R109B What causes retrograde facilitation under midazolam? 1 Running head: What causes retrograde facilitation under midazolam? Retrograde Facilitation under Midazolam: The Role of General and Specific Interference

In a double-blind, placebo-controlled experiment that used midazolam, a benzodiazepine that creates temporary amnesia, we compared acquisition and retention of paired associates of different types. Some word pairs were studied before the injection of saline or midazolam, and two lists of word pairs were studied after the injection. Critical comparisons involved retention of pairs that were practiced on all three lists, pairs studied on only one list and pairs that involved recombining cue and response terms from one list to the next, as a function of drug condition. Previous research with benzodiazepines had found retrograde facilitation for material acquired prior to injection compared with the control condition. One explanation for this facilitation is that the anterograde amnesia produced by the benzodiazepine frees up the hippocampus to better consolidate previously learned material (Wixted 2004, 2005). We accounted for a rich data set using a simple computational model that incorporated interference effects (cue-overload) at retrieval for both general (experimental context) interference and specific (stimulus term) interference without the need to postulate a role for consolidation. R109B What causes retrograde facilitation under midazolam? 3 Retrograde Facilitation under Midazolam: The Role of General and Specific Interference Psychologists have long investigated the class of mechanisms that affect retention of past experience. Wixted (2004, 2005) notes that psychologists have ignored the role of consolidation while debating the role of interference and decay as mechanisms of forgetting. He reviewed evidence from psychology, psychopharmacology and neuroscience to argue that the traditional psychological theories of forgetting “may not be relevant to the kind of interference that induces most forgetting in everyday life (p. 6).” Wixted reviewed evidence from psychopharmacology to support the claim that general interference or “mental exertion” is a major determinant in whether information is forgotten. In particular he noted that benzodiazepines, which produce amnesia for material learned after the drug, create retrograde facilitation for material learned before the drug. He argues that this results from the absence of mental exertion. This paper reports a new study that is designed to attempt to understand the mechanisms that underlie the retrograde facilitation observed under the influence of benzodiazepines. Studies using benzodiazepines, such as diazepam (Valium) and alprazolam (Xanax), as well as alcohol have been used to induce temporary anterograde amnesia. Information presented after ingesting this drug tends not to be learned; however, information acquired prior to the drug is actually better retained than it would have been had the subjects received the control (saline) instead of the drug. R109B What causes retrograde facilitation under midazolam? 4 This “retrograde facilitation” was interpreted as resulting from enhanced consolidation for material acquired prior to the amnesia. Wixted (2004) writes: “To summarize, sleep, alcohol, and benzodiazepines all result in retrograde enhancement of memory, and, theoretically, they all do so for the same reason: The reduced rate of memory formation protects recently formed memories from interference, interference that would otherwise arise because of the demands placed on a limited-resource hippocampal system (p.257).” The studies that have examined the effect of benzodiazepines on memory have compared retention of lists studied prior to injection of drug vs. saline as well as the more obvious comparison of retention of lists given post-injection. However, those studies involved free recall and thus were not able to compare retention of pre-injection items as a function of the type of items learned postinjection. If retrograde facilitation results from a reduced rate of memory formation post injection, then the type of information acquired should not necessarily matter. An alternative account that we propose posits that the facilitation for the items acquired pre-injection results from a reduction in interference rather than an increase in the ability to consolidate. The experiment reported here compares these conditions using the drug midazolam, a benzodiazepine that produces transient anterograde amnesia. It is a fast acting anxiolytic used routinely in medical procedures including dental and pediatric surgeries. In a cued recall task retention of a list studied prior to drug injection is compared with performance on a list studied prior to an injection of saline. The experiment uses a double-blind, within-subject design (subjects get R109B What causes retrograde facilitation under midazolam? 5 saline on one day and midazolam on a different day). Subjects study word-pairs and their cued-recall accuracy and latency for correct responses is measured. Of particular interest is performance on the item pairs from the list given prior to the injection (List 1) as a function of drug condition. The pairs do not differ prior to injection. It is their treatment post-injection that differentiates them. Specifically, one-third of the pairs are repeated on each list (practice pairs), one-third are only studied on one of the three lists (control pairs) and the other third have a changed cue-to-response mapping from list to list. When pairs are learned with a saline injection, we expect final cued recall performance to be best for the practiced pairs and worst for the “cue-overload” pairs, i.e., the ones for which there are multiple responses for each cue. (Which one is to be recalled at test depends on the list cue provided along with the stimulus word.) The pairs seen in only one list are expected to be intermediate in performance. Of interest is how these various conditions are affected by midazolam and how retention of List 1 pairs learned prior to the injection differs as a function of drug condition and type of pair. We develop a simulation of the experiment to try to account for the cued recall performance (including response times and errors at final test) for the different pair-types in both drug conditions. Of particular interest is whether we need to posit a role for consolidation to explain the empirical results.