THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT
ON A DOPAMINE-INDUCED MURINE MODEL
OF OBSESSIVE-COMPULSIVE DISORDER
A Dissertation
presented to
the Faculty of the Graduate School
at the University of Missouri-Columbia
In Partial Fulfillment
of the Requirements for the Degree
Doctor of Philosophy
by
ASHLEY KRISTIN RAMSEY
Dr. Todd Schachtman, Dissertation Supervisor
JULY 2016 © Copyright by Ashley K. Ramsey, 2016
All Rights Reserved
The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled
THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE- INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER
presented by Ashley K. Ramsey, a candidate for the degree of Doctor of Philosophy, and hereby certify that, in their opinion, it is worthy of acceptance.
______Professor Todd R. Schachtman
______Professor Matthew J. Will
______Professor Thomas M. Piasecki
______Professor Agnes Simonyi
ACKNOWLEDGEMENTS
The dissertation process (and perhaps more generally, the endeavor of scientific research) is practically impossible without the support of a community dedicated to the advancement of knowledge. The following dissertation was born from the combined efforts of many faculty, staff, students, and colleagues. I would specifically like to thank the following individuals/groups for their contributions to this dissertation, including their human-hours worked, encouragement, flexibility, inspiration, manuscript feedback, assistance with mouse colony care, assistance with maintaining a double-blind methodology, and overall guidance throughout the entire process:
• My advisor, Dr. Todd Schachtman
• My committee members, Drs. Agnes Simonyi, Matt Will, and Tom
Piasecki
• My research mentor and friend, Dr. Peter Serfozo
• My students at IU-Southeast and Truman State University who served as
trained behavioral analysis scorers
• My fellow members of the Conditioning and Neuroscience lab at Mizzou
• My fellow graduate students in psychology at Mizzou
• Members of the Cognition and Neuroscience training area
• The staff members of the Department of Psychology and the Graduate
School at Mizzou
ii
TABLE OF CONTENTS
Acknowledgements ...... ii
List of Figures ...... iv
List of Abbreviations ...... v
Abstract ...... vi
Chapter
1. General Introduction ...... 1
2. Experiment 1 ...... 12
Method ...... 13
Results ...... 17
Discussion ...... 18
3. Experiment 2 ...... 20
Method ...... 22
Results ...... 24
Discussion ...... 32
4. General Discussion ...... 34
References ...... 37
Vita ...... 55
iii LIST OF FIGURES
Figure Page
1. Mean choices until alternation for Experiment 1 ...... 17
2. Mean total alternations for Experiment 1 ...... 18
3. Mean choices until alternation for Experiment 2 across sensitization trials ...... 24
4. Main effects of quinpirole on grooming frequency, rearing frequency, number of visits to object 1, and time between visits to object 1 for sensitization data collapsed over MMPIP dose ...... 25
5. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 1 across all injection days ...... 26
6. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 4 across all injection days ...... 27
7. Effect of trial latency on grooming frequency across all treatment groups ...... 27
8. Effect of MMPIP on grooming frequency ...... 28
9. Effect of quinpirole and trial latency on number of visits to object 3 across the sensitization period ...... 29
10. Effect of quinpirole and MMPIP on rearing frequency ...... 30
11. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 3 across all injection days ...... 30
12. Effect of MMPIP and trial latency on grooming frequency for injection day 17 collapsed over quinpirole dose ...... 31
13. Effect of MMPIP and trial latency on time between visits to object 2 for injection day 17 collapsed over quinpirole dose ...... 31
iv LIST OF ABBREVIATIONS
ACUC: Animal Care and Use Committee
CBT: Cognitive Behavioral Therapy
CNS: Central Nervous System
CSTC: Corticostriatal-Thalamocortical
DAT: Dopamine Transporter
GPe: Globus Pallidus Externa
GPi/SNr: Globus Pallidus Interna/Substantia Nigra Pars Reticula iGlu(R): Ionotropic Glutamate (Receptor) i.p.: Intraperitoneal mGlu(R): Metabotropic Glutamate (Receptor)
NAC: N-Acetylcysteine
OCD: Obsessive-Compulsive Disorder
PFC: Prefrontal Cortex
QNP: Quinpirole
SRI: Serotonin Reuptake Inhibitor
SSRI: Selective Serotonin Reuptake Inhibitor
SUD: Substance Use Disorder vmPFC: Ventromedial Prefrontal Cortex
v THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE- INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER
Ashley K. Ramsey
Todd R. Schachtman, Dissertation Supervisor
ABSTRACT
Obsessive-compulsive disorder (OCD) is an incapacitating anxiety disorder characterized by unwanted, intrusive thoughts that lead to repetitive, ritualistic behaviors.
Current treatments for OCD are only efficacious in a small portion of its sufferers.
Animal models of OCD may lead to the development of novel treatment options such as those that modulate the glutamatergic system. The current study examined the effect of a metabotropic glutamate receptor 7 (mGluR7) antagonist, MMPIP, on two dopamine agonist-induced murine behavioral models of OCD. Although the T-maze alternation model of OCD failed to produce compulsive behaviors in the current study, the open field compulsive checking model of OCD did increase OCD-like behaviors, which were reversed after MMPIP administration. These results suggest that decreases in mGluR7 activity may provide a novel avenue of exploration for the treatment of OCD.
vi THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE-
INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER
Obsessive-compulsive disorder (OCD) is a debilitating, time- and effort- consuming clinical anxiety disorder characterized by unwanted, intrusive thoughts, impulses, or images (obsessions) that cause marked anxiety and/or by repetitive, ritualistic behaviors (compulsions) aimed at reducing the anxiety caused by the obsessions. OCD is a chronic disorder affecting the quality of life of 1-3% of the world population. Furthermore, financial setbacks from treatment and lost productivity are in excess of $8 billion annually (Rasmussen & Eisen, 2002). Common obsessions include thoughts/fears of contamination, aggressive thoughts, a need for symmetry, and somatically focused thoughts. Common compulsions include checking, repeating, washing, counting, ordering, and hoarding (van den Heuvel et al., 2008).
