Minimal effects of dextroamphetamine on scopolamine-induced cognitive impairments in humans

Minimal Effects of Dextroamphetamine on Scopolamine-Induced Cognitive Impairments in Humans Rick Martinez, Susan E. Molchan, Brian A. Lawlor, Karen Thompson, Heidi Martinson, Georgia Latham, Herbert Weingartner, and Trey Sunderland

The central anticholinergic drug scopolamine has been used to model aspects of the memory impairment that occurs in Alzheimer's disease and in aging. To determine whether nonspecific stimulant effects can attenuate the cognitive impairment induced by scopolamine, we studied the effects of scopolamine and the stimulant dextroamphetamine in 17 young normal volunteers. After a baseline day of cognitive testing, subjects participated in two study days, in which they received dextroamphetamine (d-AMP) (0.25 mgkg po) + scopolamine (0.5 mg IV) and placebo + scopolamine, in randomized order under double-blind conditions. There were no statistically sign$cant differences in cognitive test pegormance between the two drug conditions with the exception of one of the category retrieval tasks. Stimulant effects were documented to occur by other measures. We conclude that d-AMP at the dose used does not attenuate the memory impairment induced by scopolamine. O 1997 Society of Biological Psychiatry

Key Words: Scopolamine, dextroamphetamine, stimulant, cholinergic, attention

Introduction The neurotransmitter acetylcholine has been well documented to have a role in learning and memory processes (Coyle et al 1983; Drachman 1977), and the deficits in the central cholinergic system in Alzheimer's disease (AD) From the Section on Geriatric Psychophmacology. Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland (RM, SEM, KT. HM, GL, TS); Section on Old Age Psychiatry, St. James Hospital. Dublin, Ireland (BAL); and Section on Cognitive Neurosciences, National Institute of Alcoholism and Alcohol Abuse, Bethesda, Maryland (HW). Address reprint requests to Susan E. Molchan, MD, Section on Geriatric Psychiatry, NIH Clinical Center, Bldg. 10, Rm. 3D41, 10 Center Dr., MSC 1264, Bethesda MD 20892-1264. Received July 17, 1995; revised November 28, 1995.

O 1997 Society of Biological Psychiatry

are thought to be related to memory impairment in that illness (Coyle et al 1983). Disruption of cholinergic function with the centrally acting anticholinergic drug scopolamine produces temporary amnesia in healthy subjects (Drachman 1977). Its effects, therefore, have been used to model aspects of the memory and other cognitive changes that occur with aging (when administered to young healthy volunteers) (Beatty et a1 1986; Drachman and Leavitt 1974; Flicker et a1 1990; Molchan et a1 1992a) and AD (when administered to older volunteers) (Sunderland et a1 1986; Molchan et a1 1992a). In a previous study, we found that the memory-impairing effects of scopolamine in young normal volunteers 0006-3223/97/$17.00 SSDI 0006-3223(95)00674-5

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Table 1. Descriptive Characteristics of 17 Normal Control Adults Age (years) Education (years) WMS-MQ Weight (kg)

Mean 2 S D

Range

28.4 ? 7.5 17.1 t 1.4 115.7 ? 13.0 72.0 2 13.0

19-51 15-20 92-143 48-93

-

WMS-MQ

=

Wechsler Memory Scale-Memory

Quotient

were attenuated by the administration of the peptide thyrotropin-releasing hormone (TRH) (Molchan et a1 1990). This tripeptide has been shown to have positive memory and learning effects in animal studies that appear to result from its neuromodulatory effects on cholinergic transmission (Okada 1991; Suzuki et al 1989; Yamamura et a1 1991; Yamazaki et a1 1986). TRH, however, has analeptic effects (Breese et a1 1975; Horita et al 1986), which may also explain its attenuation of scopolaniineinduced impairment. Few studies on the effects of stimulant drugs on scopolamine-induced impairment in humans have been done, and they have had varying results (Drachman 1977; Mewaldt and Ghoneim 1979). There is controversy on how much sedation and attentional impairment may contribute to scopolamine's cognitive effects (Curran et a1 1991; Dunne and Hartley 1986; Molchan et a1 1992a; Sunderland et a1 1989). Conjoint administration of scopolamine and stimulant drugs should help clarify this issue. We used the stimulant, dextroamphetamine (d-AMP), which is known to enhance dopamine and norepinephrine release and block catecholamine reuptake at the synapse (Kuczenski 1983). If, in our prior study, TRH attenuated the effects of scopolamine simply because of its analeptic properties, then its attenuation of scopolamine-induced memory impairment should be mimicked by the stimulant d-AMP.

