Medical Student Research Fellowship for Summer 2007

Mentor: Bryon Adinoff, M.D.
Department: Psychiatry
Room number: FL500
Mail Code: 8564
Phone number: 214-645-6975
E-mail: bryon.adinoff@utsouthwestern.edu
Project title:
Human subjects IRB approved project number (where applicable):
Impulsivity, Neural Deficits, and Cocaine Relapse (IRB #092004-021 )
Stress, HPA Axis Dysfunction, and Relapse in Alcoholism (IRB #012007-023)
Limbic Sensitivity in Cocaine Addiction (IRB # 0801-396)

Animal subjects IRB approved project number (where applicable):

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Patient-based research

Brief Description of Project:
Project #1
R01DA023203
NIH/NIDA
Problems with impulsivity are shared across a wide spectrum of psychiatric disorders, including substance use, eating, gambling, bipolar, attention deficit, antisocial and borderline personality disorders, and may explain the common co-occurrence of these disorders and their high rates of relapse. However, the putative relationship between impulsivity and relapse has not been demonstrated. An emerging neuroimaging literature suggests that impulsivity may be a result of neural disruptions that persist with abstinence. In previous studies with abstinent cocaine-addicted subjects, we have used single photon emission computed tomography (SPECT) to identify specific disruptions in the regional cerebral blood flow (rCBF) of the orbitofrontal cortex and rostral anterior cingulate. These brain areas are key in the regulation of impulse control. We have also observed deficits in several neurocognitive and self-assessment measures of impulsivity, and have successfully determined neural activation (using functional magnetic resonance imaging, or fMRI) during two tasks of impulsivity. We now propose to concurrently assess the neurocognitive and neural disruptions associated with impulsiveness in cocaine-addicted subjects, and examine the relationship between these alterations and prospective relapse. Two- to four-week abstinent, treatment-seeking cocaine dependent subjects and healthy controls will be studied. Two ecologically relevant neurocognitive constructs of impulsivity - disinhibition and decision-making - will be assessed. fMRI will be used to assess neural activity during a disinhibition task of response inhibition (the ability to rapidly inhibit a pre-potent response) and a decision-making task of response reversal [the ability to reverse (or shift) cognitive and behavioral strategies to suppress a course of action that is no longer appropriate]. Subjects will also be assessed for resting rCBF abnormalities with SPECT. Standarized and experimental neurocognitive tests, as well as self-assessment measures, will be used to assess disinhibition and decision-making. The tendency to relapse impulsively will be measured by the Impulsive Relapse Questionnaire, a novel measure of relapse style. Cocaine-addicted subjects will subsequently be followed for six months following residential treatment and assessed for time to substance use relapse. We hypothesize that both quantitative measures of impulsivity and the neural deficits associated with disinhibition and decision-making will significantly correlate with each other and predict time to substance use relapse. These studies will significantly strengthen our understanding of the neurobiologic and neurocognitive mechanisms related to impulsivity and relapse, and provide the framework for targeted interventions to prevent relapse in an identified population of impulsive, at-risk patients.
Role: Principal Investigator