Current neuroimaging evidence consistently points to faulty corticostriatal- thalamocortical (CSTC) circuitry and abnormal activation of the orbitofrontal cortex, striatum, thalamus, and anterior cingulate cortex of OCD patients (Grachev et al., 1998;
Remijnse et al., 2006; Saxena et al., 1998; van den Heuvel, 2005; for review see El
Mansari & Blier., 2006). Within this basal ganglia circuit, there is both a direct and an indirect pathway connecting the striatum to the globus pallidus interna/substantia nigra pars reticulata (GPi/SNr) complex. This complex, which serves as the main output area of the basal ganglia, then projects to the thalamus before projecting back to the cortex
(Saxena et al., 1998; Saxena & Rauch, 2000). The indirect pathway originates in the cortex (i.e. orbitofrontal cortex), projects to the striatum, the globus pallidus externa
(GPe), the subthalamic nucleus, and the GPi/SNr complex before looping back to the
1 thalamus and cortex. The direct pathway does not pass through the GPe or the subthalamic nucleus, but instead projects from the striatum straight to the GPi/SNr complex (Saxena & Rauch, 2000).
There is accumulating evidence to suggest that OCD patients have an imbalance between the negative feedback of an underactive indirect pathway and the positive feedback of the hyperactive direct pathway in the CSTC loop (Saxena et al., 1998; Winter et al., 2008). In this model, a dysfunction in the caudate nucleus of the striatum leads to further dysfunction in the thalamus, excessive activity in the orbitofrontal cortex, and excessive activity in the anterior cingulate cortex (Deckersbach et al., 2006). In the hyperactive direct pathway, dopamine released into the synapse interacts with D1 receptors in the striatonigral pathway to increase compulsive behavior. In the underactive indirect pathway, the same dopamine release interacts with D2 receptors in the striatopallidal pathway to suppress behavior via a decrease in thalamocortical activation (Nicola et al., 2000; Pennartz et al., 1994; Saxena & Rauch, 2000; Wang et al.,
2012). The successful treatment of OCD is correlated with changes in areas of the CSTC circuitry. After either pharmacotherapy or the first line behavioral treatment of cognitive behavioral therapy (CBT), decreased activation of the caudate nucleus becomes evident
(Baxter et al., 1992; Schwartz et al., 1996). Additionally, positive response to CBT is positively correlated with pretreatment metabolic activity in the left orbitofrontal cortex
(Porto et al., 2009).
Different pharmacotherapies have shown positive yet limited efficacy in the treatment of OCD. Serotonin reuptake inhibitors (SRIs) are often the first line of treatment for those suffering from OCD, including the tricyclic SRI clomipramine and
2 the more recent selective serotonin reuptake inhibitors (SSRIs) such as citalopram, fluoxetine, paroxetine, fluvoxamine, and sertraline (Goodman et al., 1992; Grados &
Riddle, 2001; for review, see Husted & Shapira, 2004). The transition from clomipramine to the newer SSRIs decreases the risk for adverse reactions and improves the treatment side effect profile; unfortunately, SSRI treatment is still associated with numerous side effects including anxiety, headache, insomnia, sexual dysfunction, nausea, and sedation (Cartwright & Hollander, 1998; Jenike, 2004). Since OCD treatment typically requires higher levels of SSRI pharmacotherapy than when prescribed for other conditions (such as for the comorbid major depressive disorder), the risk of adverse side effects is also higher. Furthermore, less than half of patients respond either fully or partially to such pharmacotherapies, and the long-term prognosis for OCD is poor with only 35% of patients achieving some level of remission (Man et al., 2004).
There has been some efficacy with the addition of dopaminergic drugs to current
SSRI treatment regimens in SSRI-resistant patients. Augmentation of SSRI treatment with low doses of dopamine antagonists, such as olanzapine, haloperidol, pimozide, or risperidone, (Bogetto et al., 2000; Denys et al., 2004; Man et al., 2004) is significantly more effective at treating OCD than a placebo. In rats, the synergistic activity of SSRIs and dopamine is associated with an increase in dopamine release in the rat PFC (Zhang et al., 2000). However, even with an SSRI-dopamine antagonist combination, OC symptoms remain difficult to treat and many individual cases continue to be non- responsive to treatment.
For these treatment-resistant patients, laboratory animal models of OCD offer hope for the development of novel therapeutic options. Several murine models of OCD
3 exist, with some models occurring naturally, and others only occurring after experimental induction. Many animal models of OCD achieve predictive validity via their positive response to serotonergic and dopaminergic treatments, as both of these treatment types have shown some success in the human disease (Barr et al., 1993; for reviews, see
Broekkamp & Jenck, 1989; Broekkamp et al., 1986; Denys et al., 2004; Husted &
Shapira, 2004; Pigott and Seay, 1999). In the naturally occurring marble burying model, mice presented with marbles on top of their bedding express compulsive tendencies to bury these marbles, even when given the chance to habituate to their presence, but not after SSRI treatment (Njung’e and Handley, 1991). In the naturally occurring spontaneous stereotypy model in deer mice, purposeless and patterned locomotor behaviors are associated with abnormal corticostriatal activity, but diminish after SSRI or dopamine agonist treatment (Korff, Stein, & Harvey, 2008; Pappas, Leventhal, Albin, &
Dauer, 2014). In an experimentally induced model, Ahmari et al. (2013) found that activation of the striatum via chronic, but not acute, optogenetic stimulation of the corticostriatal pathway triggers long-term compulsive grooming that can be reversed via chronic SSRI administration.
Multiple transgenic murine models of OCD also exist with varying strengths of validity. Hoxb8-null, Slitrk5-null, and SAPAP3-null mice all exhibit excessive grooming and self-injury, mirroring the symptoms of human trichotillomania or dermatillomania
(Chen et al., 2010; Greer & Capecchi, 2002; Pappas et al., 2014). While the Hoxb8 mutants’ behavioral changes are associated with the development of dysfunctional microglia, SAPAP3-null mice have altered AMPA neurotransmission in the corticostriatal circuitry, the later of which appears to be controlled by a mGlu5 receptor-
4 dependent mechanism and responds favorably to SSRI treatment (Chen et al., 2010;
Pappas et al., 2014; Wan, Feng, & Calakos, 2011; Wan et al., 2013). In the Slitrk5-null mice, the excessive grooming triggered by the deletion of the transmembrane protein can be reversed via chronic SSRI treatment (Pappas et al., 2014; Shmelkov et al., 2010).
Genetic alterations aimed specifically at the dopaminergic system have also produced potential models of OCD. Mice with decreased dopamine transporter (DAT) expression functionality exhibit increased levels of synaptic dopamine in the striatum, super stereotypy of behavioral repertoires, and abnormal corticostriatal activity. (Berridge,
Aldridge, Houchard, & Zhuang, 2005; Wu, Cepeda, Zhuang, & Levine, 2007; Zhuang et al., 2001).