Methods Subjects Seventeen young normal volunteers (6 women; 11 men; mean age + SD = 28.4 + 7.5 years) were screened with a complete history, physical exam, and routine laboratory tests (Table 1). Individuals with a personal history of psychiatric illness, substance abuse, or medical illness were excluded. Assessment of each subject's intellectual functioning was made using the Wechsler Memory Scale (Wechsler 1987). Subjects were medication free for at least 2 weeks before beginning the protocol. Each subject was also abstinent from any stimulants or alcohol for at least 48 hours prior to each study day. Subjects partici-

51

pated after informed consent and were paid for their participation.

Procedure Subjects first participated in a practice day, considered to be a baseline day, during which they completed the battery of cognitive tests, summarized below. Subsequently, on 2 study days, separated by at least 48 hours, subjects were randomly assigned to two treatments, placebo + scopolamine and d-AMP + scopolamine. On each study day, prior to drug administration, behavioral ratings were done (see below). A reaction time task (described below) was also completed at baseline. Subjects were then administered either oral placebo or oral d-AMP (0.25 mgkg) in a double-blind, randomized fashion. Thirty minutes later the subjects were given intravenous (IV) scopolamine hydrobromide (0.5 mg) through an indwelling antecubital catheter. Behavioral ratings and a reaction time task (see below) were repeated 90 and 150 min after d-AMP or placebo administration (1 and 2 hours after scopolamine). Cognitive testing began 150 min after d-AMP administration (2 hours after scopolamine). The timing of drug administration and cognitive testing was chosen because the effects of i.v. scopolamine have been shown to peak from 90 to 150 min after administration (Safer and Allen 1971). Peak plasma levels of orally administered d-AMP (0.25 mgkg) have been shown to peak 2-3 hours after drug ingestion (Angrist et a1 1987). Scopolamine was given as a fixed dose because it has been shown that there is less variability in its effects when given as a fixed dose rather than on a mgkg basis (Safer and Allen 1971).

Behavioral Ratings Behavioral ratings consisting of 100-mm visual analog scales that evaluated level of alertness, mood, and physical side effects (Guy 1976; McNair et a1 1971) were completed by subjects at the time points noted above. The brief psychiatric rating scale (BPRS) (Overall and Gorham 1962) was completed by a trained staff member who was blind to drug condition.

Cognitive Tests The battery of cognitive tests used during the study can be used to assess the major domains of memory functioning and included: SELECTIVE REMINDING TASK. Subjects Were read a list of 12 unrelated words and were then asked to recall all of them. Words not recalled were repeated by the examiner and subjects were again asked to recall all of the 12 words

