Psychopharmacology (1990) 100:243-250 Psychopharmacology © Springer-Verlag 1990

Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed Charles Flicker 1, Michael Serby a' 2 and Steven H. Ferris a i Department of Psychiatry (HN 314), New York University Medical Center, New York, NY 10016, USA 2 Psychiatry Service, VA Medical Center, New York, NY 10010, USA

Abstract. Scopolamine hydrobromide was administered by subcutaneous injection to 30 young subjects in a dose of 0.22 mg/70 kg, 0.43 mg/70 kg, or 0.65 mg/70 kg. Treatment effects were compared to placebo on an extensive cognitive assessment battery. Almost all tests in the battery had been previously administered to Alzheimer's disease patients and nondemented elderly subjects. Scopolamine produced defi- cits on tests of verbal recall, visuospatial recall, visual recog- nition memory, visuospatial praxis, visuoperceptual func- tion, and psychomotor speed. Immediate memory, language function, object sorting, and frequency of intrusion errors were unaffected. The low dose of scopolamine produced some peripheral anticholinergic signs but did not affect the cognitive measures. The results support the conclusion reached in previous studies that the cognitive profile of scopolamine-injected young subjects is more similar to that of the nondemented elderly than to that of Alzheimer's disease patients.

Key words: Scopolamine - Acetylcholine - Aging Alz- heimer's disease Memory - Cognition

The amnestic effects of the muscarinic chotinergic receptor antagonist scopolamine constitute crucial experimental evi- dence in support of the hypothesis that the brain neu- rotransmitter acetylcholine (ACh) plays an important role in information processing in man (Deutsch 1971). It has been further suggested that the cognitive deficits produced by scopolamine are similar to the cognitive decline asso- ciated with aging (Drachman and Leavitt 1974).

There is some evidence supporting the parallel hypothe- sis that cognitive decline in the elderly is associated with deficient cholinergic neurotransmission (Bartus et al. 1982). This suggestion is mainly based on animal studies demon- strating that in the brains of aged rodents there is a decrease in choline uptake (Sherman et al. 1981), in ACh synthesis (Gibson et al. 1981), in muscarinic receptor binding (Strong et al. 1980), and in the electrophysiological responsivity of cholinoceptive neurons to ACh (Lippa et al. 1981).

There is a rather more extensive body of data document- ing a severe dysfunction of the cholinergic neurotransmitter system in association with the pathological cognitive deteri- oration that occurs in Alzheimer's disease (AD). In AD there is clear evidence of the degeneration of basal forebrain

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cholinergic neurons (Whitehouse et al. 1981), of decreases in particular subtypes of muscarinic receptors (Mash et al. 1985), and of reductions in the synthesizing enzyme choline acetyltransferase (CAT) that are correlated with the severity of the cognitive loss (Perry et al. 1978).

This evidence of marked cholinergic dysfunction in AD invites consideration of the extent to which cholinergic blockade by scopolamine produces behavioral changes in non-demented subjects that mimic the ,cognitive symptoms of AD. Beatty et al. (1986) have recently pointed out a number of qualitative differences between the memory defi- cits associated with scopolamine and AD. Their results tend to support the original conclusion drawn by Drachman and Leavitt (1974) that the pattern of cognitive impairment ob- served after scopolamine administration is more compara- ble to the cognitive loss exhibited by the non-demented elderly.

In the present study, the cognitive effects of scopolamine in young subjects were evaluated using a series of tests pre- viously administered to elderly and demented subjects. The assessment battery was designed to examine a broad array of discrete cognitive abilities that have proven differentially sensitive to the effects of aging and dementia. For example, although tests of recent memory (Flicker et al. 1986b) and psychomotor speed (Ferris et al. 1976) reveal deficits asso- ciated with both aging and AD, tests of object naming (Flicker et al. 1987a) and digit span (Storandt et al. 1986) are insensitive to aging but yield deficits from early and advanced AD patients, respectively.

