Kabbaj Laboratory Mohamed Kabbaj, Ph.D. University of Bordeaux II, France Florida State University College of Medicine Dept. of Biomedical Sciences 1115 West Call Street Tallahassee, FL 32306-4300 Office: (850) 5495 Lab: (850) 644-4930 Dr. Kabbaj's Faculty Profile
Research Interests
The focus of our research is to understand the brain basis of emotional behavior. Simply put, we are asking: What is it in our brains that make us different from each other in the way we react emotionally? Why are some of us very prone to stress and others not? Why are some willing to take risks and try new adventures, while others are timid and fearful? Why are some prone to becoming addicted to harmful drugs (such as cocaine or heroin), while others readily avoid them? The basis of these differences is in our genes, in our brains, but also in our environment, the way we develop and the way we interact with others around us. We are using an excellent animal model for asking, and answering, these complex questions. We have made some discoveries on the brain basis of these differences in emotionality. Moreover, the work addresses questions of great importance to psychiatric disorders, including depression, and substance abuse. The following are some of the projects we are working on: Neurobiological basis of individual differences in behavioral sensitization to amphetamine The overall aim of this work is to investigate the neurobiological basis of behavioral sensitization to amphetamine in the context of individual differences. We aim to understand the interplay between psychosocial stress and the development of behavioral sensitization to amphetamine in the context of individual differences using a model of novelty seeking behavior that distinguishes outbred rats on the basis of their high (High Responder, HR) or low (Low Responder, LR) locomotor activity in a novel environment. HR rats acquire AMPH and cocaine self-administration faster than LR rats (Kabbaj et al., 2001; Mantsch et al., 2001; Marinelli and White, 2000; Piazza et al., 1989; Piazza et al., 2000; Pierre and Vezina, 1997) and show a greater behavioral sensitization to amphetamine or cocaine after repeated administration of low doses (Hooks et al., 1992; Hooks et al., 1991a; Piazza et al., 1989; Pierre and Vezina, 1997). Behavioral and neural sensitization may have a potential role in the pathogenesis of affective disorders and drug abuse (Robinson and Berridge, 2000; White and Kalivas, 1998). One possible mechanism by which stress enhances drug taking and behavioral sensitization to psychostimulants is through an interaction between glucocorticoids and dopamine. Our working hypothesis is that differences in stress- and dopamine- related genes play a role in HR and LR behavioral differences in sensitization to AMPH, as well as in the effect of psychosocial stress on behavioral sensitization to AMPH. To test these hypotheses, we will describe the neurobiological basis of behavioral sensitization to amphetamine as well as the neurobiological basis of the effect of psychosocial stress (and glucocorticoids) on behavioral sensitization to AMPH in the context of individual differences. Neurobiological correlates of the effects of stress controllability on drug addiction: role of individual differences The overall aim of this work is to explore the effects of stress controllability on the rewarding properties of cocaine and heroin in the context of individual differences. To this end, we will use a model of novelty seeking behavior that distinguishes outbred rats on the basis of their locomotor activity in a novel environment, and terms them High Responders (HR) and Low Responders (LR). We have previously shown that these animals exhibit differences in amphetamine and cocaine taking behaviors, with HR showing a more robust drug taking behavior than LR. Importantly we have shown that an uncontrollable stress, like social defeat, differentially alters cocaine self administration in HR and LR rats. We plan to extend these observations and apply the learned helplessness model in HR and LR rats to study 1) the differential effects of this stress on the rewarding properties of cocaine and heroin, and 2) The neurocircuitry implicated in the effect of stress on the rewarding properties of cocaine and heroin. Role of glucocorticoids in determining individual differences in anxiety related behaviors The purpose of this work is to examine the role of glucocorticoids in regulating individual differences in behavioral responses on rodent tests of anxiety related behavior. We are using a model of stress responsiveness behavior that distinguishes outbred rats on the basis of their locomotor activity and hormonal responses in a novel environment. These individual differences in responsiveness are used as a basis to categorize the rats as High Responders (HR) and Low Responders (LR). We have shown that these rats show significant differences in their behavioral responses on rodent tests of anxiety-related behavior, with HR rats being less “anxious” than LR rats (Kabbaj et al., 2000). We found that these HR and LR rats differ basally in the patterns of expression of some stress and serotonin related genes, and exhibit also different patterns of glucocorticoid secretion and cfos expression in the emotional circuitry following the light-dark test of anxiety related behavior (Kabbaj et al., 2000; 2001). It is not clear however what role glucocorticoids, released during the behavioral test, play in regulating anxiety related behavior: Are glucocorticoids causing the differential behavioral response in HR and LR rats in the “anxiety” test? Or are they simply a secondary response to the behavioral test of “anxiety”? To respond to these questions, we plan to investigate the “basal anxiety” (i.e. trait) and “psychosocial stress-induced anxiety” (i.e. state) in HR and LR rats that are either adrenally intact, or are adrenalectomized with corticosterone replacement in the normal basal physiological range. In these studies we will use the properties of the immediate early gene cfos, which is a good marker of neuronal activation, to characterize potential differences in the activation of neuronal circuitry mediating the effects of glucocorticoids on anxiety related behavior in HR and LR rats. We will further characterize this neurocircuitry by identifying the biochemical nature of the neurons that mediate individual differences in the effect of corticosterone on anxiety related behavior. We believe that the animals’ differences in emotional reactivity will likely involve some of the same physiological elements that are relevant to anxiety in humans.