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(Buschke 1973). This process was repeated for a total of 8 trials. Scores for free recall and consistency of recall (recall of words that occurred without reminding) were evaluated across trials. This test has been frequently used as a method for assessing explicit memory functions (those processes that require awareness of the source of what is remembered) (Buschke 1973; Weingartner et al 1983). VIGILANCE/MEMORY TASK. Subjects were read a list of 12 categorically related words, (e.g., vegetables). Six of the words were repeated and six of the words read only once. Subjects were instructed to signal the examiner when a word was repeated and the number of correctly identified twice-presented words was used as an index of vigilance-attention and working memory (Sunderland et al 1987). After a distracter task, subjects were asked to recall as many items from the original list as possible; this was recorded as a measure of free recall (explicit memory) of these categorically related words. Next subjects were read a list of 24 categorically related words, 12 of which were from the previous list (targets) and 12 of which were new (distracters). Subjects were asked to indicate whether a word was old or new to them. The number of correctly identified words was scored separately for old and new words, and was used as a measure of recognition memory. Of the correctly identified old words, subjects were asked to judge the frequency of presentation (once or twice). The difference between the mean reported frequency of once- and twice-presented words was used as a measure of automatic memory processes (those that occur without conscious attention) (Weingartner et a1 1984). CATEGORY RETRIEVAL. Subjects were provided with two different categories of names and asked to generate as many categorically related examples (words) as possible within a 90-sec period. Subjects were then presented with two different letters and asked to generate words beginning with each letter, also for a period of 90 sec. One set of word and letter stimuli was the same for each subject (structured), the other set of stimuli was variable (random). This task was used as a measure of retrieval of knowledge in long-term memory (Battig and Montague 1969). REACTION TIME TASK. Reaction time, a measure of psychomotor performance and sustained visual attention, was measured using a cognitively weighted choice reaction time task (Latham et a1 1990). Randomly selected digits were presented on a computer screen one at a time and the subject responded by pressing the matching digit on a keyboard. The data collected during the first 1 min of

the task were output for analysis. The time between stimuli was user-dependent. As soon as the subject responded to a stimulus, it was replaced with the next stimulus.

Statistical Analysis Cognitive and behavioral data were first examined for the presence of the effect of order of treatment (placebo + scopolamine vs. amphetamine + scopolamine) by including order in the initial repeated measures analysis of variance (ANOVAR) model (SAS, version #5.18, Cary, NC). Order was not found to be a significant variable, therefore all further analyses were conducted without regard to order (carryover) effects. ANOVAR was then used to assess drug effects on the cognitive data and time and drug effects on the behavioral and reaction time data. These analyses were followed by post hoc contrast comparisons (using one-way ANOVA) when the overall ANOVAR was significant. The Greenhouse-Geisser correction was used for all analyses. To assess changes in cognitive test performance from baseline, i.e., the training session, this session was included in the ANOVAR, though it was not a blinded condition. Its inclusion was based on prior data documenting that such baseline testing does not differ significantly from a placebo day of testing (Molchan et al 1992a; Sitaram et a1 1978; Tariot et al 1987). For the BPRS, data were analyzed as stated above after the individual factors were clustered into preestablished subscales (Overall and Gorham 1962).

Results Cognitive Tests The statistically significant differences among study conditions were found to be primarily secondary to differences between the baseline and the two drug conditions (Table 2). The only significant differences between the placebo + scopolamine and d-AMP + scopolamine conditions occurred on one of the category retrieval tasks and on the reaction time task (Table 2). The subjects' performance on the choice reaction task, 1 and 2 hours following scopolamine administration, was significantly slower after placebo + scopolamine compared to d-AMP + scopolamine [F(1,16) = 8.73, p < .009] (Table 2). The drug X time interaction was significant at F(2,32) = 7.42, p < .002 overall, and was significant for both the 90- and 150-min time points, F(1,16) = 10.96, p < .004 and F(1,16) = 10.81, p < .005), respectively.

Behavioral Effects In the analysis of the subject's self-ratings, only "fatigue" and "euphoria" yielded significant drug X time effects

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53

Table 2. Comparison of Cognitive Effects across Baseline and Drug Conditions Cognitive tasks Selective reminding Free recall Recall consistency Vigilancelmemory task Vigilance-attention Free recall Recognition of old words Recognition of new words Word frequency Reaction time Time (sec) Accuracy Category retrieval Random words Random letters Structured words Structured letters