Materials and methods

Subjects

Subjects were between 18 and 30 years of age. All potential study participants were administered a physical exam, an electrocardiogram, urine and blood analysis, a health histo- ry questionnaire, the Hamilton Depression Scale, and the WAIS vocabulary subtest. Criteria for exclusion from par- ticipation in the study included the following: a history of schizophrenia, depression, head trauma with loss of con- sciousness, or seizures; concurrent use of potentially psy- choactive medications; allergies or other respiratory diffi- culties; severe puhnonary, vascular, or metabolic disorders; any significant EKG abnormality; hypertension; hypoten- sion; body weight > 250 pounds; a score > 8 on the Hamil-

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ton Depression Scale; a standard scaled score < 6 on the WAIS vocabulary subtest.

The mean WAIS vocabulary scaled score for the group was 12.8 + 0.5. Mean years o f education was 14.3 + 0.3.

Apparatus

Test stimuli were presented on the video monitor of a Grin- nell Systems G M R 274 high-speed graphics display system. The Grinnell image processor was supported by a Data General S/200 Eclipse with two 10-megabyte Diablo disk drives. This system is capable of storing and rapidly present- ing high resolution, complex color graphic stimuli. Pictures of objects were recorded with a video camera (Cohu 5122-200) for digitization and storage on disk. A touch- screen apparatus (TSD Display Products TF-124) affixed to the video monitor screen permitted subjects to interact with the CRT display. For some of the cognitive tests, stim- uli were presented on a different graphics terminal (Intelli- gent Systems Corporation) supported by a Data General MP/200 microNOVA computer linked to another Data General S/200 Eclipse with 32.5 megabytes of disk storage space. Programming of the computerized tests was based upon custom-designed software packages for stimulus pre- sentation (Van Gelder et al. 1979) and data acquisition (Tsui and Van Getder 1979). Data analyses were conducted on New York University's Courant Institute IBM 360.

Experimental design

Each subject received two subcutaneous injections, one of scopolamine and one of saline, at l-week intervals. The order of the two injections was counterbalanced across sub- jects. Three separate groups of ten subjects each were ad- ministered a different dose of scopolamine hydrobromide (Burroughs Wellcome): 0.22 rag/70 kg, 0.43 rag/70 kg, or 0.65 rag/70 kg. The three dosage groups were matched for years of education, WAIS vocabulary score, and male: fe- male ratio.

Procedure

Before drug administration, subjects were administered an anticholinergic symptoms checklist and their vital signs were recorded. This procedure was repeated approximately 15, 30, 90, 180, and 240 min post-injection. Cognitive test- ing was begun 30 min after the injection and lasted approxi- mately 2 hours.

The cognitive test battery was designed to assess a broad array of mental functions, by including tests that are differ- entially sensitive to a variety of conceptually distinct cogni- tive abilities. The tests administered were thus selected for the purpose of generating a comprehensive, high-resolution profile of scopolamine's cognitive effects. Most of the tests had been previously evaluated for their sensitivity to the effects of aging and dementia. Many of them had been computerized in order to facilitate and increase the reliabili- ty of test administration, data collection, data storage, and data analysis. The following description of the subtests in the assessment battery is organized in accordance with the a priori cognitive constructs that were used to determine the clustering of the behavioral variables for the purpose of statistical analysis. The order of test administration is documented in Table 2.

Cognitive assessment battery

1. Immediate memory

Digit Span (Wechsler 1955). The classic test of immediate memory is the forward digit span subtest of the WAIS. The tester reads a series of numbers (the length of which is incremented after each correct trial) that the subject is instructed to repeat immediately. Digit span is virtually un- affected by normal aging and is reduced by an average of only half a character in early dementia (Wechsler 1955; Ferris etal. 1980; Fozard 1985). However, it has been found to be significantly affected in more advanced AD patients and in longitudinal studies of AD (Storandt et al. 1986).

2. Language

Object naming (Flicker et al. 1987a). Images of objects for the object naming task were derived from the Boston Nam- ing Test (Kaplan et al. 1983). Twenty pictures are pre- sented, one by one, on the video monitor screen and sub- jects are instructed to name each object. This test elicits a marked deficit from AD patients, whereas the perfor- mance of non-demented young and old subjects is not sig- nificantly different.

