Does Scopolamine Directly Impair Memory? Ellen Gmber, Rosanne M. Leipzig, Richard B. Upton, Wendy Wisniewski, Mary Schroeder, Peter Davies, Wdter Ritter and Herman Buschke Albert Einstein College of Medicine Montefiore Medical Center Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 Introduction are ameliorated by cued recall or recognition (Ghoneim & Mewaldt 1977; Caine, Weingartner, Ludlow, Cudahy, An important goal in the investigation of human mem- & Wehry 1981). Inconsistency in free recall provides fur- ory is to elucidate the role of the cholinergic system. ther evidence of a retrieval deficit; words retrieved on Evidence from three areas of research suggests a ma- one trial may not be retrieved on the next (Caine et al. jor role for the cholinergic system in human memory: 1981). (1) pharmacological studies demonstrate that cholinergic Besides disrupting free recall, scopolamine also dis- blockade disrupts free recall in young normal subjects, rupts attention. Specifically, scopolamine has been (2) post-mortem studies demonstrate cholinergic deple- shown to reduce the level of active attentional con- tion in patients with Alzheimer’s disease (AD) and other trol that subjects can exert when processing information dementias, and (3) clinical studies demonstrate that choli- (Dunne & Hartley 1985,1986). The subject’s attention is nomimetric drugs improve memory in patients with AD. diffused or unfocused. In dichotic listening tasks, this is These studies are reviewed elsewhere (Kopelman 1986). suggested by decreased recall of words from the attended The purpose of the present study is to re-evaluate the channel and increased recall of words from the unat- claim that cholinergic blockade produces direct memory tended channel (Dunne & Hartley 1985). In visual infor- impairment. Previous studies show that scopolamine, an mation processing, unfocused attention following scopol- anticholinergic drug, disrupts free recall using a variety of amine intoxication is shown by increased detection of doses and routes of administration (Drachman & Leavitt targets in low probability locations as well as decreased 1974; Beatty, Butters, & Janowsky, 1986; Nissen, bop- detection of briefly presented target letters in high proba- man, & Schacter 1987; Kopelman & Corn 1988). The bility locations (Dunne & Hartley 1986). Sensitivity decre- free recall deficit is presumed to involve both encoding ments in vigilance tasks during scopolamine intoxication and retrieval mechanisms. Encoding mechanisms have also suggest an inability to maintain voluntary control of been implicated because the deficit does not occur if ini- attention over extended periods (Wesnes & Warburton tial learning takes place before the drug is administered 1983, 1984; Broks, Preston, Traub, Poppleton, Ward, & (Ghoneim & Mewaldt 1975; Peterson 1977); words en- Stahl 1988; Wesnes, Simpson, & Kidd 1988). coded into memory prior to scopolamine administration Scopolamine also may serve to reduce the already lim- can be retrieved during intoxication. Retrieval mecha- ited processing resources available in working memory nisms have been implicated because free recall deficits (Baddeley 1986). Based on the marked impairments Grok et al. 327 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 that intoxicated subjects displayed on a range of de- must be supplemented by effective cued recall to obtain manding information processing tasks, Wesnes et al. maximum retrieval. The sum of free and cued recall is (1988) suggested that scopolamine reduces the amount termed “total recall.” Total recall provides the best esti- of processing resources available to evaluate incoming mate of the amount of information a subject can encode information. While they did not directly test whether and retrieve. scopolamine-induced processing deficits produce mem- Enhanced cued recall demonstrates memory capabili- ory impairment, they suggested the possibility. If scopol- ties which may not be revealed unless deficits in attention amine disrupts the control of attentional resources and/or and other cognitive processes are circumvented. For ex- reduces the amount of processing resources, the effect ample, nondemented elderly subjects who show deficits of such disruptions on free recall needs to be tested di- in free recall display intact total recall when enhanced Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 rectly. cued recall is used (Grober & Buschke 1987; Grober, The free recall deficit induced by scopolamine has Buschke, Crystal, Bang, & Dresner 1988a). In contrast, been used to support the claim that cholinergic block- patients with dementia or amnesia display deficits in both ade disrupts encoding and retrieval mechanisms. In this free and total recall; their retrieval deficit cannot be over- study, we consider an alternative interpretation based on come by the addition of cued recall. We have suggested the fact that free recall depends on