IMPACTS OF ACUTE AND NEUROTOXIC MDMA EXPOSURE ON OLFACTORY MEMORY ...

105 Pages·2012·0.73 MB·English

IMPACTS OF ACUTE AND NEUROTOXIC MDMA EXPOSURE ON OLFACTORY
MEMORY PERFORMANCE IN RATS

Andrew B. Hawkey

A Thesis Submitted to the
University of North Carolina Wilmington in Partial Fulfillment
of the Requirements for the Degree of
Master of Arts

Department of Psychology

University of North Carolina at Wilmington

2012

Approved by

Advisory Committee

Julian Keith Katherine Bruce

Mark Galizio
Chair

Accepted by

Dean, Graduate School
TABLE OF CONTENTS

ABSTRACT .................................................................................................................................. iv
ACKNOWLEDGMENTS ...............................................................................................................v
INTRODUCTION ...........................................................................................................................1
Drug History and Classification ..........................................................................................1
Ecstasy Use in Humans ........................................................................................................2
PHARMACOLOGY OF MDMA ....................................................................................................4
Acute Effects of MDMA .....................................................................................................5
Persistent Effects ..................................................................................................................9
COGNITIVE IMPACTS OF MDMA USE IN HUMANS ...........................................................16
LIMITATIONS OF HUMAN TESTING AND NEED FOR ANIMAL MODELS .....................18
MDMA EFFECTS ON MEMORY ...............................................................................................19
MDMA and Working Memory Tasks in Rats ...............................................................................20
An Alternative Approach to Working Memory Testing ....................................................40
Span....................................................................................................................................41
EXPERIMENT 1: ACUTE EFFECTS OF MDMA ......................................................................45
Method ...............................................................................................................................48
Span Training .....................................................................................................................53
Drug Administration ..........................................................................................................59
Results and Discussion ......................................................................................................59
EXPERIMENT 2: EFFECTS OF BINGE MDMA ADMINISTRATION ...................................67
Methods..............................................................................................................................72
Drug Administration ..........................................................................................................73
ii
Results and Discussion ......................................................................................................74
GENERAL DISCUSSION ............................................................................................................87
REFERENCES ..............................................................................................................................92

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LIST OF TABLES
Table Page
1. Acute MDMA Studies of Memory in Rats ........................................................................46
2. Pool of scents for Odor Span and SD Tasks ......................................................................51
3. Training timeline ................................................................................................................56
4. Binge MDMA Studies of Memory Tasks in Rats ..............................................................68
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LIST OF FIGURES
Figure Page
1. Basic Rodent Incrementing Non-Match-to-Sample or Span procedure ............................43
2. Ex.1 Key Dependent Measures ..........................................................................................61
3. Ex.1 Within-Session Analysis ...........................................................................................63
4. Ex.2 Key Dependent Measures ..........................................................................................77
5. Ex.2 Session-by-Session Data ...........................................................................................78
6. Individual Subject Graphs..................................................................................................79
7. Ex.2 Within Session Analysis ............................................................................................81
8. Reversal Data .....................................................................................................................83
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ABSTRACT
MDMA is an amphetamine derivative which is taken recreationally in social contexts and
has been linked to disruptions in neurologic and cognitive functioning. In rodents, the effects of
MDMA have been tested on a variety of working memory tasks, but none have measured the
effects of the drug on working memory capacity. The current study used the rodent Odor Span
Task (OST) to assess the impact of two drug administration schedules on load-dependent
learning. Experiment 1 tested the impact of acute doses of MDMA (Saline, 0.3, 1.0, 1.8, 3.0
mg/kg) on the OST. Results from Experiment 1 showed a dose dependent decrease in
performance on the OST and a control task (SD). This is interpreted as a general impairment
which is unrelated to memory. Experiment 2 tested the impact of a binge dosing regimen of
MDMA (10mg/kg, 2 per day x 4 days) or saline on the OST for 4 weeks post-binge. Rats in the
MDMA group scored similarly to controls on all OST measures except omissions, where they
failed to respond more often than controls. This effect was task-independent and appeared to
recover over time. This is interpreted as a general impairment which is unrelated to memory.
MDMA-treated rats did show impaired acquisition on early trials of a simple discrimination
reversal, replicating a previous finding that binge MDMA produces cognitive inflexibility. In
conclusion, the current study suggests that acute MDMA exposure does not produce impairments
on accuracy in the OST or an SD control at any dose. Acute MDMA disrupts olfactory memory
task performance primarily by reducing responding. Furthermore, the current study suggests that
binge or neurotoxic MDMA administration does not produce deficits on olfactory memory, as
accuracies were unaffected in both the OST and SD tasks. Measurable performance disruptions
were related to non-responding (omissions) and reversal learning.

iv
ACKNOWLEDGEMENTS
The author would like to thank his Advisor and Thesis Committee Chair, Dr. Mark
Galizio for his support and direction in the design and completion of this project, as well as Dr.
Kate Bruce and Dr. Julian Keith for their support and input. Special thanks are also due to the
members of the Galizio lab at UNC-Wilmington: Brooke April, graduate researchers Melissa
Deal and Christine Hausmann, and undergraduate researcher Kevin Jacobs; for assistance in data
collection. This study was funded by DA029252 through NIDA.
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IMPACTS OF ACUTE AND NEUROTOXIC MDMA EXPOSURE ON OLFACTORY
MEMORY PERFORMANCE IN RATS