Object function recall (Flicker et al. 1987a). While the ob- jects presented in the above task are still on the screen, the subject is asked what they are used for. Any accurate contextual information is scored as correct.

Object name recognition (Flicker et at. 1987a). The subject is instructed to select the name of the object from a list of four words presented under the representation of the object on the video monitor.

Object function recognition (Flicker et al. 1987a). The sub- ject is presented with a representation of a 25-room house. Each of the rooms in the 5 x 5 matrix is filled with the image of an object derived from the set of pictures standard- ized by Snodgrass and Vanderwart (1980). Subjects are in- structed to point out (i.e., touch on the screen) the eight items that would be most useful for a particular chore (e.g., dressing). Responses are automatically recorded via the touchscreen. As with the other language tasks above, early dementia patients are impaired on this task whereas the nondemented elderly exhibit no deficit (Flicker et al. 1987 a).

3. Concept formation

Object sorting (Flicker et al. 1986a). The subject is pre- sented with the 25-room house, full of household items, and is instructed to pick out (touch on the screen) the eight items that are most alike. AD patients are severely impaired on this task, and elderly normals perfon~n significantly worse than young normals.

4a. Recent memory: verbal recall

Paragraph recall (Gilbert et al. 1968; Crook et al. 1980). In this subtest of the Guild Memory Test, the subject is

read a short paragraph and then asked to recall as many items as he can. The test is sensitive to both aging and dementia (Ferris et al. 1980).

Shopping-list task (McCarthy et al. 1981). On this task the subject is presented with a list of ten grocery items to recall. Five trials are administered, after each of which the subject is reminded of the items not recalled. In comparison to young normal subjects, this task elicits progressively more severe performance decrements from elderly normals and elderly demented subjects.

4b. Recent memory: visuospatial recall

Delayed spatial memory task (Flicker et al. 1984). On this task, the subject is presented with the representation of a 25-room house that has common household objects in one or more rooms. After a delay interval of 0, 15 or 30 s, the subject is instructed to point out (touch on the screen) the room, or rooms, that the objects were in. The subject performs the driving test described below as a distractor task during the t5- and 30-s delay intervals. The slope of the forgetting curve is progressively steeper in young nor- mals, elderly normals, early dementia patients and ad- vanced dementia patients. The test is conceptually and oper- ationally similar to a delayed response task that is sensitive to scopolamine administration (Bartus and Johnson 1976) and aging (Bartus et al. 1978) in nonhuman primates.

4c. Recent memory: visual recognition

Visual recognition span (Flicker et al. 1987b). On this task the subject is presented with a group of household objects whose number is progressively incremented. On each trial, the subject is instructed to point out (touch) the new object. This test has been shown to be sensitive to aging and de- mentia.

Facial recognition task (Ferris et al. 1980). In this test the subject is presented with a series of faces and must identify which faces are being presented for the first time and which faces are repeat presentations. The subject responds by touching a "yes" or " n o " box on the screen. Repeat pre- sentations occur at delay intervals of 0, 5, 15, 30, 120 and 300 s. The current computerized version of this task is sensi- tive to both age and AD (Flicker et al. 1989).

5. Visuospatial praxis

Block construction (Wechsler 1955). On this WAIS subtest, subjects are presented with a two-color, two-dimensional pattern which they attempt to replicate using a set of four or nine blocks. On each block two faces are all white, two are all red, and two are half-and-half. The test trials were divided in half for the purpose of repeat administration. This test is highly sensitive to both aging (Wechsler 1955) and dementia (Gonen 1970).

Digit symbol (Wechsler 1955). On this WAIS subtest, the subject is presented with a set of numbered symbols and a series of numbers and is instructed to draw the appro- priate symbol below each number. Significant performance decrements are apparent on this test in association with

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both aging (Wechsler 1955) and dementia (Ferris et al. 1980). Since the above two tests of visuospatial praxis are either timed or time-limited, performance measures derived from them are also dependent upon overall psychomotor speed.

