Recent research using TF analysis has suggested that two processes underlie performance feedback event-related potentials (ERPs): a reward sensitive process in the delta range (delta-reward positivity; 0-3 Hz) and a loss sensitive process in the theta range (theta-feedback negativity; 3-7 Hz). In addition to being sensitive to gain outcomes, delta-RP appears to be sensitive to more complex reward context information, such as alternative outcomes and reward magnitude. The current study evaluated delta-RP with respect to reward history, a previously unassessed example of reward context information. Reward history considers trial sequence context and the specific reward outcomes on previous trials, relative to the current trial. The current study assessed the extent to which delta-RP is not only sensitive to primary feedback (i.e. current outcome), but also reward history, Further, the current study evaluated whether theta-FN is best characterized as a loss sensitive index of primary feedback characteristics. A college sample (N=43) completed a common gambling task, while EEG data was recorded. TF-PCA was utilized to parse overlapping delta and theta activity during the the traditional time-domain FN-P300 period. Delta-RP was sensitive to both current trial reward feedback and more distal reward feedback. The current study determined that delta-RP linearly scaled with the amount of overall reward accumulated over the course of two trials. Theta-FN was primarily sensitive to the current trial outcome with greater activity in response to loss feedback. Further, analysis of behavioral correlates suggested that consecutive loss feedback resulted in a decrease in subsequent reaction time. Overall, results suggest that delta-RP may be a dynamic index of more complex reward information. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Fall Semester, 2014. / July 31, 2014. / EEG, feedback negativity, gambling, psychophysiology, reward positivity, reward processing / Includes bibliographical references. / Norman B. Schmidt, Professor Directing Thesis; Thomas Joiner, Committee Member; Walter Boot, Committee Member.

Postpartum depression (PPD) is a mood disorder that affects women shortly after the birth of their newborn. Prevalent symptoms include sadness, anxiety, fatigue, and lack of interest in activities that used to be pleasurable. Severe cases may include suicide ideation. While the pathogenesis and treatment methods are similar to major depressive disorder (MDD), it is not until recently that individual research has been performed to further understand PPD and its origins as well as efficacy of treatments on mothers with their wavering biology. Risk factors that are statistically significant in contributing to a higher risk of PPD include biological and genetic predispositions, environmental factors such as demographics, and most importantly, the mother’s previous mental history. Clinicians suggest treatment methods depending on the severity of the case and the mother’s lifestyle. Psychotherapy is the first-line treatment recommended to mothers with mild to moderate PPD; this is also a favorable choice for mothers breastfeeding as all antidepressants can secrete into breast milk. Antidepressants fall under several classifications, with selective serotonin reuptake inhibitors (SSRIs) being the optimal choice as they produce less side effects compared to the others. Mothers with a previous mental history or severe PPD are immediately recommended antidepressants as the therapy of choice. Electroconvulsive therapy (ECT), while controversial, has become a more prominent option for mothers with severe PPD or for patients who simply want results sooner. Meta-analyses performed explore the origin of PPD and compare treatments currently in place. Similar confounding variables arise time and time again in these studies; region, local demographics, and self-report surveys make it difficult to apply data from one city, much less another country, to another. Studies with a large population of people of color or areas where seeking mental health counseling is looked down upon show large numbers of subjects dropping out of studies midway. The accuracy of data from self-report surveys is also questionable. As research continues to find more effective treatments and better comprehend the biological aspect of PPD, an increased understanding of current studies may aid in the management of PPD.