Baseline training session

Placebo + scopolamine

d-AMP + scopolamine

F

P

10.53 + 1.01 0.81 + 0.20

8.30 t 1.70 0.60 ? 0.24

8.68 t 1.42 0.61 t 0.23

27.02 22.72

,0001 .0001

5.70 + 0.60 8.72 2 1.30 11.40 + 1.04

5.44 + 0.70 6.61 + 1.85 10.33 + 1.14

5.40 t 0.60 6.71 t 2.00 10.80 t 1.30

1.18 7.72 6.77

NS ,002 ,003

10.30 + 1.30

9.60 + 1.82

9.82 t 1.30

0.97

NS

0.60 + 0.30

0.33 t 0.40

0.24 t 0.40

3.83

.03

0.82 t 0.15 0.97 + 0.03

0.91 t 0.16 0.96 t 0.03

0.84 t 0.15" 0.97 t 0.03

6.71 0.06

,004

24.56 ? 7.20 21.06 t 5.55 42.10 t 9.20 27.00 + 7.62

19.30 t 4.50 20.33 + 8.33 35.40 + 5.84 27.30 2 7.74

21.70 + 5.10 23.70 2 6.80 39.60 2 6.70" 28.80 + 6.20

4.06 2.43 6.69 0.60

.04

NS

NS .04 NS

Values are mean 2 standard deviation. Statistics are for initial ANOVAR across all conditions. Difference between placebo + scopolamine and d-AMP scopolamine for reaction time ( F = 8.73, p < ,009) and for structured words (F = 7.95, p < .01). For reaction time, baseline score is the mean of the scores from the 2 study days; reaction time scores for the drug conditions are the mean of the +90 and + 150 time points from each day.

+

(Table 3). The mean scores show that d-AMP attenuated the increase in "fatigue" induced by scopolamine. On the ANOVAR, several significant time effects were seen (Table 3); these were between the baseline and 120-min time points. For the subscale and total BPRS scores, no overall drug X time or drug effects were seen. Significant overall time effects were seen for three of the subscales and the total score (Table 4). Post hoc analysis revealed that these resulted from differences between the baseline and 120-

min time points, and in addition between the baseline and 60-min point for "anergia" and the total score.

Discussion Scopolamine caused significant cognitive impairment, as expected from results of many prior studies (Beatty et a1 1986; Drachman 1977; Flicker et al 1990; Molchan et a1 1992a; Sunderland et al 1987). D-AMP did not significantly attenuate the cognitive effects of scopolamine

Table 3. Comparison of Behavioral Self-Ratings (Visual Analog Scale) across Baseline and Drug Conditions Measure

Baseline

Placebo + scopolamine

d-AMP + scopolamine

F

P

9.8 t 7.1 34.0 + 21.0 6.4 + 4.5 22.5 + 17.0 34.0 + 32.0 13.0 t 18.3" 22.4 t 18.0" 22.0 t 14.0 6.5 t 4.0 31.4 t 20.2 8.0 t 8.0 8.5 t 12.0

6.59 12.74 2.25 15.11 10.77 1.08 4.45 33.75 0.54 40.29 2.75 1.71

,009 ,001 NS

-

Anxious Alert Sad Energetic Trouble concentrating Euphoria Fatigue Dizzy Sweaty Drowsy Nauseated Warmlflushed

19.0 t 14.0 55.0 + 19.2 9.3 + 11.5 39.0 + 20.3 9.0 t 6.6 7.0 t 8.0 16.0 t 10.2 5.3 t 4.4 7.0 t 6.3 16.5 t 10.0 4.5 t 3.0 4.2 + 2.4

7.6 + 6.0 32.0 + 17.0 6.5 + 7.6 15.0 2 14.6 28.0 + 21.0 4.5 2 2.0 34.0 + 13.0 25.0 Z 19.3 5.0 + 3.0 26.0 15.1 7.8 + 7.0 8.3 + 11.3

+

.OOO4 .001 NS .02 .OOO1 NS .0001 NS NS

Values are mean 2 standard deviation. Baseline values are the mean of the baselines from each of the 2 drug study days. The values given under each drug condition are from the 120-min time point. Statistics are for the overall ANOVAR across all three conditions for time. "For "euphoria" and Yatigue" the drug X time interaction was significant (F = 4.45, p < .04 and F = 7.80, p < ,005, respectively).