6. Visuoperceptual function

Judgment of line orientation (Benton et al. 1983). On this task the subject is required to select from a set of test lines that line whose spatial orientation matches the angle of a sample line. This test of the perception of spatial relations has been found to be sensitive to aging and dementia (Es- linger and Benton 1983).

Face matching (Benton et al. 1983). On this task the subject is required to select from a set of test faces that face which matches a simultaneously presented sample face. This test is sensitive to both aging and dementia (Eslinger and Ben- ton 1983).

7. Psychomotor speed

Finger tapping speed (Lehman and Ban 1970). The number of times the subject can depress a hand-tally counter in 15 s with both the dominant and non-dominant index finger (two trials with each hand) serves as a measure of simple motor speed. Finger tapping speed has been found to dece- lerate in association with both aging and AD.

Driving Test (Flicker et al., unpublished). On this task a traffic stoplight, a "b rake" box, and an "accelerator" box are presented on the video monitor touchscreen and the subject is instructed to press the brake box when the Stop - light is red and the accelerator box when the stoplight is green. The overall reaction time (from brake to accelerator or accelerator to brake) can be broken down into its release time and travel time components. This task thus provides separate measures of sensorimotor speed (including cogni- tive processing speed) and pure motor speed. Results from this task indicate that psychomotor slowing is present in even the earliest stages of AD.

8. Perseveration

Intrusions. The frequency of intrusion errors on the shop- ping list verbal recall task was used as a measure of perse- verative tendency. Scopolamine administration has been re- ported to increase intrusion errors on a category retrieval task (Drachman and Leavitt 1974). In AD patients the in- trusion of prior responses has been linked to low levels of choline acetyltransferase and high levels of cortical senile plaques (Fuld et al. 1982).

Data analysis

Data were analyzed in a two-way mixed-measures analysis of variance including Dose as the grouping factor and Drug as the within-subject factor. Multivariate (MANOVAs) and univariate (ANOVAs) analyses of variance were used to examine the effect of scopolamine upon the seven hypothet- ical cognitive constructs defined a priori by the test mea- sures listed above. Order effects were evaluated on the basis

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of the interaction between the Drug effect and the Order effect in three-way analyses that included the grouping fac- tor Order.

R e s u l t s

Cardiovascular effects

After placebo injections there appeared to be a mild de- crease in pulse and blood pressure (see Table 1). Scopola- mine produced a significantly larger fall in pulse rate than placebo [F{1,27} = 10.29, P < 0.01]. Blood pressure was not significantly affected [systolic: F{1,27} = 0.97, NS; diastol- ic: F{1,27} =0.05, NS].

Anticholinergic signs

Scopolamine also produced a significant post-injection in- crease in anticholinergic signs relative to placebo [see Ta- ble 1 ; F{ 1,27} = 129.98, P < 0.0001 ]. Anticholinergic symp- toms most frequently reported were dry mouth, lighthead- edness, and pupil dilation, with no instances of hyperten- sion, tachycardia or nausea. The effect of scopolamine on the incidence of anticholinergic signs was even present after administration of the 0.22 mg/70 kg dose [F{1,9} = 18.69, P<0.01].

Subjective impression

On 25 of the 60 test days subjects were asked post-injection whether they thought they had received scopolamine or placebo. Of 13 subjects given scopolamine, 12 correctly identified the treatment as active, and one responded "don ' t know" at the low dose. Of 12 placebo-injected subjects, 9 correctly identified the condition, 2 did not know, and I gave a false positive response.

Cognitive tests

The cognitive test results are presented in Table 2.

1. Immediate memory. The immediate memory MANOVA, which was based on the digit span forward subtest of the WAIS, the 0-s delay of the spatial recall test, and the 0-s delay of the facial recognition memory task, demonstrated a significant scopolamine effect [Piltais' F{3,25} = 3.13, P < 0.05]. However, univariate analyses revealed that, of the three measures, only the hit rate at the 0-s delay on the facial recognition memory task was significantly affected by scopolamine [F{1,27}=9.42, P<0.005]. The construct validity of this test variable as an immediate memory mea- sure is discussed below.

