Behavioral Pharmacology Division – Symposia for 2015
Presented below are the symposia of the division for presentation at the Experimental Biology meeting of 2015. Please send new symposia ideas to us at any time for consideration (jwitkin@lilly.com).
Emerging Role of Trace Amine Associated Receptor (TAAR) 1 in Drug Abuse and Mental Disorders
Jun-Xu Li and Gregory Miller
Co-sponsored: Neuropharm, Mol Pharm, DDD, ISTCP
Sunday AM
Trace amines refer to a family of metabolites of aromatic amino acids that include octopamine, tyramine, β-phenethylamine as well as several other non-catechol amines. Although trace amines were discovered more than 100 years ago, their effects have long been considered non-specific until recently when two groups independently reported the cloning of TAAR 1 in 2001.
One decade has passed since the cloning of TAAR 1 and some exciting findings have been just emerging in the past several years with the availability of genetically modified mice and highly selective TAAR 1 ligands. In particular, current consensus is that TAAR 1 plays critical roles in the modulation of monoamine system and TAAR 1 agonists may be potential pharmacotherapies for drug abuse and other mental disorders. This symposium will discuss current understanding of TAAR receptor systems from genetic, pharmacological, and behavioral perspectives and new evidence that TAAR 1 agonists as potential treatments for cocaine abuse and schizophrenia.
Novel Therapeutic Targets and Preclinical Models for Post-Traumatic Stress Disorder
Carrie Jones
Co-sponsored: Neuropharm, Toxicology
Tuesday AM
Post-Traumatic Stress Disorder (PTSD) is characterized by symptoms of a persistent, inextinguishable fear response following a traumatic event. One potential mechanism for the development of these symptoms is impaired fear extinction. The phenomenon of fear conditioning and extinction can be reproduced in animals but preclinical PTSD models remain poorly validated due to a lack of effective pharmacotherapies for PTSD patients. Currently, selective serotonin reuptake inhibitors (SSRIs) are the only FDA approved treatment for PTSD. However, these drugs rarely result in full or lasting remediation nor do they improve fear extinction learning in PTSD patients.
The lack of effective therapies highlights the need for valid preclinical models which can facilitate the discovery of novel pharmacological targets as well as reveal the underlying pathobiology that causes PTSD symptom development and expression. This symposium will describe novel pharmacological agents being investigated for the treatment of PTSD, the preclinical models employed to test their efficacy and probe their mechanism of action, and clinical studies of fear extinction which inform the development of translational PTSD models.
Chemistry, Pharmacology, and Clinical Applications of Atypical Reuptake Inhibitors as Wake Promoting Agents
Larry Carter/Bruce Blough - accepted
Co-sponsored: Neuropharm, Mol Pharm, ISTCP
Wednesday AM
The proposed symposium will demonstrate how translational and reverse translational approaches have been used to identify new drugs that promote wakefulness. Specifically, Dr. Tafti will speak about the clinical problems and unmet needs associated with sleep disorders of hypersomnolence, how the identification of compounds that promote wakefulness without causing rebound hypersomnolence have advanced the treatment of these disorders, and how these drugs can be identified using animal models.
Dr. Baumann will describe some of the pharmacological differences between monoamine releasers and uptake inhibitors and the impact of those differences on abuse liability. Dr. Blough will describe how different characteristics of the chemical structures of these molecules translate into predictable effects on monoamine uptake and release, allowing for the rationale design of atypical and hybrid transporter ligands and substrates.
Dr. Reith will describe molecular approaches for differentiating traditional stimulants from atypical uptake inhibitors at the dopamine transporter. Dr. Carter will describe how the characteristics described by the previous speakers have been used to identify a novel drug candidate that has been shown to have robust wake-promoting properties in patients with narcolepsy.
Methamphetamine: Preclinical and Clinical Findings
Raj Desai/Michael Nader
Co-sponsored: Neuropharm
Monday AM
Psychomotor stimulant abuse and addiction continue to be a major public health problem worldwide, with an estimated 1.6 million Americans confirming current cocaine or methamphetamine (MA) use (SAMHSA, 2013). Despite substantial research investment, there are no medicines available for treating stimulant abuse and addiction.
While significant attention has been directed towards understanding the behavioral and neuropharmacological mechanisms that underlie cocaine's addiction-related effects, MA has not received such attention. This symposium will: a) discuss our current understanding of the behavioral and neuropharmacological consequences of MA exposure across species (i.e., rodents, non-human primates, and humans), and when possible, compare its effects with those of cocaine; and b) discuss sequelae of MA exposure that call for both novel treatment strategies for MA addiction and additional research. Dr. Erin Calipari will present data on how previous drug history alters MA's actions at the dopamine transporter in rodents, and how these effects compare with dopamine transporter blockers and other dopamine releasers, which are pharmacotherapeutic targets for stimulant addiction.
Dr. Michael Taffe will present results from preclinical studies in rats and nonhuman primates that will highlight similarities and differences in the physiological and behavioral (unconditioned, conditioned, and cognitive) consequences of MA administration. Dr. Jack Bergman will provide data regarding tolerance and cross-tolerance among dopaminergic drugs following chronic MA exposure. Dr Michael Nader will directly compare the behavioral pharmacology of chronic exposure to MA and cocaine in nonhuman primates and how that impacts treatment strategies. Finally, the discussant, Dr. Richard De La Graza, will present new data on the subjective, reinforcing, and cognitive effects of MA in human subjects, and lead a discussion on the implications of the four preclinical presentations in developing future treatment strategies for MA and stimulant addiction.
Sigma Receptor Symposium
Habibeh Khoshbouei
Tuesday, March 31
3:00 PM–5:30 PM
The concept of sigma receptors was first proposed nearly 40 years ago from studies of opioid ligands. Since then, two sigma receptor subtypes have been proposed, sigma1 and 2. Much of our understanding of this system is based on pharmacological characterization of the cloned sigma1 receptor subtype (Sigma1). Since its initial description it has become clear that Sigma1 is not a canonical receptor. It is highly conserved among mammalian species, however, it does not share significant homology with any other mammalian protein. Although a range of structurally diverse small molecules bind Sigma1 with high affinity, and it has been associated with a broad range of signaling systems, Sigma1 itself has no known signaling or enzymatic activity.
The evolution of this field over nearly four decades has more recently led to a fundamental shift in the concept of “sigma receptors” to what may more accurately and generally be called sigma proteins. Largely based on traditional pharmacologic approaches, the Sigma1 protein has been associated with a broad range of signaling systems, including G-protein coupled receptors, NMDA receptors, and ion channels, and biogenic amine trasporters. Sigma1 has been linked to a range of physiological processes, including intracellular calcium signaling, neuroprotection, learning, memory, cognition and psychostimulant abuse. Emerging genetic, clinical, and mechanism focused molecular and behavioral pharmacology data demonstrate the involvement of Sigma1 in a range of pathophysiologies and disorders including neurodegenerative disease, pain, addiction, psychomotor stimulant abuse, and cancer.
However, an understanding of the physiological role of sigma proteins has remained elusive. Emerging data associate Sigma1 with chaperone-like activities or molecular scaffold functions. The evolution of the concept of sigma proteins has been documented by a rapidly increasing number of remarkably diverse publications in the literature. This symposium aims to provide an updated perspective on this rapidly evolving field undergoing changes in fundamental concepts of key importance to the discipline of pharmacology. We will focus on the reported roles of sigma proteins in diverse pathophysiology and on emergent therapeutic initiatives. The symposium will be attractive to a broad audience interested in area of cell biology and development of therapeutic potential for the treatment of alcohol and substance abuse, dopamine transmission and cancer biology.