Academic journal article Cognitive, Affective and Behavioral Neuroscience

Differential Effects of Scopolamine and Lorazepam on Working Memory Maintenance versus Manipulation Processes

Academic journal article Cognitive, Affective and Behavioral Neuroscience

Differential Effects of Scopolamine and Lorazepam on Working Memory Maintenance versus Manipulation Processes

Article excerpt

Between-study comparisons of benzodiazepine and anticholinergic drugs on working memory suggest that anticholinergics may produce greater impairment in maintenance processes, whereas benzodiazepines may produce greater impairment in manipulation processes. This study directly compared acute effects of the benzodiazepine lorazepam (1.0 and 2.0 mg/70 kg, orally administered) and the anticholinergic scopolamine (0.25 and 0.50 mg/ 70 kg, subcutaneously administered) on working memory maintenance (storage and rehearsal) and manipulation processes in a placebo-controlled, double-dummy, double-blind, crossover design in 20 healthy volunteers. Using a modified Sternberg paradigm, storage, rehearsal, and manipulation processes were parametrically manipulated by varying memory load, delay between stimulus presentation and test, and number of operations performed on the letter strings, respectively, while controlling for drug effects on nonmemory processes. As predicted, the results suggested greater impairment in maintenance processes (rehearsal) with scopolamine than with lorazepam and greater impairment in manipulation processes with lorazepam than with scopolamine. In addition, the results suggested greater overall slowing of working memory processes with lorazepam.

It is well established that benzodiazepine (e.g., diazepam, or Valium; lorazepam, or Ativan) and anticholinergic (e.g., scopolamine) drugs induce temporary amnesia when administered acutely to healthy volunteers (for reviews, see Curran, 1991, 2000; Kopelman, 1986; Polster, 1993). Several researchers (Duka, Curran, Rusted, & Weingartner, 1996; Hirshman, Passannante, & Arndt, 2001; Mintzer & Griffiths, 2001b; Polster, 1993; Reder et al., 2006) have argued that, like neuropsychological studies of brain-damaged patients, which have played a critical role in advancing the understanding of normal and abnormal memory mechanisms, investigation of drug-induced amnesia can also be a powerful tool for elucidating memory mechanisms. In fact, investigation of drug-induced amnesia has several distinct advantages over traditional studies of amnesic patients. Most importantly, unlike the memory deficits found in amnesic patients, effects of drugs on memory processes are reversible and can be empirically manipulated in controlled laboratory experiments with large numbers of healthy volunteers. Furthermore, the quantitative dosing properties of drugs can be exploited to produce a graded amnesic effect in a dose-effect design. Findings of selective effects of drugs on particular aspects of memory performance but not others, or of dissociations between drugs, can provide converging evidence with data from nonpharmacological studies for the dissociability of specific processes or subcomponents (see Hirshman, Fisher, Henthorn, Arndt, & Passannante, 2002; Hirshman et al., 2001; Mintzer, 2003; Mintzer & Griffiths, 2001b). In addition, comparison of memory-impairing drugs with distinct neurochemical or pharmacological mechanisms of action can elucidate the brain mechanisms underlying specific cognitive processes.

The present experiment was designed to compare the acute effects of the benzodiazepine lorazepam and the anticholinergic scopolamine on working memory processes. Benzodiazepines facilitate the action of gammaaminobutyric acid (GABA) by acting as agonists at specific sites on the GABA^sub A^ receptor complex (Mohler & Okada, 1977; Squires & Braestrup, 1977), whereas scopolamine inhibits the action of acetylcholine by acting as an antagonist at muscarinic cholinergic receptors (Ketchum, Sidell, Crowell, Aghajanian, & Haines, 1973). Working memory refers to the temporary maintenance and online manipulation of a limited amount of information in the service of current behavioral goals (Baddeley, 1986, 1992; for recent reviews, see D'Esposito, 2001; Smith & Jonides, 1998). The concept of working memory was originally introduced by Baddeley (1986) and replaced earlier conceptualizations of a unitary, passive, short-term storage system (Atkinson & Shifrrin, 1968). …

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