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2000 March

The Reinforcing Effects of Alcohol: Is Dopamine Required?

Michelle D. Brot, PhD
Research Assistant Professor

Orthodontics

Description: It is widely believed that dopamine (DA) is a critical neurotransmitter in mediating the reinforcing properties of drugs of abuse, yet in the case of alcohol, there are many other neurotransmitters that have been implicated in its rewarding effects (e.g. GABA, serotonin, glutamate, opiates). These studies will test whether DA in particular is required for self-administration of alcohol. This will be assessed using DA-deficient (DA-/-) mice and wild-type (WT) controls, which will be trained to orally self-administer alcohol. Mice will be exposed to alcohol gradually by implementing the sucrose-fading methodology in which they are first habituated to drinking water from the tube, then sucrose is introduced into the water, then the drug is added to the sucrose solution, and finally the sucrose is faded out. Following the training period, when sucrose has been entirely faded out and the mice are consuming pure drug solution, a preference test between water and alcohol will determine whether the mice find alcohol rewarding. The results will be compared between DA-/- groups, and ad lib drug-consuming WT group, and a yoked control WT group that will have been provided with the same drug dose as the DA-/- mice consumed each day. Because DA-/- mice consume very small volumes in the absence of DA, it is necessary to have an accurate way to measure the amount consumed. This is feasible using a lickometer, which counts the actual number of licks the mouse makes to each substance. The hypothesis is that if DA is critical for alcohol's rewarding or addictive properties, then DA-/- mice will not prefer drinking alcohol to water. Alternatively, DA-/- mice might show a similar (high) preference ratio for alcohol compared to that of the control WT groups if DA does not play an important role in the reinforcing effects of alcohol.

Integrating Clinical Practice Guidelines for Smoking Cessation Into Primary Mental Health Care for Veterans with Posttraumatic Stress Disorder

Miles McFall, PhD
Associate Professor

Psychiatry & Behavioral Sciences

Description: Introduction: Most veterans with posttraumatic stress disorder (PTSD) who smoke do not follow through with treatment upon referral to a smoking cessation specialist. Treatment of these patients is complicated by the fact that anxiety and depression may be exacerbated by quit attempts and increase risk for relapse to smoking. Therefore, referral to smoking cessation clinics may constitute suboptimal intervention for veterans with PTSD who smoke. This project aims to (a) determine the feasibility of integrating smoking cessation into primary mental health care for veterans with PTSD and (b) gather preliminary data showing superior outcomes from an integrated care approach, compared with referral to a smoking specialty clinic.

Method: This randomized controlled clinical trial will use a 2-group design and an intention-to-treat analysis. Patients admitted to a Veterans Affairs (VA) PTSD clinic will be randomly assigned either to integrated care for PTSD and tobacco use administered by mental health clinicians (n=25), or to usual care for smoking provided by a specialized Smoking Cessation Clinic (n=25). After subjects receive five sessions of smoking cessation treatment, smoking outcomes will be assessed at weeks 8, 16, and 24. Effects on psychiatric and functional status will be measured at week 24. Exit interviews and review of documentation provided by clinicians will verify that interventions were implemented.

Analysis Plan: Point-prevalence of smoking abstinence and other dichotomous measure of smoking outcomes will be analyzed by x2 tests and odds ratios. Continuous measures of smoking outcomes and psychiatric and functional status will be analyzed using t-tests. A primary goal of analysis is to establish that our effect size estimate (11% minimum difference between conditions) is realistic, for computing power analyses supporting subsequent clinical trials.

Significance: Demonstrating the feasibility and efficacy of an integrated approach to smoking cessation for mentally ill veterans will potentially improve access to, and compliance with, smoking cessation treatment for this large population. It will also provide a new model for intervention that addresses dynamics between nicotine dependence and psychiatric symptoms.

Resulting articles & projects:

  • McFall ME, Saxon AJ, Thompson CE, Yoshimoto D, Malte C, Straits-Troster K, Kanter E, Zhou XA, Dougherty CM, Steele B. Improving the rates of quitting smoking for veterans with posttraumatic stress disorder. Am J Psychiatry 2005;162:1311-1319. [PubMed abstract | Free online]
  • In addition to the article above, this pilot study was instrumental in securing funding for a large, multisite trial funded by the US Department of Veterans Affairs Cooperative Studies Program (CSP 519, Total Funding: $11,000,000). An article based on that larger project was published in JAMA in 2010:
  • McFall M, Saxon AJ, Malte CA, Chow B, Bailey S, Baker DG, Beckham JC, Boardman KD, Carmody TP, Joseph AM, Smith MW, Shih MC, Lu JJJ, Holodniy M, Lavori PW, CSP 519 Study Team. Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial. JAMA 2010;304(22):2485-2493. [doi:10.1001/jama.2010.1769 | PubMed abstract]
  • McFall M, Atkins DC, Yoshimoto D, Thompson CE, Kanter E, Malte CA, Saxon AJ. Integrating tobacco cessation treatment into mental health care for patients with posttraumatic stress disorder. Am J Addict 2006 Sep-Oct;15(5):336-44. [PubMed abstract]
  • McFall, M.E. Integrating Practice Guidelines Into Primary Health Care for PTSD. Presentation at the symposium "Smoking Cessation and the Practice of Psychotherapy" (Frank Collins, Chair). Presentation at the American Psychological Association Annual Convention, San Francisco.

