested objectively by the 2 blind judges. Figure 1 plots average spontaneous movementsper 15-s segment counted by each of the 2 judges for


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FIGURE 2. Reduction in spontaneous motility 1 hour afteradministration of cholinergic drugs. Values are

percentage decrements in each drug conditionrelative to vehicle-only baseline (vhc) and areaveraged across 5 macaques. * P 0.025; one-sided t-test of the hypothesis movement rate difference isless than zero. For more details and denitions ofabbreviations, see Table 1.

TABLE 1. Reduction in spontaneous motility by systemiccholinomimetics in 5 macaques

Age (yr) Vehicle Lo AF102B Hi AF102B Lo THA Hi THA

7 29.3 3.2 26.2 5.2 17.2 23.8 2.9 19.7 3.8 8.816 32.3 3.7 26.8 6.4 24.5 25.4 3.8 24.5 4.2 6.626 12.9 3.6 11.7 7.3 10.5 11.8 2.1 10.7 2.9 2.628 8.9 3.3 11.4 3.8 8.6 12.7 3.1 3.9 8.9 3.833 10.6 6.4 10.9 3.5 9.3 4.1 8.7 3.7 6.4 3.6Mean 18.8 17.4 11.1 8.3 14.0 16.5 6.8 14.0 7.6 7.7

Note: Values ((SD) are numbers of spontaneous movements per15-s segment averaged across 12 segments (means of 2 blind judges).AF102B (cevimeline) is a centrally acting M 1 muscarinic agonist.THA (tacrine) is a centrally acting cholinesterase inhibitor. AF102Bwas given intramuscularly, THA was given orally, each 1 hour before observations. Lo AF102B 0.5 mg/kg for young monkeys( 20 yr), 0.2 mg/kg for old monkeys ( 20 yr); Hi AF102B 3.5 mg/kg (young), 2.0 mg/kg (old); Lo THA 1.0 mg/kg (young), 0.5 mg/kg (old); Hi THA 3.0 mg/kg (young), 2.0 mg/kg (old).

FIGURE 1. Rater counts of spontaneous movements per quarter-minute for 5 bonnet macaques as a function ofmonkey age. Each value is a mean of 12 15-svideotape segments (SD 1). Curves for identicalsegments are shown for two blind judges to indicateinterrater reliability (Pearson r 0.966, P 0.007).Values shown were taken 1 hour after intramuscularinjection of 1 cc normal saline (baseline values).Similar high interrater reliability was obtained foreach of the other drug conditions. Also note gap inbaseline motility between young ( 20 yr) and old( 20 yr) subjects.

each of the 5 monkey subjects under the vehicle-onlycondition. The curves for the 2 judges overlap well(r 0.966, P 0.05). Similar correlations between the 2 judges were found for the other four conditions (notshown). Therefore, mean values for the 2 judges arecited below.

Mean spontaneous movements per quarter-minuteare listed for each monkey under each drug conditionin Table 1. The 2 young monkeys had signicantlyhigher motility than the 3 old monkeys under all drugconditions (e.g., 1-ANOVA for vehicle: F 114.65, df 4,P 0.002). Low-dose AF102B was associated withmove-ment reduction for 3 of 5 monkeys. Movement decre-ment, slight for the old monkeys, was recorded for 5 of 5 monkeys on high-dose AF102B. Movement reductionwas found for 4 of 5 monkeys on both low- and high-dose THA. The 28-year-old monkey responded poorlyto both doses of both drugs. Comparing dose-responseswithin drugs, spontaneous movement rates were lowerat high-dose than at low-dose for both cholinomimeticsfor all monkeys. In R-ANOVA computed on differences between movements per 15 s on drug and movementsper 15 s on vehicle, the effect of dose of AF102B did notreach signicance for differences in absolute numbers

( F 5.57, df 1,4, P 0.078), but did become signicantwhen values were expressed as percentage differences( F 13.00, df 1,4, P 0.05). For THA, the opposite ap-plied: the effect of dose of THA was signicant for ab-solute numbers ( F 13.54, df 1,4, P 0.05), but not forpercentage differences ( F 6.70, df 1,4, P 0.061). One-

sided t-tests across all 5 monkeys (Figure 2) indicatedmovement-rate drops to levels signicantly below con-trol for Hi-AF102B and for Hi-THA (for both conditions:absolute numbers P 0.05, percent differences P 0.025),


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but not for Lo-AF102B or for Lo-THA ( P 0.10 for bothmeasures and both conditions). Tremor, rigidity, and ab-normal posture were not visible; nor were other sideeffects, in particular sedation and hypercholinergicsigns, noted for any monkey for either drug at any dose.