54

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BlOL PSYCHIATRY 1997;41:50-57

Table 4. Comparison of Behavioral Ratings across Baseline and Drug Conditions by Subscale of Modified 24-Item Brief Psychiatric Rating Scale (BPRS) BPRS subscale

Baseline

Placebo + scopolamine

d-AMP + scopolamine

F

P

Depression Anxiety-depression Hostility Anergia Activation Thought disorder Mania Impairment Total score Values are mean i- standard deviation. Baseline values are the mean of the barielines from each of the 2 drug study days. Statistics are for overall time effect across all three conditions. No significant drug X time or drug effect was seen.

except on one of the four category retrieval tasks, though increased word output was seen after d-AMP for all four categories tested (Table 2). Increased verbal output is a known effect of d-AMP (Stitzer et a1 1978) and may have contributed to this effect. Subjects' decrease in psychomotor speed as measured by the reaction time task during the placebo + scopolamine condition was significantly improved during the d-AMP scopolamine condition. This is an indication that the effects of scopolamine on psychomotor slowing and sustained visual attention were attenuated, and that the relatively low dose of d-AMP administered was enough to cause a stimulant effect (Rapoport et a1 1980). The portion of the vigilance1 memory task that was used as a measure of attention and working memory was not significantly affected by scopolamine. This type of task has been shown in prior studies to be relatively insensitive to the effects of scopolamine at the dose used (Molchan et a1 1992a for review). On both study days, subjects reported feeling fatigued after drug administration, which corroborated with observer ratings for the BPRS subscales of anergia, thought disorder, and impairment. Subjects felt significantly less fatigued on the day they received d-AMP as compared with placebo (Table 3). As with the reaction time data, lessened fatigue during the day subjects received d-AMP is an indication that the d-AMP did indeed have a stimulant effect. On the other hand, observer ratings for the BPRS subscales did not indicate any significant attenuation of the scopolamine effect by the stimulant (Table 4). The self-rating in this instance appears to have been a more sensitive measure of degree of fatigue. This is not unexpected, as the BPRS was not designed to measure acute drug effects in normal control subjects (Overall and Gorham 1962). These findings contrast with findings in some early studies of the behavioral effects of the two drugs in animals. In those studies, scopolamine and

+

psychostimulants had synergistic effects on enhancement of locomotor activity and stereotyped behaviors (Oka and Hosoya 1977). Some controversy exists about the etiology of the amnesuc and other cognitive effects of scopolamine. It has been argued that the effect is nonspecific, and not necessarily related to its central antimuscarinic action on memory itself. These arguments stat that the drug's effects relate more to its sedative properties and its impairment of attention (Curran et a1 1991; Dunne and Hartley 1986). Support for this argument comes from the fact that other sedating agents such as benzodiazepines, which do not have direct antimuscarinic activity, can also impair recent memory and attention (Curran et a1 1991). This assertion though, is challenged by data collected during a comparison of the effects of low-dose lorazepam (1 mg po) and scopolamine (0.25 mg IV). That study reported equal levels of sedation secondary to the two drugs in a group of AD patients, though with marked memory impairment documented after scopolamine and not after lorazepam (Sunderland et a1 1989). This study's results therefore suggested that sedation was not sufficient cause for the cognitive impairment caused by scopolamine. Another approach to this controversy is to examine whether the cognitive and sedative effects of scopolamine are alleviated by administration of pharmacologic agents that do or do not enhance cholinergic system function. It has been clearly shown that drugs that enhance cholinergic function such as arecoline and physostigmine reverse scopolamine-induced impairment (Bartus 1978; Drachman 1977; Mewaldt and Ghoneim 1979; Sitaram et a1 1978). We previously reported an attenuation of scopolamine's cognitive effects with the neuropeptide TRH (Molchan et a1 1990), as well as a mild enhancement of cognitive performance in patients with Alzheimer's disease after TRH (Molchan et a1 1992b). While TRH has