What biological processes underlie self-control, such that this adaptive skill differs among people and appears to be functionally limited? The current research aims to answer this question by proposing that adenosine, an inhibitory neurotransmitter that helps to link the rate of energy expenditures to available energy resources in the brain, signals self-control depletion. Two studies were conducted to test the adenosine hypothesis, taking advantage of caffeine’s ability to block adenosine’s action. A first, correlational study furnished evidence for the hypothesis that people who can benefit most from a boost in self-control (i.e., who have lower trait self-control and higher demands for self-control at work) would consume and depend on caffeine to improve their performance in domains which require self-control more than people with sufficient self-control resources (i.e., who have higher self-control and lower demands for self-control at work). A second, experimental study using a self-control depletion manipulation tested whether caffeine directly improves self-control and counteracts ego depletion. However, Study 2 did not furnish support for the adenosine hypothesis. Implications and future directions are discussed. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Summer Semester 2016. / May 4, 2016. / Adenosine, Caffeine, Ego Depletion, Practice Effects, Self-Control / Includes bibliographical references. / Roy F. Baumeister, Professor Directing Thesis; James K. McNulty, Committee Member; Lisa A. Eckel, Committee Member.

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Depression is a devastating disease that is the leading cause of disability worldwide. One reason for its massive disease burden is that classical antidepressants require several weeks of administration to take effect, and they are only effective in roughly half of patients. Ketamine, previously known as primarily a veterinary anesthetic, rapidly alleviates treatment-resistant depressive symptoms at sub-anesthetic doses. Indeed, a single intravenous (i.v.) infusion of ketamine elicits an antidepressant effect within 2 hours and can last up to 2 weeks. Furthermore, this therapeutic effect of ketamine can be prolonged with repeated intermittent treatments. However, there are still many unanswered questions regarding ketamine’s safety, especially with respects to the long-term effects of prolonged, repeated exposure. Since ketamine is also a popular club drug with addictive properties, it is critical to characterize the safety and abuse liability of this drug. Additionally, women have twice the prevalence rates of depression as compared to men, and they progress more rapidly through the phases of drug addiction than men. Despite these known sex differences, females have been heretofore underrepresented in clinical and pre-clinical research. We sought to determine if intermittent self-administration of ketamine in rats can trigger drug-seeking behavior, at a dose that is close to the therapeutic human dose, and if the stage of the four-day estrous cycle can influence this behavior, as antidepressant-like effects of ketamine in females depends on estrous cycle stage (Dossat 2016). To that end, rats were trained to self-administer ketamine (0.1 mg/kg/infusion) in an operant chamber once every fourth day for males, while females’ self-administration sessions coincided with either diestrus 1 (when estradiol and progesterone are low), or proestrus (when these hormones are high). Ketamine intake in diestrus-trained females rapidly declined, while proestrus-trained females and males were stable across the acquisition phase of the experiment. After extinction training, proestrus-trained females and males (but not diestrus-trained females) displayed reinstated ketamine-seeking behavior when re-exposed to discrete cues that were previously paired to ketamine availability. Interestingly, a ketamine priming injection in the absence of cues did not reinstate ketamine-seeking behavior as is consistently seen with a priming injection of cocaine, a drug with very high abuse potential. Together, this indicates not only that ketamine-paired cues are more salient precipitators of relapse than the pharmacological effects of ketamine on its own, but also that the stage of estrous cycle associated with high levels of gonadal hormones supports female’s ketamine intake and subsequent ketamine relapse. To address comorbid depression and ketamine addiction, we assessed ketamine addictive-like behaviors in males and females previously exposed to unpredictable chronic mild stress (CMS), a procedure shown to induce a depressive-like phenotype in rodents. They were treated with four intermittent therapeutic i.v. ketamine infusions, designed to mimic infusion protocols used in clinics. They were then given access to self-administer 0.5 mg/kg/infusion ketamine and tested for their motivation to obtain ketamine using progressive ratio schedule (PR) and persistence of incubated ketamine craving after a period of forced abstinence, which is a major factor in the precipitation of relapse. CMS decreased sucrose intake in both sexes, but ketamine had no