DISCUSSION

The high interrater correlation on the movement fre-quency measure suggests that results recorded are reli-able and that the videotape technique may represent apractical means of documenting and quantifying mod-els of primate agitation. As the form of agitation com-monly found in dementia features frequent purposelessstereotypies such as hand-wringing, foot-tapping,picking, 45 behaviors akin to those observed in our rest-less, partially restrained monkeys, the present model

may have some relevance for the study of agitation indementia.Signicant decrements in spontaneous nonpurposive

movement rates of nonhuman primates were found inresponse to the cholinesterase inhibitor THA and the M 1muscarinic agonist AF102B, at clinically nontoxic doses.Although the study has a small population sample, andwe therefore can claim little in terms of statistical power,the presence and relative uniformity of cholinergic-as-sociated movement decrement across subjects suggestthat a notable effect may be present. Consequently, wethink further studies on larger numbers of animals andin agitated dementia patients are needed. We postulate

that dampening of spontaneous, nonpurposive move-ments (restlessness, agitation) may be exerted throughcholinergic action in the striatum 46 in the absence of DAdeciency (nonparkinsonian subjects) and may be me-diated through indirect pathway connections with fron-tal cortices elaborating movement. 47

A high dose and a low dose of each drug were givento each subject. For both cholinomimetics, high doseswere more effective than low doses in reducing move-ment, even though low doses were closer to previouslyobserved best doses for cognitive task performance, andwe therefore expect greater cognitive enhancement atlow than at high doses. This dissociation between agi-tation-reducing and cognition-enhancing doses may bedue to a receptor populationrelated differential sensi-tivity between cortex and striatum. Ideally, maximal ag-

itation reduction would occur at doses yielding best cog-nitive enhancement. But, given the likelihood thatcognitive functions and motoric agitation are mediated by somewhat independent (e.g., cortical versus subcor-tical) mechanisms in the primate brain, such coincidenceof doses seems unlikely. Therefore, a cognitive benet

might attend in some, but not all, AD patients who weretreated with AF102B or THA for agitation.AF102B and THA were each given 1 hour before vid-

eotaping. The aforementioned enhancements in ma-caque memory and attention 4143 were also recorded 1to 2 hours after dosing with AF102B or THA. In futurestudies, it might be useful to examine agitation at latertimes postdrug, since, for example, the THA metabolitevelnacrine still improves cognitive function as late as 24hours after ingestion. 48 Because of the small number of subjects, the vehicle, AF102B, and THA were given inthe same order to all subjects in the present study, intro-ducing a potential bias from order effects. We have notdetected order effects in our past monkey behavioralwork with THA and AF102B, 41 but this question none-theless should be examined more systematically.

In the present study, as well as in previous work withchronic administration of AF102B and THA in ma-caques, 41 we have only rarely noted externally visibleadverse effects at doses tested. We cannot comment onpossible internal organ pathology induced by thesedrugs, since we did not test for it. Importantly, in thepresent study reduction in agitation was observed with-out obvious tremor, rigidity, or abnormal posture at thedoses tested. One explanation of this result might be thatelevated central cholinergic agonism leads to hypoki-nesia, but not to other parkinsonian symptoms, as longas normal DA levels are maintained. Motility was alsolowered in the absence of sedation. This nding is con-sistent with our previous work, 49 in which we foundthat EEG slow-wave production was decreased in themacaque in response to central cholinergics. Therefore,further research with cholinomimetics is recommended,since reduction of agitation, with possible cognitive en-hancement, was achieved at doses not inducing parkin-sonoid or other systemic side effects.

This work was supported by the U.S. Department of Vet-erans Affairs Merit Review Program. It was previously pre-sented at the Fourth International Conference for Progress in Alzheimers and Parkinsons Diseases, Tel Aviv, Israel, May1417, 1997.

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