Although other psychological disorders such as depression can be treated with
SSRI therapy with or without dopaminergic augmentations, OCD does not respond to non-serotonergic anxiety/depression medications, and therefore a predictively valid animal model of OCD should distinguish itself from animal models of anxiety or depression by a non-response to non-serotonergic antidepressants. Ichimaru et al. (1995) demonstrated such an effect in ICR mice, as the non-serotonergic antidepressant desipramine did not decrease marble burying behavior, further supporting the hypothesis that marble burying may represent a model of compulsive behaviors and not a model anxiety or depression (Gyertyán, 1995; Londei et al., 1998; Njung’e and Handley, 1991).
Furthermore, because the marbles have no intrinsic aversive properties, it has been suggested that marble burying begins as a non-defensive investigatory behavior, but frustration due to the dormant and non-responsive nature of the marbles may lead to compulsive burying because the animals are dissatisfied with the outcome of the
5 investigation (Londei et al., 1998; Joel, 2006). Szechtman and Woody (2004) proposed that such a lack of a feeling of closure disrupts the normal termination of an innate security motivation system that is activated by unknown or threatening stimuli in order to protect the animal from potential environmental dangers. The failure of this system to reach an adequate state of completion results in a loop of repetitive, compulsive behaviors.
In a pharmacologically induced rodent model of OCD, administration of the 5-
HT1A agonist 8-OH-DPAT produces a repetitive pattern of behavior in a T-maze (Yadin et al., 1991). When placed in repeated T-maze runs in which both arms are baited with an equal amount of reward, rodents instinctively alternate their arm choice on each successive trial (ex: right, left, right, left), exploring the more novel environment in a systematic fashion. After administration of 8-OH-DPAT, however, rats will persist in their arm choice on successive trials (ex: right, right, right). This disruption of spontaneous alternation behavior is akin to compulsive checking and can be reduced with chronic pretreatment of SSRIs, but not desipramine, further supporting the model’s predictive validity (Fernandez-Guasti et al., 2003; Yadin et al., 1991).
In addition to the serotonergic system, methods aimed at altering the dopaminergic system have also decreased spontaneous alternation behavior. Chronic administration of the D2/D3 agonist quinpirole disrupted spontaneous alternation in rats after chronic administration, which may model compulsive checking (Einat &
Szechtman, 1995; Ulloa, Nicolini, & Fernández-Guasti, 2004). Further lending support to the model, sub acute pretreatments with the serotonin reuptake inhibitor (SRI) clomipramine prevented the perseveration effect of quinpirole (Fernandez-Guasti et al.,
6 2003; Ulloa et al., 2004). Chronic quinpirole treatment in both rats and mice also leads to changes in open field behavior, including compulsive checking and increased stereotypy of behavioral repertoires (de Haas et al., 2012; Szechtman et al., 1998; Szechtman et al.,
2001). In quinpirole-sensitized animals, post mortem changes in the dopaminergic system can be seen such as an upregulation of subcortical dopaminergic activity, including in brain areas implicated in OCD such as the striatum and prefrontal cortex
(Sullivan et al., 1998). Similar receptor supersensitivities are thought to occur in human
OCD patients. Understandably, the inhibition of dopaminergic neurons via D2 antagonists has been shown to decrease compulsive symptoms in both humans and animals, but they are unfortunately not effective for everyone (Bogetto et al., 2000;
Denys et al., 2004; Man et al., 2004; McDougle, Epperson, Pelton, Wasylink, Price,
2000).
Glutamate may serve as an alternative treatment target, as it heavily regulates serotonin and dopamine release in the faulty CSTC circuit (Amargós-Bosch et al., 2007;
Karreman & Moghaddam, 1996; Wu et al., 2012). It is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and serves as the main neurotransmitter within the CSTC circuitry (Baxter, Clark, Iqbal, & Ackermann, 2001).
Glutamate acts on both ionotropic (iGlu) and metabotropic (mGlu) receptors (McGeer et al., 1987; Pilc & Ossowska, 2007), which have different effects in the CNS. While iGluRs (NMDA, kainate, AMPA) exist as fast-acting ligand-gated ion channels
(Hollmann & Heinemann, 1994), mGluRs are G-protein linked receptors that mediate slower, longer lasting effects through second-messenger systems and are responsible for other neuronal functions that are not typically controlled by iGluRs (Conn, 2003). Eight
7 different subtypes of mGluRs have been discovered based on their pharmacological profile, sequence homology, and preferred signal transduction pathway (Cartmell &
Schoepp, 2000). These different subtypes are divided into three distinct groups. Group I mGluRs (mGluR1 and mGluR5) activate phospholipase C and phosphoinositide hydrolysis, while group II mGluRs (mGluR2 and mGluR3) inhibit the cAMP cascade and inhibit adenylyl cyclase via Gi proteins. Like group II mGluRs, group III mGluRs
(mGluR4, mGluR6, mGluR7, and mGluR8) also inhibit adenylyl cyclase (Conn & Pin,
1997).
Glutamate’s various receptors have promising roles in the treatment of many psychopathological conditions including anxiety, depression, impaired learning and memory, schizophrenia, Parkinson’s disease, Alzheimer’s disease, chronic pain, basal ganglia disorders, and addiction (Gravius et al., 2010; Lavreysen & Dautzenberg, 2008;
Li et al., 2010; Niswender & Conn, 2010; Riedel et al., 2003; Wu et al., 2012). Addiction and OCD have commonalities in their face validity, co-morbidity, and pathophysiology, and it may prove useful to further examine links between the two in an attempt to develop novel treatment options for OCD (Fontenelle et al., 2011). The cravings and drug- seeking/consuming behaviors associated with substance use disorders (SUD) can be seen as similar to the obsessions and compulsions of OCD, respectively; however, SUD are often seen as impulsive rather than compulsive. Interestingly, users of cocaine, a drug that elevates dopaminergic neurotransmission, are more likely to develop OCD than non- users (Rosse et al, 1994). Blom and colleagues (2011) have demonstrated a solid link between the co-morbidity of various SUD and OCD, as the co-occurrence of SUD and
OCD is higher than that of SUD and non-OCD disorders, especially in men. Furthermore,
8 SUD and OCD both involve abnormalities of the orbitofrontal cortex, the striatum, and the glutamatergic system (Fischer-Smith et al., 2012; Fontenelle et al., 2011; Wu et al.,
2012; for review see Duncan & Lawrence, 2012; Kalivas, 2009).