other cognitive fac- previously that free recall deficits which are completely tors such as attention and processing resources as well eliminated by enhanced cued recall may be due to indi- as specific memory mechanisms. Reduction in the abil- rect effects of impairment of other cognitive processes. In ity to direct attention and focus on each word as it is our view, only deficits in free recall which cannot be elim- presented for learning could impair free recall in the fol- inated by enhanced cued recall or similar procedures can, lowing way. Before the to-be-remembered words can be with relative confidence, be considered genuine mem- encoded into memory, each word must be attended to, ory deficits. Here, direct impairment of memory mech- decoded, and related to existing knowledge; only then anisms is shown by diminished cued recall in spite of can the resulting representation be stored. If an adequate adequate attention and cognitive processing and coor- representation is not formed, recall failure could occur. dination of encoding and retrieval (Buschke & Grober Impaired free recall may also occur because of an inabil- 1986; Grober, Buschke, & Bang 1988a). To analyze the ity to use appropriate retrieval strategies. For example, effects of scopolamine on memory, it is important to dis- reductions in the distribution or amount of attentional tinguish between direct effects due to impairment of spe- resources could interfere with the identification or ex- cific memory mechanisms such as encoding or retrieval ecution of effective strategies which permit subjects to and indirect effects due to impairment of other cogni- fully demonstrate their capacity for retrieval. Thus, free tive processes which are necessary but not sufficient for recall deficits may result from impairment of the sup memory and learning. However, this is not to deny that porting cognitive operations essential to normal memory in real life many older people have memory problems; functioning as well as to dysfunction of memory mech- rather, it emphasizes that their memory problems may anisms themselves (Buschke 1987; Grober & Buschke be secondary to impairment of other cognitive processes 1987). which may require different treatment. Since scopolamine disrupts attention and information Two experiments were conducted to determine wheth- processing, impaired free recall following scopolamine er or not scopolamine produces such genuine memory intoxication may reflect indirect effects on attention and impairment. If scopolamine disrupts memory mecha- other cognitive processes rather than direct drug effects nisms directly, deficits in total recall as well as free recall on memory mechanisms. To distinguish between these should occur, consistent with previous findings of gen- two possibilities, we used the procedure of enhanced uine memory impairment in demented and amnestic sub- cued recall to control attention and cognitive process- jects (Grober et al. 1988a). If instead, enhanced cued re- ing (Buschke 1984). Enhanced cued recall begins with call eliminates the retrieval deficit as shown by intact total a search phase in which subjects search for and identify recall when free recall is impaired, then scopolamine may items (e.g., onion) in response to category cues (e.g., veg- not produce genuine memory deficits. In the first experi- etable). The search is intended to optimize encoding by ment, we compared performance on a 16-item enhanced circumventing inattention and inducing appropriate se- cued recall test after administration of 0.7 or 0.8 mg of mantic processing; it also demonstrates that the specified scopolamine to a baseline condition. Because total recall operations have been executed. The search also pro- was unaffected, we conducted the second experiment in motes optimal retrieval because the same cues are used which subjects performed a 32-item enhanced cued re- for encoding and retrieval to assure encoding specificity call test after administration of either active placebo, 0.5, (Thomson & Tulving 1970; Tulving & Thomson 1973; or 1.0 mg of scopolamine. Robust total recall persisted Tulving 1979; Schacter & Tulving 1982). Because free despite high doses of scopolamine and clinical delirium, recall does not result in the retrieval of all items avail- consistent with the hypothesis that cholinergic blockade able in memory (Tulving & Pearlstone 1966), free recall does not produce genuine memory impairment. 328 Journal of Cognitive Neuroscience Viutne 1, Number 4 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 Table 1 FREERECALL* TOTALRECALL* Amount of DN8cme> Basehe Treatment Baseline Treatment 12 3 12 3 12 3 123 1 30 .7t 14 15 16 35 5 16 16 16 16 16 15 Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 2 27 .7 16 16$ 16$ 10 9 10 16 16$ 16$ 16 16 16 3 22 .7 13 15 15 67 7 16 16 16 15 15 16 4 35 .8t 12 14 16 13 7 16 16 16 11 14 16 Free Recall and Total Recall for Individual Subjects in Study 1.