Differential effects of MDMA and scopolamine on working versus reference memory in the radial arm maze task
Introduction
(±) 3,4-methylenedioxymethaphemtamine (MDMA) is a ring-substituted amphetamine that is chemically related to hallucinogens and stimulants (Farre et al., 2004) that acts as both an indirect serotonin (5-hydroxytryptamine, or 5-HT) agonist as well as dopamine (DA) agonist when administered acutely (e.g. Colado et al., 2004, Green et al., 2003, Kish, 2002). When MDMA is used recreationally in the form of ‘ecstasy’ people describe feelings of euphoria and enhanced self-awareness without visual distortions typical of other hallucinogens (Peroutka, Newman, & Harris, 1988). A variety of human studies have also shown that ecstasy exposure impacts on a variety of cognitive functions including memory-task performance. For example, Fox, Toplis, Turner, and Parrott (2001) examined auditory verbal learning in ecstasy users and polydrug controls and found ecstasy users required more trials to reach the same level of performance as controls. They also found ecstasy users showed significant impairment in delayed recall that implied a problem with long-term memory. Ecstasy use has also been associated with impairments in executive functioning, as well as working, visuospatial, and prospective memory functioning (Heffernan et al., 2001, Heffernan et al., 2001, Wareing et al., 2000, Wareing et al., 2004).
However for ethical and practical reasons the large majority of human studies have focused on the chronic effects of ecstasy in occasional to regular users, who often use MDMA in conjunction with other drugs (Fox et al., 2001). Therefore relatively little is known about the acute effects of MDMA on cognitive functioning. One of the few exceptions is a study by Parrott and Lasky (1998) who found that acute exposure to MDMA caused an impairment in word recall and visual search performance. The verbal reports of participants in their study suggested that these impairments may have been related to general problems in attending to relevant environmental events (i.e., a tendency to be more distracted by extraneous non-task relevant events). Thus one possibility suggested by their data is that MDMA’s acute effects on memory-task performance may not be related to a problem with memory storage per se but are the product of a more general impairment.
A number of animal studies have investigated the acute effects of MDMA on memory function using delay matching (or non-matching) to sample procedures. For example LeSage, Clark, and Poling (1993) examined the effects of acute and chronic MDMA in pigeons using a delayed matching-to-sample (DMTS) task. They found MDMA produced dose-dependent decreases in accuracy and response rates in both the acute and chronic phases of their study. Similarly, Marston, Reid, Lawrence, Olverman, and Butcher (1999) used a delayed non-matching-to-sample task to assess the effects of acute and post-treatment consequences of a chronic regime of ascending MDMA doses. MDMA rats showed disrupted performance compared to controls during the drug administration phase. In contrast, Frederick, Gillam, Allen, and Paule (1995) assessed the acute effects of 0.0 (saline), 0.1, 0.3 and 1.0 mg/kg MDMA on performance in a DMTS task with rhesus monkeys. They found no significant change in performance between the MDMA and saline and therefore argued acute doses of MDMA did not produce any impairment in short-term memory. However, it should be noted that these doses are rather low compared to other studies and this could be a reason why no impairments were found.
Although matching to sample tasks have been used as evidence for working memory deficits following acute exposure to MDMA there is an alternative explanation. Harper, Wisnewski, Hunt, and Schenk (2005) found that the pattern of deficit in DMTS performance with rats following acute MDMA administration was a product of increased susceptibility to proactive interference from events that occurred on previous trials. They showed that it was not that rats were unable to recall what target stimulus they had experienced on the current trial, but the reason rats were impaired on any given trail was that they tended to return to a response option they had chosen in an immediately preceding trial. Consistent with this proactive interference pattern of effect, Harper, Hunt, and Schenk (2006) found that when the inter-trial interval was lengthened (i.e. increasing the temporal distance between trials) the MDMA-induced enhancement of the impact of a preceding trial on the next was significantly ameliorated. These studies suggest that MDMA causes an impairment with regard to discriminating trial structure (i.e., an impairment with regard to the stable ‘trial-independent’ aspects of task performance), rather than via a direct influence on short-term or working memory performance per se. Therefore, we suggest that rats remember episodic events in each trial (i.e., stimuli presented and responses made) but they are impaired with respect to procedural or reference memory (i.e., what to do with the information they have). This distinction is consistent with Honig (1978) and Olton, Becker, and Handelman (1979) who argue that working memory can be operationalized as task accuracy in situations where information (or the appropriate response based on that information) changes frequently (i.e., from trial to trial), whereas reference memory reflects task accuracy when information (or the appropriate response based on that information) remains constant indefinitely (i.e. across trials and/or sessions).