One commonly used drug with minimal to no side effects that is now being explored for use in addiction and compulsive disorders is N-acetylcysteine (NAC). NAC is typically recognized as the first-line treatment for acetaminophen overdose and also has been shown to have mucolytic, antioxidant, neuroprotective, immune-supportive, and glutamatergic/dopaminergic modulatory properties (Dean, Giorlando, & Berk, 2011;
Green, Heard, Reynolds, & Albert, 2013; Samuni et al., 2013). NAC supports the biosynthesis of glutathione, which is capable of uniquely binding to NMDA and AMPA receptors (Varga, Jenei, Janáky, Saransaari, & Oja, 1997). When used on cocaine-treated rats, NAC reversed glutamatergic abnormalities in the nucleus accumbens (Baker et al.,
2003). Though sample sizes were limited, there are also some reports of NAC reducing the symptoms of trichotillomania, dermatillomania, and, when used in conjunction with an SSRI, OCD in human patients (for review, see Deepmala et al., 2015). In the murine marble-burying model of OCD, NAC dose-dependently decreased burying behavior, along with the NMDA antagonists memantine and amantadine (Egashira, Okuno, Harada et al., 2008; Egashira et al., 2012). Other glutamatergic drugs such as riluzole, ketamine, d-cycloserine, and tianeptine have also demonstrated some efficacy in treatment- refractory OCD in humnas (Pittenger, Bloch, & Williams, 2011).
The expansive variety and widespread distribution of metabotropic glutamate receptors in the CNS allows for the development of selective ligands that activate increasingly specific neural systems with fewer side effects than ionotropic ligands
9 (Gravius et al., 2010; Niswender & Conn, 2010; Riedel et al., 2003). In the marble- burying model, administration of the selective group II antagonists LY341495,
LY404039, and MGS0039 reduced burying behavior (Bespalov et al., 2008; Rorick-Kehn et al., 2007; Shimazaki et al., 2004). A similar reduction was found with the administration of the group I mGlu5 receptor antagonist MPEP (Spooren et al., 2000).
These group I and II mGlu receptors, along with mGlu4, mGlu7, and mGlu8 receptors, have also been shown to affect different aspects of drug addiction (Blednov et al., 2004;
Dravolina et al., 2007; Lea & Faden, 2006; Li et al., 2009; Timmer & Steketee, 2012;
Zhang et al., 2008). However, less is known about the role of specific group III receptors in addiction and other related disorders such as OCD because of limited pharmacological tools.
The discovery of the mGlu7 receptor negative allosteric modulator, MMPIP, provides an opportunity to investigate the role of a specific group III receptor on an animal model of OCD. MGlu7 receptors interact with multiple proteins and neurotransmitter systems, which makes exposing their role in psychopathological states a complex task (Boudin et al., 2000; Enz & Croci, 2003). The mGlu7 receptor is a widely distributed presynaptic autoreceptor with a low affinity for glutamate (Kinoshita et al.,
1998; Nicoletti et al., 2011), and it is therefore suggested to inhibit excessive glutamate release when synaptic activity is high (Nicoletti et al., 2011). This characteristic, along with the high expression of mGluR7 in the globus pallidus and ventral pallidum of the basal ganglia, may prove to be relevant to the neurological underpinnings of OCD, as glutamatergic abnormalities in the CTSC circuitry have been proposed (Fontenelle et al.,
2011). MGluR7 is thought to play a role in addiction, as the mGluR7 agonist AMN082
10 decreases cocaine and alcohol self-administrations and inhibits cocaine-induced reinstatement of drug-seeking behavior via nucleus accumbens glutamatergic mechanisms (Li et al., 2009; Li et al., 2010; Salling et al., 2008). It also may play a role in OCD, as mGluR7 knockout mice and mice treated with the mGluR7 negative allosteric modulator ADX71743 both exhibited a decrease in marble-burying behavior (Callaerts-
Vegh et al., 2006; Kalinichev et al., 2013). Since mGluR7 has been shown to play a role in non-pharmacologically induced OCD-like behavior such as marble-burying and other overlapping psychopathological conditions (i.e. addition), the current experiments aim to investigate the role of mGluR7 in two D2/D3 agonist-induced models of OCD.
11 EXPERIMENT 1
Experiment 1 investigated the role of mGluR7 in a murine model of OCD. In an adaption of Einat and Szechtman’s (1995) procedure for rats, chronic injections of the
D2/D3 agonist quinpirole were used in mice in an attempt to decrease spontaneous alternation behavior in a T-maze, with such a lack of alternation being indicative of OCD behavior. After chronic quinpirole administration, the mice received a systemic injection of MMPIP, an mGluR7 allosteric antagonist, in order to explore the effects of mGluR7 on dopamine-induced changes in compulsivity. Although some glutamatergic studies on
OCD-like behavior exist, none have investigated the role of mGlu7 receptors in an OCD task that is clearly distinct from a model of general anxiety.
12 Method
Subjects
Thirty-three male ICR (CD-1) mice (Harlan, Indianapolis, IN) weighing 28-42 grams were used. The mice were housed in groups of two in the colony room with a 16:8 light/dark cycle (time on at 6:00 AM), unless aggressive behavior between cagemates required individual housing. Before the experiment began, all mice were randomly assigned to either the 0 mg/kg, 1 mg/kg, or 4 mg/kg quinpirole group while counterbalancing for body weight. Throughout the experiment, all mice had free access to water and were on a food deprivation schedule, with access to food occurring once a day for 3 hours. No food was available for at least 16 hours before each trial. All procedures occurred during the light portion of the light/dark cycle, were carried out in accordance with federal animal usage guidelines, and were approved by the University of Missouri-
Columbia Animal Care and Use Committee (ACUC).
Drugs
Based on former compulsivity research using mice and quinpirole (de Haas et al.,
2012), quinpirole (Sigma-Aldrich, St. Louis, MO) was dissolved in saline and administered to mice via an intraperitoneal (i.p.) injection at a quantity of either 0 mg/kg,
1 mg/kg, or 4 mg/kg. MMPIP (Ascent Scientific, Princeton, NJ) was suspended in 0.5% methylcellulose and administered intraperitoneally at either 0 mg/kg or 10 mg/kg based on previous behavioral experiments in ICR mice during which locomotor activity was not affected (Hikichi et al., 2010).