2. Language. The language MANOVA, including the four dependent variables object naming, object name recogni- tion, object function recall, and object function recognition revealed no effect of scopolamine administration [Piltais' F{4,24} =2.09, NS].

3. Concept Jbrmation. Concept formation, as reflected in performance on the object-sorting task, was also unaffected by the drug [F{1,27} = 1.50, NS].

T a b l e 1. Effects of scopolamine on pulse, blood pressure, and anti- cholinergic signs

Treatment Mean peak change from pre-injection baseline

Pulse rate Systolic BP Diastolic BP Anti- cholin- ergic signs

Saline - 7.6±1.6 - 7.5±2.1 - 3.0±2.3 0.5+0.2

Scopolamine 0.22 mg/70 kg - 13.2 + 2.6 0.43 mg/70 kg -19.9±4.1 0.65 mg/70 kg - 13.2± 3.9

-11.6±3.6 -10.2±2.8 2.3±0.3 - 7.2±5.4 + 1.4±4.4 3.0±0.3 -12.5±3.9 - 2.0±3.7 3.4±0.3

4. Recent memory. The tests of recent memory, including paragraph recall, the shopping-list task, the 15- and 30-s delays of the spatial recall task, visual recognition span, and the facial recognition memory task, revealed a robust effect of scopolamine administration [Pillais' F{6,22}= 9.83, P<0.001]. Significant scopolamine effects were still apparent when this cluster of variables was segregated into tests of verbal recall [shopping-list task and paragraph re- call; Pillais' F{2,26} = 17.54, P < 0.001], of spatial recall [15- and 30-s delays; Pillais' F{2,26}=7.51, P<0.003], and of visual recognition memory [visual recognition span and fa- cial recognition memory; Pillais' F{2,26} = 4.96, P < 0.02].

5. Visuospatial praxis. The tests of visuospatial praxis, in- cluding the block design and digit symbol subtests of the WAIS, were also clearly sensitive to drug administration [Pillais' F{2,26} = 11.89, P < 0.001].

6. Visuoperceptualfunction. The MANOVA of the passive visuoperceptual tasks, face matching and judgment of line orientation, revealed significant differences between test performance after scopolamine injection versus placebo in- jection [Pillais' F{2,26} = 12.71, P < 0.001].

7. Psychomotor speed. The measures of psychomotor speed, including release latency from the driving test, travel time from the driving test, and finger tapping speed, revealed significant psychomotor slowing after the scopolamine in- jection [Pitlais' F{3,25}=4.52, P<0.051.

8. Perseveration. Frequency of intrusions on the shopping- list task, which was used as an index of perseveration, was not significantly affected by scopolamine [F{1,27} = 1.92, NSl.

Dose effects

Only the psychomotor speed MANOVA yielded a signifi- cant Drug x Dose interaction [Pillais' F{6,52} = 2.36, P < 0.05]. Univariate analyses confirmed the presence of a sig- nificant interaction for finger tapping [F(2,27} = 6.42, P < 0.01] but not the other two variables. All of the other analy- ses failed to demonstrate significant Drug x Dose interac- tions. Post-hoc analyses of simple main effects (MANO-

Table 2, Scopolamine effects on cognitive test performance (group means and standard deviations)

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Cognitive construct Test name Order Dosage group

Low (0.22 mg/70 kg)

Placebo Active

Medium (0.43 mg/70 kg) High (0.65 rag/70 kg)

Placebo Active Placebo Active

Immediate memory Digit span (11) 7.3 (0.8) Delayed spatial recall (5) 11.8 (0.6)

(0-s delay) Facial recog, memory (8) 3.25 (0.77)

(0-s delay)

Language Object naming (1) 17.3 (1.8) Obiect function recall (2) 18.7 (I.3) Object name recognition (3) 19.1 (0.7) Object function recog. (6) 31.3 (1.1)