Predictors of Symptom Severity in the Alcohol Withdrawal Syndrome: Testing a Patient Self Report Screening Instrument

Joseph P. Reoux, MD
Assistant Professor

Psychiatry & Behavioral Sciences

Description: Appropriate management of alcohol withdrawal syndrome (AWS) is a critical challenge facing addiction treatment providers. Non-optimal management can result in serious medical complications or unnecessary utilization of costly services such as hospitalization. While many patients experiencing AWS require little medical management, others experience emergent conditions such as delirium treatments (DTs). A history of DTs helps identify patients at high risk for complicated AWS, however most patients have not had previous DTs and predicting the severity of the AWS or the intensity of medical monitoring needed for these patients is less well delineated. Given evidence that inpatient management is not necessary for all patients with AWS, treatment programs increasingly offer outpatient detoxification. Empirically tested predictors of the course of AWS are needed to identify patients most appropriately managed in the outpatient setting. While instruments exist to guide treatment by monitoring the severity of active withdrawal symptoms (i.e. CIWA-Ar), no assessment tool is available to predict which alcohol dependent individuals will require close monitoring and medical intervention for their AWS. The intent of this project is to evaluate the validity of a brief patient self-report screening instrument to predict whether or not the severity of AWS in alcohol dependent patients will need medication to manage the AWS as indicated by an accepted threshold score on the CIWA-Ar. An effective screening instrument would assist treatment providers in making more efficient and cost effective decisions about management of AWS.

2000 October

Role of P-glycoprotein in Human Opioid Pharmacodynamics

Evan D. Kharasch, MD, PhD
Professor

Anesthesiology

Description: There is considerable clinically significant and largely unexplained inter- and intra-individual variability on the dose-effect relationship for opioids. Although pharmacokinetic differences exist and account for some of this variability, inter- (and possibly) intra-individual differences in pharmacodynamics (blood concentration-CNS effect relationship) are substantially greater. Nevertheless, the mechanism of such differences is poorly understood. The drug efflux pump P-glycoprotein (Pgp), located on the luminal surface of endothelial cells in the brain, is an integral component of the blood-brain barrier and regulates drug access in the CNS. It was recently discovered that opioids such as morphine, fentanyl, and methadone are substrates for P-gp in vivo. In animals, P-gp is a major determinant of opioid CNS access and pharmacodynamics. However the role of P-gp in therapeutic/addicting opioid CNS access and pharmacodynamics in humans is totally unknown. The aim of this investigation is to test the hypothesis that opioids (specifically morphine and fentanyl) are substrates for human brain P-gp, and that P-gp is a major determinant of opioid pharmacodynamics and clinical effect. A recently identified human brain P-gp inhibitor will be used as an in vivo probe to test this hypothesis in a series of clinical studies measuring blood opioid concentrations and CNS effects. Using a randomized, double-blind, placebo-controlled, balanced crossover design, we will evaluate the clinical effects (pupil diameter change and subjective self-assessment of sedation, energy level, confusion, clumsiness, anxiety, and nausea) and arterial blood concentrations of morphine and fentanyl after inhibition of P-gp or control. The hypothesis will be tested by comparing clinical effects and pharmacodynamic parameters (EC50 and ke0 determined by pharmacokinetic-pharmacodynamic modeling) with and without P-gp inhibition. Verification of the hypothesis will yield the first report of P-gp determination of therapeutic/addicting opioid CNS access and pharmacodynamics, and will spawn an entire field of human investigation regarding mechanisms of opioid effect, variability, toxicity, tolerance, and addiction.

Teensmart / Informa-T /Ayuda-T : Exploring the Acceptability and Feasibility of Conducting an Internet Web-Based ATOD and Sexual Risky Prevention Intervention for Latino Adolescent Youth and Their Families

Cathy Strachan Lindenberg, RN, DrPH
Associate Professor

Family and Child Nursing

Description: This project will assess the acceptability and feasibility of a theory-driven, empirically-based, bilingual, web-based, Youth Risk and Resilience Multi-Scale Profile (YMSP) and a 10 module psycho-educational Risk and Resilience curriculum, for Latino youth and their families. The measures and the prevention curriculum, based on the Social Stress Model for Substance Abuse and Other Risk Behavior Prevention, are designed to promote protective factors (personal competence, and positive family support and peer influence) and prevent or reduce alcohol, tobacco and other drug use (ATOD) and risky sexual behaviors (RSBs) among Latino youth and their families. A voluntary sample of 20 Latino high school adolescent boys and girls from Cleveland High School and their parents will participate in this pilot study. Adolescents will pilot test the self-administered bilingual web-based YMSP and the Risk and Resilience Prevention Curriculum. Both qualitative (focus groups with adolescent boys and girls and parents) and quantitative research methods (self-administered web-based questionnaires) will be used to achieve the pilot study objectives. Findings from this pilot study will support the future development of a NIH sponsored R01 grant proposal to conduct a randomized field trial to assess the efficacy of this web-based bilingual adolescent telehealth prevention intervention to reduce and/or prevent ATOD and RSBs among Latino teens.