13 Apparatus
The testing apparatus for measuring spontaneous alternation behavior was a T- maze made of grey, non-reflective plastic (Stoelting Co., Wood Dale, IL) covered by a clear Plexiglas lid with air holes. Each arm of the maze was 35 cm long with a lane width of 5 cm wide and an arm wall height of 9 cm. The ends of the goal arms were baited with a sweetened cereal reward (Honey Nut Cheerios, General Mills, Golden
Valley, MN) for each trial. The maze was cleaned after each subject.
Procedure
On day one, the mice were injected with either 0 mg/kg (n = 14), 1 mg/kg (n =
11), or 4 mg/kg (n = 8) quinpirole and were returned to their home cages. Based on previous work by Einat and Szechtman (1995) and Ulloa et al. (2004), these injections occurred every other day for 21 days, yielding a total of 11 injections per mouse. On day
10 of the experiment, the mice were exposed to the sweetened breakfast cereal in their home cage for a total of three consecutive days in order to reduce neophobia towards the
T-maze reward. After the seventh injection on day 13, the mice were allowed to fully explore and habituate to the T-maze apparatus for 20 min. During this time, the ends of the goal arms were continuously baited with the cereal reward. On day 14, the mice were confined in each baited goal arm for 5 min each.
Prior to the eighth quinpirole injection on day 15, each goal arm was baited with sweetened cereal, and the mice were confined to the beginning of the start arm for 10 seconds via a grey guillotine door. After 10 seconds, the door was lifted and the mice were given up to 90 seconds to choose a goal arm. An arm decision was defined as when
14 a mouse placed all four of its paws in a goal arm. If 90 seconds passed and a mouse had still not chosen an arm, the run was terminated. If three consecutive runs were terminated, the remaining runs of the seven-run trial were not completed.
When the mice made an arm choice, they were allowed to eat some of the cereal before they were removed from the maze and placed in a separate holding cage for 10 seconds. After waiting in the holding cage, the mice were placed back into the confined beginning portion of the start arm. This was repeated until the mice had completed seven runs in the T-maze (i.e. a trial) or the entire trial was terminated due to lack of arm choice. Perseveration, i.e. the opposite of alternation, was defined as when the mice chose the same arm in two consecutive maze runs. For example, if a mouse displayed perfect perseveration and chose the same arm for all seven runs of a trial, RRRRRRR or
LLLLLLL, it would receive a score of 7. If a mouse displayed no perseveration and alternated its arm choice on each of the seven runs of the trial (RLRLRLR or
LRLRLRL), it would receive a score of 1 because one arm choice (i.e. the decision on the first run) was made before an alternation occurred, as defined by the opposite decision on the second run. The number of perseverations per each seven-run trial on day 15 served as the baseline perseveration rate for each mouse, as chronic quinpirole treatments have been shown to not produce a perseveration effect until after the eighth injection, which occurred later on day 15 in Experiment 1 (Einat & Szechtman, 1995; Ulloa et al., 2004).
After the mice completed their seven-run trial on day 15, they received their eighth injection of quinpirole. On both days 17 and 19, after their ninth and tenth quinpirole injections, respectively, the mice completed additional seven-run trials in the
T-maze. On day 21, the mice were administered their eleventh and final quinpirole
15 injection and were returned to their home cages. Thirty minutes later, the mice received an injection of either the 0 mg/kg (n = 16) or 10 mg/kg (n = 17) MMPIP solution. Post-
MMPIP injection, the mice were returned to their home cages for an additional 30 minutes before completing a final seven-run trial in the T-maze.
16 Results
Alternation behavior was analyzed on four separate injection days: one that occurred before the proposed emergence of receptor sensitization (pre-injection 8), one that occurred midway through the sensitization period (post-injection 9), one that occurred at the end of the sensitization period (post-injection 10), and one that occurred following the administration of MMPIP (post-injection 11). Multiple three-way, mixed design ANOVAs exploring any changes in the number of repetitive T-maze choices made until an alternation occurred and the total number of alternations per seven-run trial did not reveal significant effects of injection day, quinpirole dose, or MMPIP dose (ps > .05)
(see Figure 1 for data collapsed over MMPIP dose). However, a test of within-subjects contrasts revealed a quadratic effect of total alternations for injection day, suggesting a nonlinear effect of drug treatment over time (F(1, 24) = 4.384, p = .047). Although the lack of an effect of quinpirole persists across all injection days, the nonlinear effect of injection day, which originates from the 4 mg/kg quinpirole group, suggests that acute quinpirole, chronic quinpirole, and/or acute MMPIP administration may differentially affect perseveration behavior throughout the experiment.
Figure 1. Mean choices until alternation for Experiment 1. There were no significant effects of quinpirole, injection day, or MMPIP. Error bars: +/- 1 SE.
17 Discussion
While previous studies have shown compulsion-inducing effects from quinpirole in both mice and rats, only rats have been used to demonstrate this effect in a T-maze alternation task (Einat & Szechtman, 1995; Kontis et al., 2008; Szechtman et al., 1994; de
Haas et al., 2010; Egashira et al., 2008). The current experiment did not show an effect of chronic quinpirole administration on T-maze perseveration behavior in ICR mice. This failure of quinpirole to induce compulsivity prevents a meaningful interpretation of the effect of MMPIP in Experiment 1. However, further investigation of the quadratic effect of injection day suggests a return of behavior towards baseline levels towards the end of the experiment that is not significantly related to MMPIP dose (see Figure 2 for data collapsed over MMPIP dose).
Figure 2. Mean total alternations for Experiment 1. There was a significant non-linear effect for injection day independent of MMPIP. Error bars: +/- 1 SE.
One potential explanation for the lack quinpirole-induced perseveration is that genetic differences amongst mice strains may differentially affect neurological responses
18 to dopaminergic drugs. Multiple dopaminergic processes have been shown to vary across different mouse strains including D2 receptor functioning, quinpirole-induced compulsive behavioral repertoires, and changes in non-compulsive locomotor activity induced by a dopamine agonist. (de Haas et al., 2012; Egashira et al., 2008; Ny, O’Dowd,
& George, 1994). For example, while chronic quinpirole treatment dose-dependently increased motor activity in the A/J strain of mouse, it had no effect on motor activity in
C57BL/6J mice at doses up to 6 mg/kg, and acute administration decreased locomotor activity in ICR mice at doses as low as 0.1 mg/kg (de Haas et al., 2012; Egashira et al.,
2008).