Concept formation Object sorting (7) 19.2 (3.2)

Recent memory Paragraph recall (t0) 16.6 (5.3) Shopping list (9) 43.8 (4.4) Delayed spatial recall (5)

(15-s delay) 10.9 (1.0) (30-s delay) 10.4 (t.8)

Visual recognition span (4) 22.7 (3.9) Facial recog, memory (8) t.96 (0.43)

Visuospatial praxis Block contruction (16) 13.9 (5.3) Digit symbol (12) 62.2 (7.6)

Visuoperceptual Line orientation (15) 28.0 (2.8) function Face matching (14) 23.5 (2.0)

Psychomotor speed Finger tapping (13) 85.7 (8.2) Driving test (5)

release 276 (68) travel 382 (65)

Perseveration Intrusions (9) 0.5 (1.6)

6.7 (1.2) 7.3 (1.6) 7.3 (0.7) 8.2 (0.6) 7.7 (1.2) 11.9 (0.3) 11.8 (0.4) 11.6 (0.7) 12.0 (0.0) 11.3 (1.3)

2.99(0.86) 3.32 (0.45)2.58(0.94) 3.38(0.88) 2.67(0.86)

15.9 (2.8) 18.1 (1.8) 18.6 (1.4) 19.0 (1.6) 17.8 (2.1) 18.3 (1.9) 19.4 (1.1) 19.5 (0.7) 19.3 (0.9) 18.9 (1.4) 18.0 (1.9) 19.1 (1.0) 19.5 (0.7) 19.4 (1.0) 19.3 (0.8) 30.9 (1.8) 31.6 (0.8) 31.3 (1.1) 31.9 (0.3) 31.1 (1.3)

19.4 (4.6) 19.4 (2.8) 19.1 (3.5) 19.0 (4.5) 16.7 (4.7)

16.3 (5.3) 16.3 (4.4) 12.0 (4.0) 16.7 (5.7) 1t.8 (3.2) 41.3 (6.7) 44.7 (4.0) 39.9 (7.1) 43.9 (3.6) 38.8 (6.1)

10.6 (1.4) 11.6 (0.8) 8.9 (2.9) 11.3 (1.1) 9.9 (2.3) 10.2 (2.4) 10.7 (1.1) 8.5 (2.7) 11.2 (1.0) 10.2 (0.9) 22.9 (2.7) 24.0 (•.5) 22.4 (3.0) 23.6 (1.9) 23.3 (2.2)

1.92 (0.63) 1.87 (0.51) 1.53 (0.58) 2.•8 (0.69) •.65 (0.61)

12.4 (5.2) •4.6 (3.9) 13.7 (3.8) •6.0 (4.1) 11.7 (4.5) 60.7 (•0.4) 69.0 (•0.4) 61.7 (•3.3) 62.9 (11.1) 53.7 (•4.4)

27.1 (2.8) 27.1 (2.3) 27.1 (3.1) 28.5 (1.6) 26.9 (2.6) 23.2 (2.9) 23.6 (•.5) 21.8 (1.9) 23.5 (1.6) 21.1 (1.6)

88,5 (5.•) 87.2 (13.7) 76.7 (12.1) 93.3 (17.7) 84.0 (12.9)

295 (65) 277 (41) 302 (33) 263 (70) 259 (44) 394 (88) 413 (•28)460 (163) 354 (66) 397 (74)

0.7 (2.2) 0.2 (0.4) 1.3 (2.5) 0.6 (1.3) 1.2 (1.8)