Drug History and Classification
Methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine,
commonly referred to as ecstasy. Merck Corporation first synthesized MDMA in the early 1900s
as a parent compound (McDowell & Kleber, 1994), and it was patented with related compounds
in an effort to develop a new blood clotting drug (Freudenmann, Oxler & Bernschneider-Reif,
2006). Very little is known about the drug for the next several decades beyond development, but
it became publicly available in the United States in the early 1970’s (Freudenmann et al., 2006).
From the mid-1970’s until the drug was given the Schedule 1 designation in 1985, the drug was
sometimes used in psychotherapy, as it was thought to increase openness and aid insight-oriented
therapy (McDowell & Kleber, 1994). Since restrictions were put in place, the licit uses of the
drug have been few, so much of the research on the drug focuses on risks associated with
recreational use.
MDMA is related to a group of compounds with a similar chemical structure (Green,
Mechan, Elliott, O’Shea, & Colado, 2003). In addition to MDMA, this class of compounds
includes amphetamine (AMPH), methamphetamine (MA), 3,4-methylenedioxyamphetamine
(MDA), and 3,4 methylenedioxyethamphetamine (MDEA), among others. MDA, MDEA, and
MDMA have been shown to reduce serotonin reuptake (Green et al., 2003), as well as producing
effects on other neurotransmitter systems. Despite structural similarities, they produce different
effects on an array of cognitive/behavioral tests and tend to produce distinct behavioral profiles,
at least in rodents (Quinteros-Munoz et al., 2010). The MDMA compound has two isoforms, S+
and R-, both of which are pharmacologically active (Karlsen, Spigset & Slordal, 2007). The drug
tends to exhibit stimulant-like effects, as well as a number of socially relevant effects on mood
and behavior. These effects complicate the classification of the drug and have led some to refer
to it as an entactogen (e.g. Gouzoulis-Mayfrank and Daumann, 2006; Quinteros-Munos et al.,
2010), rather than a psychostimulant. An entactogen increases social behavior such as
communication or physical contact, and increases subjective feelings of emotional connection or
closeness to others.
In its pure form, MDMA is a white, tasteless powder, but human users typically take the
drug in pill form (Karlsen et al, 2007). It can also be found in other forms, allowing it to be
injected, inhaled, or smoked. Street drugs bearing the name ecstasy may include MDMA or a
number of other drugs with similar properties (Karlsen et al., 2007), but research on the drug has
generally focused on these compounds separately. Within the drug literature, it is often assumed
that the effects of ecstasy are due to the actions of MDMA, but given that a variety of chemicals
may be in ecstasy tablets, there are limits to the validity of this assumption. Within this
discussion, only the illicit use of specific forms of ecstasy, ones which contain solely or
primarily MDMA, can be adequately modeled by studies of MDMA-induced effects.

Ecstasy Use in Humans
Ecstasy users tend to report a wide variety of euphoric and dysphoric symptoms (Karlsen
et al., 2007). Reported physiological effects generally include increased heart rate and body
temperature, dry mouth, nausea, reduced hunger, and insomia. Ecstasy users also tend to report
bruxism (or teeth grinding) and trismus, an involuntary muscular tightening in the jaw. Sensory
symptoms tend to include vestibular abnormalities and altered perception. Subjective emotional
symptoms often include feelings of euphoria, closeness to others, well-being, extroversion and
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heightened social communication. In some cases, anxiety or panic can also occur. At high doses,
hallucinations or acute psychoses have been reported.
Ecstasy use has been largely associated with adolescents and young adults, particularly
within “rave culture” (McDowell & Kleber, 1994). Raves are parties with loud electronic or
techno music that encourages extended periods of dancing in crowded dance halls. It has been
noted that these conditions encourage the use of stimulants, to assist in sustaining high energy
activities like dancing, and hallucinogens, which alter sensory perception. While raves certainly
contribute to the popularity of the drug, findings from a recent study suggest that ecstasy is often
used in private settings as well (Ramtekkar, Striley & Cottler, 2010). In addition, this study
found that ecstasy is commonly consumed with other substances, most often marijuana or
alcohol. Overall, ecstasy is perceived as being a relatively safe drug and patterns of use appear to
be mediated by a number of different factors (Ramtekkar et al., 2010).
One important factor in the patterns of ecstasy use appears to be based on the rewarding
nature of the context in relation to the drug. Klein, Elifsen and Sterk (2009) investigated
behaviors which occur based on their amplification of the effects of ecstasy. Such behaviors
often include seeking environments with opportunities for intense stimulation. Other behaviors
are exhibited within these environments to provide further stimulation, such as the tendency to
use soft objects to provide tactile stimulation or using certain beverages or lotions to intensify
gustatory and olfactory stimulation. The occurrence of these stimulation-promoting behaviors
was associated with binge consumption of the drug and more adverse effects related to ecstasy
use.
Historically, ecstasy has been considered to be a relatively non-addictive drug, as
compared to other club drugs. Cases of dependence on ecstasy were considered to be relatively
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