Put another way, it might be argued that common short-term or working memory tasks (such as DMTS) still actually involve a reference memory component and it is this component that is disrupted by MDMA in non-matching and matching to sample tasks. Such a conclusion would also be consistent with findings in the chronic MDMA literature of a reference memory impairment following 5-HT or DA toxicity from MDMA exposure (e.g., Sprague, Preston, Leifheit, and Woodside, 2003). However, many of the tasks used to assess acute effects of MDMA on memory have not allowed for an independent assessment of working memory from reference memory.
One possible experimental preparation that can allow for some degree of explicit separation of a working memory from a reference memory component involves the use of a radial arm maze. Radial arm mazes are frequently used to study spatial memory. The animal is placed in the middle of the maze and is allowed to explore. In its most basic form the task involves baiting each arm and assessing how frequently rats revisit arms (with revisits counting as errors in working memory). Braida, Pozzi, Cavallini, and Sala (2002) used an eight-arm radial maze to assess the acute effects of MDMA on rats and found it impaired working memory and long-term working memory when a 2 h delay was introduced into the task. They also found arm entry patterns were disrupted in a dose dependent fashion. Although Braida et al. interpreted their findings in terms of a working memory deficit, the disruption of the strategy required to solve the task is also akin to a reference memory deficit. That is, the trial-independent sequences of responding adopted by individual rats to navigate the maze was disrupted. Unfortunately the basic eight-arm maze paradigm used by these researchers is unable to distinguish between reference and memory impairments.
One version of the eight-arm radial maze task, however, does enable researchers to differentiate reference and working memory deficits (see Olton and Papas, 1979, Wirsching et al., 1984). In this version a subset of the available arms in the radial maze are always baited while the remaining ones are never baited. Working memory is then required to prevent re-visiting the baited arms while reference memory is required to avoid visiting arms that have never been baited. Wirsching et al. (1984) used this paradigm to assess the effects of scopolamine, an acetylcholine receptor antagonist, on rats. They found that scopolamine selectively impaired the working memory component but not the reference memory component; a trend that other studies have found (Pilcher et al., 1997, Wang and Tang, 1998). However, to date no study has assessed the effects of MDMA on reference and working memory in the radial arm maze.
In summary, both human and non-human research suggests that acute doses of MDMA can produce impairments in various memory tasks. However, there is some debate as to what aspects of memory are disrupted by MDMA. There is also a paucity of research on the acute effects of the drug; an area that warrants further investigation. Therefore, the current study investigated the comparative acute effects of MDMA versus scopolamine on working and reference memory in rats using an eight-arm radial maze. Although the focus of the current study is primarily on MDMA, scopolamine provides an important reference point given its extensive use as a classic amnetic drug (e.g., Harper, 2000). Because previous findings (Wirsching et al., 1984) have indicated that scopolamine produces working memory deficits it was hypothesized that scopolamine would produce significantly more working memory errors than reference memory errors. Based on the conclusions of Harper and colleagues (Harper et al., 2005, Harper et al., 2006) plus the previous pattern of deficit observed by Braida et al. (2002) using the basic eight-arm maze task, our second hypothesis was that MDMA would produce significantly more reference memory errors than working memory errors.
Section snippets
Subjects
The subjects were fifteen male Sprague–Dawley rats bred in-house. They were approximately three months old at the beginning of the study, were housed individually and were experimentally naïve at the beginning of the study. They were kept at approximately 85–90% (between 183 and 255 g) of their free feeding body weight and began training around a week after reaching this weight. They had continuous access to water and were kept on a reversed 12:12 h light:dark cycle and were run during the dark
Results
Both MDMA and scopolamine impaired overall accuracy. A one-way repeated measures ANOVA for the MDMA data (with MDMA dose, including the saline control, as the repeated measure) revealed a significant impairment on overall accuracy, F(3, 42) = 38.7, p < 0.001. Likewise, scopolamine also showed a main effect for dose, F(3, 42) = 41.8, p < 0.001. Consistent with the trends illustrated in Fig. 1, planned post hoc analyses revealed a significant impairment relative to saline at the highest two doses of each
Discussion
Working memory is a temporary memory that is trial dependent in that it is only relevant for one trial (Olton et al., 1979, Olton and Papas, 1979, Wirsching et al., 1984). In the current paradigm working memory involved the rat being able to retain information of where it has been and where it had yet to go within a trial. It is this kind of memory that was more disrupted by scopolamine than MDMA in the present study. Reference memory is trial independent in that the information available for
Acknowledgments
The authors wish to acknowledge the help provided by staff and students working in the Drugs of Abuse Laboratory at Victoria University of Wellington. This research was conducted with the approval of the Animal Ethics Committee, VUW and was supported by research grants from the Neurological Foundation of New Zealand and Lottery Health New Zealand.
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