VAs) demonstrated significant scopolamine effects upon the spatial recall, verbal recall, and visuospatial praxis variables at both the middle dose [spatial recall: Pillais' F{2,8} = 5.26, P < 0 . 0 5 ; verbal recall: Pillais' F{2,8}=22.82, P < 0 . 0 0 1 ; visuospatial praxis: Pitlais' F{4,6} = 5.96, P < 0.05) and the high dose (spatial recall: Pillais' F{2,8} = 6.00, P < 0.05; verbal recall: Pillais' F{2,8}=5.44, P < 0 . 0 5 ; visuospatial praxis: Pillais' F{4,6}=8.73, P<0 .05 ) but not at the low dose (spatial recall: Pillais' F{2,8} = 0.13, NS; verbal recall: Pillais' F{2,8}=2.16, NS; visuospatial praxis: Pillais' F{4,6} =0.78, NS]. None of the post-hoc analyses of simple main effects upon other dependent variables, including analyses of the immediate memory and recognition memory variables, revealed significant effects of drug administra- tion. Thus, none of the above analyses revealed significant effects of the low dose of scopolamine.

Order effects

Three-way ANOVAs and M A N O V A s including the group- ing variable Order were conducted in order to detect any order effects that might have been associated with the re- peated administration of the cognitive battery. In analyses of the eight key cognitive constructs no significant order

effects were found and there were no significant interactions between the Order factor and either the Drug Treatment factor or the Dosage Group factor.

Discussion

As has been repeatedly demonstrated in previous studies (Drachman and Leavitt 1974; Ghone im and Mewatdt 1975; Caine et al. 1981 ; Beatty et aI. 1986; Mohs et al. 1986) sco- polamine administration produced an impairment in the recall of verbal material f rom recent memory. The present study extends these findings by also revealing deficits on tests of visuospatial recall and visual recognition memory. There is a previous report o f a scopolamine-induced impair- ment on a picture recognition task (Dundee and Pandit 1972); however, subsequent investigations failed to reveal scopolamine effects on other verbal or visual recognition memory paradigms (Ghoneim and Mewaldt 1975; Beatty et al. 1986).

The tests of visuospatial praxis also proved sensitive to both the middle and high dose of scopolamine. These results are consistent with Drachman and Leavit t 's (1974) discovery of prominent deficits on the performance subtests

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of the WAIS after scopolamine administration. Caine et al. (J98I) likewise demonstrated impaired visual reproduction of matrix patterns after scopolamine injections. Mobs et at. (1986), using a dose of scopolamine equivalent to the middle dose in the present experiment, failed to discern a significant drug effect upon a copying task. However, performance on the task was near-perfect in all subjects so that the failure to detect a significant impairment may be attributable to a ceiling effect. In addition to deficits on tests of visuocon- structional praxis that are dependent upon motor coordina- tion, the present study also revealed a scopolamine-induced disruption of passive visuoperceptual function.

Psychomotor speed was also affected by scopolamine administration, especially the finger tapping speed measure. This effect is consistent with previous reports of slowed reaction time and motor speed after scopolamine adminis- tration (Caine et al. 1981; Nuotto 1983). The effect upon the pooled set of psychomotor speed variables - finger tap- ping, reaction time, and travel time - produced a significant interaction with the drug dose factor. The motor slowing is perhaps suggestive of the encroachment of non-specific sedative effects at the higher dose levels.

Since there was no significant interaction between the scopolamine effect and the dose effect for the other cogni- tive variables, it cannot be stated that the effects of the drug were dose dependent. However, it should be noted that the low dose of scopolamine (0.22 rag/70 kg) uniformly failed to produce significant effects upon test performance. An increase in anticholinergic signs (such as dryness of the mouth and pupil dilation) was observed in response to the low dose, but these effects were presumably peripherally mediated. The decrease in pulse rate produced by scopola- mine was probably a centrally mediated drug action. Injec- tions of methyl scopolamine, which should have difficulty crossing the blood/brain barrier, are followed by a mono- phasic increase in blood pressure and heart rate (Ketchum et al. 1973).

As has been previously reported (Drachman and Leavitt 1974), immediate memory as measured by the digit span subtest of the WAIS was unaffected by scopolamine admin- istration. Intact immediate recall in scopolamine-injected subjects was also apparent at the 0-s delay interval of the visuospatial recall task. It seems likely that the scopola- mine-induced decrease in hit rate at the 0-s delay interval of the facial recognition memory task might be attributable to factors other than immediate memory. It has been pre- viously suggested (Flicker et al. 1989) that this task, which is not subject-paced, is sensitive to both psychomotor speed and visuoperceptual function. Since scopolamine adminis- tration produced psychomotor slowing and deficient visuo- perceptual function (specifically including face matching ability), and did not affect the other two measures of imme- diate memory, the decrement in 0-s facial recognition mem- ory should probably be ascribed to deficits in the former cognitive capacities rather than to impaired immediate memory.