The Effect of Viral Mediated Overexpression of 5-HT 1B Receptors in Rat Nucleus Accumbens on Cocaine Sensitization

John Neumaier, MD, PhD
Assistant Professor

Psychiatry & Behavioral Sciences

Description: Drug addiction involves many adaptations in brain function, including sensitization, tolerance, and withdrawal. For example, cocaine induces changes in the function of neurotransmitters and their receptors, neuronal circuitry, and complex behaviors of rats and other research animals; many of these animal observations have been confirmed in studies of brain function of addicted humans. These changes are likely to account for the physical and psychological processes that lead to the abuse of psychoactive drugs; elucidating these mechanisms may offer us insights into more effective treatments for addiction. Similarly, manipulations of various neurotransmitter systems may modulate the acute and long-term effects of cocaine on brain function. For example, central 5-HT 1B serotonin receptors modulate cocaine's actions, but the available data is complex and sometimes contradictory. It is our hypothesis the axon terminal 5-HT1B receptors, contained within nucleus accumbens neurons that project to the ventral tegmental area, disinhibit dopamine transmission and contribute to several important effects of serotonergic drugs on cocaine related behaviors. However, the 5-HT1B receptor has been technically difficult to manipulate in a single neuron population. We propose to use viral mediated gene transfer to increase 5-HT1B expression in nucleus accumbens neurons, allowing the hypothesis to be addressed directly. Our preliminary data indicate that overexpression of 5-HT1B receptors in these neurons alters the rewarding and aversive properties of cocaine. We propose to test whether selectively increasing 5-HT1B receptor expression in nucleus accumbens neurons will sensitize (enhance) the biochemical and behavioral responses of rats to acute and subchronic cocaine administration as measured by cFOS expression, delta-cFosB expression, and cocaine-induced hyperactivity. The results may suggest a role for 5-HT1B receptors in cocaine addiction, leading to redefined neurobiological models for drug addiction and improved therapies for its treatment.

Resulting articles & projects:

  • The preliminary findings of this grant were used in a successful application by Dr. Neumaier for a NIDA grant, "The role of serotonin receptors in brain reward circuits," with funding of $1,125,000. [1R01DA016432-01A1]
  • Neumaier JF, Arvanitogiannis A, Wise RA, Carlezon WA. Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine. J Neuroscience 2002; 22(24): 10856-10863. [PubMed abstract | Free online]
  • Clark MS, Sexton TJ, McClain M, Root D, Kohen R, Neumaier JF. Overexpression of 5-HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress. J Neurosci 2002;22(11):4550-62. [PubMed abstract | Free online]

The Role of Specific Neuropeptide Y Receptors in Neurobiological Responses to Ethanol and Diazepam

Todd Theile, PhD
Research Scientist

Psychology, Alcohol and Drug Abuse lnstitute

Description: Little is known about the role that modulatory neuropeptides play in ethanol-seeking behavior. One promising candidate is neuropeptide Y (NPY), a 36 amino acid neuromodulator that is distributed widely throughout both the peripheral and central nervous systems. Genetic linkage and neurochemical analyses or rats that were selectively bred for alcohol preference indicated the NPY may be involved with high alcohol consumption in these rats. Consistent with this hypothesis, we have found that NPY knockout mice drank significantly more ethanol, and recovered from ethanol-induced sedation significantly sooner, than wild-type littermate mice. On the other hand, transgenic mice that overexpress NPY drank more ethanol and were more sensitive to the sedative effects of this drug. These data provide direct evidence that ethanol consumption and resistance are inversely related to NPY levels in the brain. This project will address the following questions: (A) Which specific NPY receptor(s) are involved in regulating the effects of NPY on sedation caused by high doses of ethanol and locomotor activation caused by low doses of ethanol? To address this question, we will assess ethanol-induced sedation and ethanol-induced locomotor activation in mice with targeted gene disruption of NPY Y1, Y2, or Y5 receptors. (B) Are NPY receptor(s) involved in regulating sedation caused by high doses of diazepam and locomotor activation caused by low doses of diazepam? We will assess diazepam-induced sedation and diazepam-induced locomotor activation in mice with targeted gene disruption of Y1, Y2, or Y5 receptors to determine if the NPY system modulated neurobiological effects of another abused drug. Determining how NPY acts to influence responses to ethanol is critical to a complete understanding of the neurobiological mechanisms that determine alcohol use and abuse. Such knowledge will be useful for the development of pharmacological treatments targeted at preventing excessive alcohol intake.