Strain differences have been observed in the rate of sensitization to dopaminergic drugs, which is highlighted in the quinpirole-induced perseveration model (Cabib, 1993;
Mead, Katz, & Rocha, 2002). Although significant perseveration is observable in Long
Evans rats after only 10 injections, Wistar rats seem to require a larger number of injections to induce such behavior (Einat & Szechtman, 1995; Hatalova et al., 2014;
Kontis et al., 2008; Ulloa et al., 2004). Because the rate of behavioral sensitization to chronic quinpirole administration has not been studied in ICR mice, it is possible that this strain also requires more than 10 injections to induce quinpirole sensitization effects. It is also possible that the T-maze perseveration model of OCD is not sensitive enough to detect differences in compulsivity in ICR mice, but a different rodent model of OCD, such as the open field compulsive checking model, may provide a better alternative for this mouse strain.
19 EXPERIMENT 2
ICR mice may require more exposure to quinpirole to achieve receptor sensitization than those strains used in previous quinpirole research (de Haas et al., 2012;
Egashira et al., 2008). In order to accommodate a potentially longer quinpirole sensitization period in ICR mice compared to A/J and C57BL/6J mice, Experiment 2 increased the number of quinpirole injections to 17 over a period of 49 days. This also allowed for further investigation into the nonlinear effects of quinpirole, as perseveration during performance in the T-maze model of OCD was measured after each of the 17 injections.
In order to detect differences in compulsivity that may not be sensitive to the T- maze perseveration task, Experiment 2 also used the open field model of compulsive checking behavior. Two of the main behavioral characteristics of this model are a preoccupation with an object/place and a hesitancy to leave it, as defined by a higher frequency of visits to an object/place, a quicker latency between consecutive visits to it, and a lower frequency of visits to other objects/places before returning back to the preferred object/place (Szechtman et al., 1998; Szechtman et al., 2001). These unique behavioral characteristics are predicted to increase with the administration of chronic quinpirole. The open field model of compulsive checking also takes into account behavioral repertoires during non-locomotor activity. These behaviors include rearing, grooming, crouching, and turning (Szechtman et al., 1998). Experiment 2 tracked the frequency of both rearing and grooming. It was predicted that quinpirole would increase the frequency of rearing, but not the frequency of grooming, as quinpirole has not been shown to alter grooming behavior (Szechtman et al., 1998).
20 Because Experiment 1 did not show differences in compulsivity between the 1 mg/kg and 4 mg/kg quinpirole groups during the T-maze task, and because previous research has shown that general locomotor behavior, which is crucial for both the T-maze perseveration and open field compulsive checking models of OCD, may be particularly vulnerable to the effects of quinpirole in ICR mice (de Haas et al., 2012; Egashira et al.,
2008), Experiment 2 only used the 1 mg/kg experimental dose. By using both the T- maze and open field tasks, the present study is the only one known to compare different quinpirole-induced models of OCD in mice. Post sensitization, Experiment 2 used
MMPIP in these models to continue investigating the role of mGluR7 in OCD. In the T- maze model, MMPIP was predicted to decrease any quinpirole-induced increases in perseveration. In the open field model, MMPIP was predicted to reverse any quinpirole- induced behavioral changes including number of visits to a preferred object, latency between visits to a preferred object, number of visits to non-preferred objects, frequency of rearing, and any unpredicted changes in frequency of grooming.
21 Method
Subjects
After adjusting for subject dropout, nineteen male ICR (CD-1) mice (Harlan,
Indianapolis, IN) weighing 36-47 grams were used. All other details concerning the housing, care, and maintenance of the mice were the same as in Experiment 1.
Drugs
The MMPIP and vehicle solutions were prepared in the same manner as
Experiment 1. The quinpirole solution was only prepared at a single strength of 1 mg/kg.
All solutions were administered via i.p. injection. While 11 quinpirole injections occurred across 21 days before MMPIP treatment in Experiment 1, 17 quinpirole injections occurred across 33 days before MMPIP treatment occurred in Experiment 2.
Apparatus
The testing apparatus for measuring spontaneous alternation behavior was the same T-maze with the same parameters as used in Experiment 1. Additionally, an open field was used to evaluate compulsive checking behavior and was built in accordance with de Haas et al.’s (2011) adaptations for mice. The open field was 80 cm x 80 cm and composed of black painted wood placed 60 cm above the floor. Four small objects approximately 4 cm x 4 cm x 4 cm each including an inverted clear drinking glass (object
1) two metal bolts (objects 2 and 3), and a PVC end pipe (object 4) were placed at fixed locations throughout the open field. Originally the open field was built without walls, but repeated escapes by the subjects required the addition of ~35 cm walls composed of black
22 painted wood. The corners of the walls were covered with clear packing tape to prevent climbing and additional escapes. The open field was cleaned after each trial. All open field behaviors were recorded via a webcam (Logitech, Newark, CA) mounted above it.
Procedure
The procedures for reducing neophobia to the cereal reward, habituating to the T- maze, and recording baseline alternation levels on days 1-15 of Experiment 2 were similar to those used in Experiment 1. On days 14 and 15, the mice were habituated to the open field for 50 consecutive min/day. This occurred either before or after their previously described T-maze exposures as determined by random assignment. Beginning on day 16, the mice were injected with either 0 mg/kg (n = 9) or 1 mg/kg (n = 10) quinpirole every three days for 49 days, yielding a total of 17 injections per mouse.
Immediately after each quinpirole injection, the mice completed both seven runs (i.e. a single trial) in the T-maze and a 50 min session in the open field. As in Experiment 1, if three consecutive T-maze runs were terminated due to a lack of arm choice, the remaining runs of the seven-run trial were not completed and the mouse was returned to its home cage. After the 17th and final quinpirole injection on day 65, the mice did not immediately complete a behavioral task but instead were returned to their home cages.
Thirty min later, the mice were administered either 0 mg/kg (n = 8) or 10 mg/kg (n = 11)
MMPIP in a contralateral manner to that of their recent quinpirole injection. The mice were then returned to their home cages for an additional 30 minutes before completing a post-treatment seven-run T-maze trial and 50 min open field session.
23 Results
T-Maze
Similar to Experiment 1, a three-way, mixed-design ANOVA exploring changes in the number of repetitive T-maze choices made until an alternation occurred did not reveal significant effects of injection day, quinpirole dose, or MMPIP dose (ps > .05) (see
Figure 3 for sensitization data collapsed over MMPIP dose).