The lack of a scopolamine effect on object naming, ob- ject name recognition, object function recall, and object function recognition is consistent with the insensitivity to scopolamine of the WAIS verbal IQ (Drachman and Lea- vitt 1974). With regard to other language functions, some have reported a scopolamine effect on verbal fluency

(Drachman and Leavitt 1974; Caine etal. 1981), while others have not (Beatty et al. 1986; Mohs et al. 1986). This is a timed task that requires the retrieval from semantic memory of words in a specified category or with a specified initial letter. Drachman and Leavitt (1974) used a procedure that maximized the task's dependence upon the speed of word production, so the performance decrement they ob- served after scopolamine might have been secondary to a more general decline in cognitive processing speed rather than a specific language deficit.

The lack of a language deficit in scopolamine-injected young normals establishes a fundamental distinction be- tween the cognitive profile of "scopolamine dementia" and AD. Patients in even the early stages of AD exhibit a pro- nounced deficit on object naming tests (Flicker et al. 1987a) and this impairment is one of the three most common cogni- tive symptoms of the disorder (Sire and Sussman 1962).

The lack of a scopolamine effect on intrusions in the shopping list task establishes a second critical feature differ- entiating the cognitive effects of scopolamine from those of AD. This form of perseveration is characteristic of AD patients and has been associated with increased senile plaque concentrations and decreased choline acetyltransfer- ase levels in postmortem brain tissue (Fuld et al. 1982).

The lack of a scopolamine effect on digit span is a third feature differentiating the cognitive effects of scopolamine from the cognitive effects of AD. Patients advanced beyond the earliest stages of the disorder exhibit significant de- crements on this task (Ferris et al. 1980; Storandt et al. 1986).

In summary, the results of this study are clearly consis- tent with the viewpoint first adopted by Drachman and Leavitt (1974) from which the cognitive effects of scopola- mine in young normals are seen as quite similar to the cognitive effects of normal aging. Both conditions are asso- ciated with loss of recent memory, preserved immediate memory, impaired visuospatial praxis, deficient visuoper- ceptual function, psychomotor slowing, and intact language function (Flicker et al. 1986b). The effects of scopolamine administration upon cognitive function in young subjects have also been used as a model for the cognitive symptoms of AD (Davis et al. 1981). However, the present data argue against the validity of this approach. The errors of intru- sion, decreased digit span, and impaired object naming that are characteristic of AD patients (Fuld et al. 1982; Storandt et al. 1986; Flicker et al. 1987a) were not observed after the scopolamine injections.

It might be contended that dementia-like effects are eli- cited only by higher doses of scopolamine than those ad- ministered in the present study and that increased drug concentrations might yield a more useful model of demen- tia. However, higher scopolamine doses produce sedative effects (Serby et aI. 1984) and can induce drastic alterations in sensorimotor responsivity and vigilance state (Ketchum et al. 1973). Such changes in level of consciousness and in perceptual function are inconsistent with the defining characteristics of dementia (McKhann et al. 1984) and would hamper the delineation of the concomitant cognitive effects of the drug. These difficulties in specifying the cogni- tive processes affected by higher doses of scopolamine would tend to undermine the validity of the resulting model of cognitive dysfunction in AD.

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Acknowledgements. ]'his research was supported in part by grant #MH40410 from the National Institute of Mental Health. The authors thank Dr. Barry Reisberg for supervision of subject selec- tion, Grete Greene for assistance in manuscript preparation, and Elizabeth Mattin, Bart Rypma, and Scott Weber for assistance in test administration.

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Received April 13, I988 / Final version June 19, 1989