Scopolamine-Induced Cognitive Impairment

documented procholinergic properties (Breese et al 1975; Horita et al 1986; Suzuki et a1 1989; Yamamura et a1 1991; Okada 1991), it also has been reported to have analeptic effects in animals (Horita et a1 1986). The paucity of cognitive effects of d-AMP on scopolamine-induced cognitive impairment in this study suggests that our previous finding of attenuation of scopolamine-inducedimpairment by TRH may not have been secondary to a nonspecific analeptic effect, and was a more specific cholinergic effect. Other investigators have explored the effects of stimulant compounds on scopolamine-induced memory impairment in animals (Bartus 1978; Yamazaki et al 1986) and humans (Drachman 1977; Mewaldt and Ghoneim 1979). As with Drachman (1977), we observed no significant attenuation of free recall impairment after amphetamine. The Drachman study also found no significant effect on semantic memory impairment, though we found an attenuation of effect on one of the four category retrieval tasks used. Perhaps with higher doses more attenuation of scopolamine's effects would have been seen on this test, and it may relate to the enhanced verbal output that has been shown to occur after d-AMP (Stitzer et a1 1978). In Drachman's study, subjects received a set dose of 10 mg po d-AMP, whereas our subjects received d-AMP on a milligram per kilogram basis (approximately 18 mg po for an average 70-kg man). Another difference from the Drachman study was the timing of the cognitive testing. In our study, cognitive testing started 2.5 hours after the oral amphetamine administration, a time known to correlate with peak behavioral effects and rising serum levels (Angrist et a1 1987). The cognitive testing in the Drachman study was performed 30 min after drug administration, possibly too early to document an effect. Results of one prior study using methamphetamine in humans found significant improvement in delayed recall of information in scopolamine-treated individuals (Mewaldt and Ghoneim 1979). Those authors hypothesized that their results differed from those of Drachman for two reasons. First, methamphetamine has more potent central effects than d-AMP, which Drachman used. Second, they used a higher stimulant dose (0.2 and 0.3 mgkg vs. 10 mg orally, which is approximately equivalent to 0.1 mgkg for an average 70-kg man) and lower scopolamine dose (8 pgkg vs. 1 mg subcutaneously, which is equivalent to 14

BIOL PSYCHIATRY 1997:41:50-57

55

p g k g for an average 70-kg man) than Drachman (Mewaldt and Ghoneim 1979). As noted above, scopolamine has been used to model aspects of the memory impairment that occurs in Alzheimer's disease (Sunderland et al 1986; Molchan et a1 1992a), as a central cholinergic deficit is related to the memory deficit in that illness (Coyle et a1 1983). This had been the rationale for attempts to treat Alzheimer's disease using centrally active cholinergic drugs (Davis et a1 1992; Knapp et a1 1994). Cholinergic drugs have stimulant effects; it is possible that these effects are responsible for the mild improvement seen in cognitive performance in some studies (Sahakian et al 1993). Our documentation of a significant attenuation of scopolamine's effects by dAMP on reaction time and on one category retrieval task, with movement toward attenuation on the others, may be consistent with this idea. Patients with Alzheimer's disease are known to have deficits in reaction time and other attentional measures, as well as in explicit memory, including retrieval from knowledge memory, which these tests evaluate. We have a study underway to evaluate the effects of more chronically administered d-AMP in Alzheimer's patients to address some of these issues.

Conclusions The focus of this experiment was to extend our study of the scopolamine model of memory impairment, utilizing a stimulant drug. Scopolamine-induced cognitive impairment was not found to be attenuated by preadministration of d-AMP for most of the cognitive measures examined. In a prior study, we found that the peptide TRH, which has procholinergic and analeptic effects, attenuated the effects of scopolamine (Molchan et a1 1990). The pattern of attenuation of scopolamine impairment previously reported with TRH was not mimicked by d-AMP. These data suggest that the neuropeptide mediates cognitive processes independent of its analeptic effects and supports its as role as a procholinergic agent (Horita et al 1986; Molchan et al 1990; Yamarnura et al 1991;Yamazaki et a1 1986). Our data also indicate that the amnestic effects of scopolamine are not simply secondary to the sedative and attention-impairing effects of the drug, at least at the doses used in this study.

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