Figure 3. Mean choices until alternation for Experiment 2 across sensitization trials.
There were no significant effects of quinpirole, or injection day. Error bars: +/- 1 SE.
Open Field
Open field behavior was analyzed on four separate injection days: one that occurred before proposed receptor sensitization (post-injection 6), one that occurred midway through the sensitization period (post-injection 12), one that occurred at the end of the sensitization period (post-injection 16), and one that occurred following the administration of MMPIP (post-injection 17). Ten four-way, mixed design ANOVAs
24 explored the effects of quinpirole dose, injection day (6, 12, 16, or 17), trial latency in 10 minute intervals, and MMPIP dose on the ten open field response measures of grooming frequency, rearing frequency, the number of intentional visits to each of objects 1-4, and the time between visits to each of objects 1-4. A main effect of quinpirole was revealed for grooming (p = .013), rearing (p < .001), visits to object 1 (p < .001), and time between visits to object 1 (p = .024) (see Figure 4). With regards to the rearing and object 1 differences, the mice treated with quinpirole reared more often and visited object 1 more frequently with less time between visits compared to the mice that did not receive any quinpirole. Out of the four objects of interest in the open field, object 1 was also the most frequently visited across all mice (M = 30.97, SD = 33.301), F(3, 300) = 20.534, p < .001.
Even taking into account this frequency data, the percentage of all object visits that occurred at object 1 was higher than expected in quinpirole-treated mice until injection day 17, when they were administered MMPIP and the effect of quinpirole was reversed
(see Figure 5).
Figure 4. Main effects of quinpirole on grooming frequency, rearing frequency, number of visits to object 1, and time between visits to object 1 for sensitization data collapsed over MMPIP dose. Error bars: +/- 1 SE.
25
Figure 5. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 1 across all injection days. Error bars: +/- 1 SE.
A main effect of MMPIP was revealed for visits to objects 2 and 4 (ps < .005), although the interpretation of these differences is difficult due to the lack of an effect of quinpirole on number contacts with these objects. When compared to the last quinpirole- only sensitization trial (post injection 16), there was an increase in visits to object 4 after
MMPIP administration, but only in the group that also received chronic quinpirole treatment (see Figure 6). The effect of injection day was significant for rearing responses
(p = .005) and visits to object 1 (p < .001), which both temporarily increased on injection day 12, and time between visits to object 2 (p = .048), which was longer after MMPIP administration. The effect of trial latency was significant for grooming (p = .002), as grooming behavior was higher during the first ten minutes of the open field task (see
Figure 7).
26
Figure 6. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 4 across all injection days. Error bars: +/- 1 SE.
Figure 7. Effect of trial latency on grooming frequency across all treatment groups. Error bars: +/- 1 SE.
Two-way interactions occurred between quinpirole and injection day for grooming (p = .014), visits to objects 2 and 4 (ps < .05), and time between visits to object
27 2 and 3 (ps < .05). Grooming behavior was lower in quinpirole-treated mice on injection days 12 and 17, visits to object 2 were higher for quinpirole-treated mice on days 6 and
16, visits to object 4 were lower for quinpirole-treated mice on days 12 and 16 (see
Figure 6), and time between visits to object 2 was lower for quinpirole-treated mice on day 16 but higher for object 3 on day 6. Two-way interactions also occurred between
MMPIP and injection day for grooming (p < .001), rearing (p = .038), visits to objects 2 and 3 (p < .05), and time between visits to object 2 (p = .020), where grooming behavior, visits to object 3, and time between visits to object 2 all increased after MMPIP administration (see Figure 8). Additional two-way interactions occurred between quinpirole and MMPIP for visits to object 4 (p = .035), as MMPIP administration only increased these visits in quinpirole-treated mice (see Figure 6), between quinpirole and trial latency for visits to object 3 (p = .001), as only quinpirole-treated mice had fewer visits during the first ten minutes of the open field task (see Figure 9), and between injection day and trial latency for time between visits to object 3 (p = .007), as this time was lower during the 10-20 minute interval on injection day 16.
Figure 8. Effect of MMPIP on grooming frequency. Error bars: +/- 1 SE.
28
Figure 9. Effect of quinpirole and trial latency on number of visits to object 3 across the sensitization period. Error bars: +/- 1 SE.
Three-way interactions were revealed amongst injection day, quinpirole, and
MMPIP for rearing (p = .021) and visits to object 3 (p = .013). Quinpirole-treated mice had higher levels of rearing on injection day 16 and fewer visits to object 3 on injection day 12, but not after MMPIP administration on injection day 17 (see Figures 10 and 11).
An additional three-way interaction was revealed amongst injection day, MMPIP, and trial latency for grooming (p < .001) and time between visits to object 2 (p = .019), as the previously noted increase in grooming behavior after MMPIP administration was most evident during the second and fourth ten-minute intervals of the trial (see Figure 12), and the previously noted increase in time between visits to object 2 after MMPIP administration was most evident during the last 30 minutes of the trial (see Figure 13).
29
Figure 10. Effect of quinpirole and MMPIP on rearing frequency. Error bars: +/- 1 SE.
Figure 11. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 3 across all injection days. Error bars: +/- 1 SE.
30
Figure 12. Effect of MMPIP and trial latency on grooming frequency for injection day 17 collapsed over quinpirole dose. Error bars: +/- 1 SE.
Figure 13. Effect of MMPIP and trial latency on time between visits to object 2 for injection day 17 collapsed over quinpirole dose. Error bars: +/- 1 SE.
31
Discussion
When comparing the T-maze perseveration and open field compulsive checking models of OCD in ICR mice chronically treated with the D2/D3 agonist quinpirole, the open field model appears to be more sensitive to differences in compulsive behavior.
While the T-maze perseveration model of OCD failed to reveal a significant effect of chronic quinpirole treatment on alternation behavior, quinpirole-treated mice in the open field model of compulsive behavior displayed the previously described hallmark behaviors of preoccupation with an object (i.e., object 1) and hesitancy to leave it. This is highlighted by an increased frequency of visits to only object 1 and a decreased latency between consecutive visits to object 1 in quinpirole-treated but not control mice (ps <
.001). The mGluR7 antagonist MMPIP reversed these group differences (ps > .05), suggesting that decreases in mGlu7 receptor activity may offer a novel and promising treatment approach for OCD.