effect on anhedonia like-behaviors. Ketamine treatment reduced anxiety-induced neophagia, measured by the novelty-suppressed feeding test, suggesting that i.v. ketamine’s antidepressant-like effects may be symptom- and species-specific. While prior ketamine exposure and CMS had no effect on subsequent ketamine addiction-like behavior in males, females that underwent CMS displayed more addiction-like behavior than non-stressed females, suggesting that chronic stress can increase the risk for ketamine abuse in females. Additionally, ketamine pre-exposed females displayed lower ketamine intake, with no alterations in motivated responding or craving. Finally, dendritic spine density and morphology was assessed in the nucleus accumbens (NAc), the central processor for rewarding stimuli that is affected by both depression and addiction. Females with prior ketamine exposure regardless of stress condition had an increase in spine density that was primarily driven by the formation of immature thin spines; there were no changes in males. Together this suggests that although ketamine pre-treatment may alter NAc plasticity in a sex-dependent manner, it does not potentiate ketamine addiction-like behavior. Taken together, this work demonstrates that although ketamine and drug-paired cues have strong reinforcing effects, prior exposure to therapeutic ketamine infusions do not increase the risk of abuse. Estrous cycle stage and prior exposure to chronic stress influences the reinforcing properties of ketamine in females, suggesting an influence of ovarian hormones. The fact that ketamine-seeking behavior was dependent on the drug-paired cues rather than the acute pharmacological effects of ketamine, and that prior therapeutic ketamine did not increase the subsequent development of addiction-like behavior, suggests that there may be little overlap in ketamine’s antidepressant effects and addictive effects. It is possible that ketamine, if administered under the appropriate conditions, may have limited abuse potential, but research is necessary to determine if these sex-specific effects in rats translate to humans. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2017. / November 8, 2017. / addiction, dendritic spines, depression, ketamine, self-administration, sex differences / Includes bibliographical references. / Mohamed Kabbaj, Professor Directing Dissertation; Laura Keller, University Representative; Pradeep Bhide, Committee Member; Jamila Horabin, Committee Member; Jian Feng, Committee Member.

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Benzodiazepines (BZs) and selective serotonin reuptake inhibitors (SSRIs) have both been approved for use in the treatment of anxiety disorders. Benzodiazepines offer immediate therapeutic benefits; however, tolerance and the potential for abuse may limit their long-term use. While little or no abuse potential is associated with SSRI use, therapeutic benefit is achieved only after several weeks of chronic treatment. During initial SSRI treatment, symptoms of anxiety may increase in some individuals and can lead to incomplete remission of anxiety symptoms or non-compliance. Evidence for the short-term use of BZs with long-term SSRI treatment is limited but some reports suggest faster symptom remission and/or greater global anxiolytic effect compared to SSRI treatment alone. The goal of the present research was to investigate the extent to which combinations of BZs and SSRIs interact to reduce behavioral and physiological measures of anxiety-like behavior and to investigate the mechanisms underlying these interactions. Acute treatment with SSRIs was shown to increase anxiogenic-like measures of behavior, with differences in dose-dependent decreases in locomotor activity associated with fluoxetine and citalopram, while a non-selective BZ (diazepam) produced acute anxiolytic-like effects with dose-dependent decreases in locomotor activity. Combinations of SSRI+BZ produced acute anxiolytic-like effects, attenuating both the anxiogenic-like effects associated with SSRI treatment and decreased locomotor activity associated with BZs. Investigation with GABAA subunit selective ligands indicate that α2, 3, and/or 5 subunit containing GABAA receptors are likely involved in the anxiolytic-like effects and decreases in locomotor activity, while the role of a1 subunit containing GABAA receptor is unclear, but play no role in decreased locomotor activity or anxiolytic-like effect of combined treatment. Investigation with selective serotonin (5-HT) receptor subtype ligands indicates that 5-HT1A and 5-HT2C receptors are not involved in the anxiogenic-like effects of acute SSRI treatment in this model. Acute treatment with anxiolytic-like dose of BZ, and anxiogenic-like dose of SSRI and anxiolytic-like doses of combined SSRI+BZ all result in significant increases in stress hormone release following administration. Altogether, these results suggest that acute, combined SSRI+BZ treatment may be useful in decreasing measures of anxiety-like behavior and minimizing decreases in locomotor activity and are implicated in a complex relationship with the hypothalamic pituitary axis.