Project #2
U01AA016668
NIH/NIAAA
Stress, HPA Axis Dysfunction, and Relapse in Alcoholism
The hypothalamic-pituitary-adrenal (HPA) system is posited as a key biologic link in stress-induced relapse. The HPA axis provides a regulatory feedback network between the brain and the body's behavioral and physiologic responses to stress, recovery, and adaptation. Both trauma and chronic alcohol use produce persistent disturbances in the HPA response to stress. The chronic use of alcohol may also impair the stress-induced release of neurosteroids, compounds that directly modulate GABAergic activity. Thus, altered glucocorticoid and neurosteroid responsiveness during abstinence may impair the central nervous system's ability to mount an appropriate response to environmental stressors, heightening the probability of relapse. However, the relationship between stress, relapse, and HPA axis disturbances remains tentative. In the proposed study, the investigators will expand their extensive work on stress, HPA axis disturbances, and substance use disorders to directly assess the contribution of trauma, stress, and alcohol use upon pituitary-adrenocortical functioning in alcohol dependence. The relative contribution of adrenocortical disruption and episodic stress to prospective drinking behaviors will then be determined.
Hypothesis: We hypothesize (1) that lifetime trauma, recent stress, and chronic alcohol use will additively contribute to HPA axis disruption, (2) alterations in glucocorticoid and neurosteroid release, moderated by episodic stress, will predict a return to drinking. Genotyping and linkage analysis will also be obtained.
Methods: One hundred treatment-seeking, one-month abstinent, alcohol-dependent subjects will be studied. Standardized assessments will be used to assess childhood and adult trauma as well as recent (six months) stress. Pituitary-adrenal (including ACTH, cortisol, and neurosteroids) responses to both neuroendocrine [ovine corticotropin releasing hormone (oCRH), cosyntropin, and dexamethasone] and experiential (public speaking) challenges will be measured. Drinking behavior and episodic stress will be prospectively assessed for six months following neuroendocrine assessment.
Significance: If our hypotheses are supported, a definitive connection between previous trauma, biological stress response mechanisms, and ongoing stress upon prospective drinking behavior will be demonstrated. The identification of a specific biologic mechanism that underlies this association will provide a fertile framework for the development of targeted pharmacological interventions to decrease relapse in this vulnerable population. In addition, elucidating the concurrent contributions of stress-response biologic systems and externals stressors will provide the therapist and patient with a constellation of specific risk factors for focused treatment.
Role: Principal Investigator

Proeject #3
NIDA
Limbic Sensitivity in Cocaine Addiction

The limbic system is an integrated brain area involved in the regulation of reward, motivation, emotional expression, and memory. These regions are considered critical to the development and persistence of addiction. In our currently-funded proposal, the regional cerebral blood flow (rCBF) response to the limbic-stimulant procaine was assessed relative to saline in cocaine-addicted subjects (n=38) and healthy controls (n=37). Our findings revealed that cocaine-addicted men and women exhibit a blunted limbic rCBF response to procaine compared to age and gender matched controls. Procaine, unlike cocaine, has minimal interaction with the monoamine transporters, but has potent affinity with both cholinergic and 5HT3 receptors. Preclinical studies indicate that these latter receptor systems are altered following the acute and chronic administration of cocaine, and disruptions in these systems may modulate subsequent drug reinforcement. Our competitive renewal is designed to further elucidate the putative neurobiologic differences in the cholinergic and 5HT3 systems revealed by procaine. Hypotheses: We hypothesize that cocaine-addicted subjects will demonstrate impairment of the cholinergic and 5HT3 receptor systems. Preliminary Studies: To explore cholinergic and 5HT3 receptor functioning, healthy controls (n=3) and cocaine-addicted subjects (n=3) were administered (1) the cholinergic agonist physostigmine, (2) the muscarinic cholinergic antagonist scopolamine, (3) the 5HT3 antagonist ondansetron, and (4) saline. Preliminary analyses suggest that the limbic rCBF response (relative to saline) following all three probes is blunted in cocaine-addicted subjects compared to controls. Methods: Male (n=12) and female (n=12) cocaine-addicted subjects between two and six weeks abstinence will be compared to age and gender matched controls (12 male and 12 female). All subjects will receive physostigmine, scopolamine, ondansetron, and saline. Single photon emission computed tomography (SPECT) and SPM analytic techniques will be used to assess rCBF and differences within and between groups. Significance: The cholinergic and 5HT3 receptor systems have not previously been studied in cocaine-addicted subjects using neuroimaging techniques. Our competing renewal will be used to identify specific changes in these neuroreceptor systems, providing avenues for new pharmacologic investigations in the treatment of cocaine dependence.
Role: Principal Investigator

Specific Roles of Student:
1. Learn the general strategies in conducting clinical laboratory studies, including subject screening, recruitment, consent process. Student will accompany study staff at recruitment sites for Project #1 and #2.
2. Learn the basics of neuroimaging and neuroendocrine clinical studies, including imaging paradigm development and laboratory techniques. Student will accompany study staff during performance of study sessions for both Project #1 and Project #2.
3. Student will participate in the analysis, interpretation, literature search, and manuscript preparation of data previously generated (Project #3). Specifically, student will take part in preparation of the manuscript describing the effects of the 5HT3 antagonist ondansetron in regional cerebral blood flow in cocaine-addicted subjects and controls.