While the quinpirole-treated mice did visit objects 3 and 4 significantly fewer times during the latter part of the sensitization period than their control counterparts (days
12 and 16; ps < .05), this likely reflects the preference of the quinpirole-treated mice to spend time visiting object 1 instead of other locations. In the case of object 3, it is also possible that this reflects a temporary decrease in general locomotor activity, as another
D2 receptor antagonist, YM-09151-2, decreased locomotion for 15 minutes after administration, and the current study shows that quinpirole-treated but not control mice had fewer visits to object 3 only during the first ten minutes of the open field task
(Bolaños-Jiménez et al., 2011; Yokoyama, Okamura, Nakajima, Taguchi, & Ibata, 1994).
Furthermore, if the first 10 minutes of open field behavior are excluded from the current
32 analysis, the effect of quinpirole on days 12 and 16 disappears. This potential locomotor consequence of quinpirole may also explain the unexpected decreased grooming behavior of quinpirole-treated mice, as the main effect of quinpirole on grooming also disappears when excluding the first 10 minutes of open field behavior. Quinpirole treatment also increased rearing frequencies, which were also reversed by MMPIP and may be indicative of specific compulsive behavioral repertoires. Taken together, these results suggest that while certain compulsive-like behaviors can be induced via chronic quinpirole administration, these behavioral abnormalities can be reversed with an acute administration of the mGlu7 receptor antagonist MMPIP, suggesting a novel and clinically expeditious role for the mGlu7 receptor in the neuropathology of OCD.
33 GENERAL DISCUSSION
Obsessive-compulsive disorder is an etiologically complex condition with strong evidence for a role of corticostriatal-thalamocortical circuitry. Current pharmacological treatments for OCD are mostly limited to serotonergic and dopaminergic drugs, which are only successful for a small portion of the afflicted. The continuous development and exploration of new models of OCD is essential for discovering which medications may work best for otherwise treatment-resistant OCD sufferers. The role of glutamate in
CSTC dysfunction may be a key component to the development of new medications, as glutamate is the primary neurotransmitter in these circuits and heavily regulates its serotonergic and dopaminergic activity. As a presynaptic receptor with a low affinity for glutamate, mGluR7 is specially poised to reduce the CSTC glutamatergic hyperactivity associated with OCD (Nordstrom & Burton, 2002). In the current study, mGluR7 was able to reverse D2/D3 agonist-induced increases in compulsive behavior such as the preoccupation with a specific object and a hesitancy to leave it. It is the only study known to investigate a glutamatergic drug in a pharmacologically induced model of
OCD.
Although the current study was unable to induce perseveration behavior indicative of compulsions via chronic quinpirole administration in a T-maze model of OCD, it was able to trigger significant increases in compulsive behavior in an open field. This series of experiments are the only ones known to compare different quinpirole-induced models of OCD in mice. The lack of an effect of quinpirole in the T-maze alternation task may be due to the genetic characteristics of ICR mice, as other strains of mice have found an effect of quinpirole in this model. Specific genetic components linked to the etiology of
34 OCD are under investigation. For example, Kas (2010) found that mouse chromosomes
2, 6, and 7, which are homologous to human chromosomes 7p and 15q, are linked to compulsive wheel running. Different pharmacological models of OCD may also highlight different subtypes of underlying dysfunction in the disorder, as the 8-OH-
DPAT- and quinpirole-induced T-maze perseveration models of OCD each have unique effects in the CTSC circuitry (Alkhatib et al., 2013). If the various correlates of OCD dysfunction can be elucidated, then it may be possible to develop medications personalized to the underlying physiological needs of individual OCD patients.
In line with Szechtman and Woody’s (2004) proposal that obsessive-compulsive symptoms result from the failed shutdown of an internal security motivation system which fails to trigger “a feeling of knowing”, it is fathomable that there is a role for working memory and/or attention in the disorder. When an organism has an inadequate memory trace of the previous completion of a task, especially when that task is aimed at protecting the organism from potential danger, repetitive and compulsive completion of that task in an attempt to strengthen the memory trace of task completion may occur. If attentional resources are improperly allocated during task completion, the resulting memory trace may be deemed too weak to trigger the feeling of knowing that the task was already completed.
Attentional processing is reliant upon dopaminergic activity in the ventromedial prefrontal cortex (vmPFC), and infusions of quinpirole into the vmPFC have been shown to disrupt this type of processing in ICR mice (Delatour & Gisquet-Verrier, 2000; Wall,
Blanchard, Yang, & Blanchard, 2003). A reduction in the expression of group I mGluRs in the vmPFC is also evident in some forms of drug-seeking, a behavior which shares
35 many commonalities with the obsessions and compulsions of OCD (Ben-Shahar et al.,
2013). In humans, abnormal activity in the vmPFC of OCD patients usually normalizes after successful treatment, which, in extreme cases, may include invasive neurosurgical techniques that affect vmPFC/basal ganglia pathways (Greenberg, Rauch, & Haber,
2010; Haber & Heilbronner, 2013). The future development and subsequent glutamatergic treatment of animal models of OCD may benefit from tasks that explore the role of attention and memory on compulsive behavior. Based on the positive findings of the current study, mGlu7 receptors offer a promising avenue of exploration for these future clinical applications.
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54 VITA
Ashley Kristin Ramsey was born in St. Charles, Missouri, USA, on August 23,
1985. She grew up as both an athlete and a scholar, graduating from high school in 2003 with both gymnastics-based and academic-based college scholarship opportunities. At the age of 17, Ashley began studying at Truman State University, where she later graduated with a B.S. in psychology in 2007. Her senior thesis on the function of consciousness in multisensory integration was published in the journal Cognition in 2012 with Dr. Terry Palmer.
For her post-graduate education, Ashley attended the University of Missouri –
Columbia under the supervision of Dr. Todd Schachtman. She received her M.A. in psychological sciences in 2010 for her research on the role of metabotropic glutamate receptor 7 (mGluR7) on the acquisition and extinction of aversive gustatory memories, which was published in the journal Behavioural Brain Research in 2013. In 2016, she received her Ph.D. in psychological sciences with an emphasis in cognition and neuroscience for her dissertation work on mGluR7-based treatments for obsessive- compulsive disorder in dopamine-induced murine models.
Ashley has taught undergraduate psychology classes at the University of Missouri
- Columbia from 2008-2013 as a graduate student, at Indiana University – Southeast from
2013-2015 as a visiting professor of psychology, and has been teaching at Truman State
University since 2015 with a tenure-track position in the department of psychology.
55