Techniques used in Dr. Kabbaj’s Laboratory
Molecular In situ hybridization (single and double) Immunohistochemistry Radioimmunoassays Westerm Blot Northerm Blot Microarray RT-PCR and quantitative real time RT-PCR Behavioral Locomotor activity Tests of anxiety (Light dark box, elevated plus maze, open field) Learned helplessness Tests for learning and memory Conditioned place preference Operant chambers of drug self-administration
Current Laboratory Members
David Dietz, Rutgers University, 2000 Graduate student, Neuroscience program Ashley Stack, FSU 2006 Graduate student, Neuroscience program Fiona Smyth, FSU 2006 Graduate student, Biomedical Sciences Hui Wang, Tianjin University China 1992 Laboratory assistant
Selected References
M. Kabbaj*, C. Isgor, S. J. Watson, H. Akil (2002) Stress during Adolescence Alters Behavioral Sensitization to Amphetamine. Neuroscience, 113 (2): 395-400.   Evans SJ, Datson N, Kabbaj M, Thompson RC, Vreugdenhil, DeKloet ER, Watson SJ and Akil H (2002) Evaluation of Affymetrix Gene Chip Sensitivity in rat hippocampal tissue using SAGE analysis. European Journal of Neuroscience, 16(3):409-413   Lu XY, Shieh KR, Kabbaj M, Barsh GS, Akil H and Watson S.J. (2002) Diurnal Rhythm of Agouti-Related Protein and Its Relation to Corticosterone and Food Intake. Endocrinology, 143 (10): 3905-3915.   Kabbaj M , Yoshida S, Numachi Y , Sato M, Devine D.P and Matsuoka H (2003) Metamphetamine differentially regulates hippocampal glucocorticoids and mineralocorticoids receptors mRNA in Fischer and Lewis rats (2003). Molecular Brain Research, 117(1):8-14.   C. Isgor; M. Cecchi; M. Kabbaj; H. Akil and S.J. (2003) Watson Estrogen Receptor B in the Paraventricular Nucleus of Hypothalamus Regulates the Neuroendocrine Response to Stress and is regulated by Corticosterone. Neurosciences: 121:837–845.   Neal Jr CR, Weidemann G, Kabbaj M, Vazquez DM (2004) Effect of Neonatal Dexamethasone Exposure on Growth and Neurological Development in the Adult Rat. In press in Am J Physiol, Aug;287(2):R375-85   Isgor C, M Kabbaj*, S.J. Watson and H. Akil (2004) Delayed Effects of Chronic, Variable Stress During Peripubertal-Juvenile Period on Hippocampal Morphology, Cognitive and Stress Axis Functions in Rats. Hippocampus. 2004;14 (5):636-48. *Isgor and Kabbaj are first coauthors   Kabbaj M (2004) Neurobiological bases of individual differences in emotional and stress responsiveness: high responders/low responders model. Arch Neurol. Jul; 61(7):1009-12. Review   Kabbaj M, Evans S, Watson SJ, Akil H (2004) The search for the neurobiological basis of vulnerability to drug abuse: using microarrays to investigate the role of stress and individual differences. Neuropharmacology. 47 Suppl 1:111-22.   Dietz D.M, Tapocik J, Gaval-Cruz M and Kabbaj M (2005) Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine. Physiology and Behavior: 86(3):347-55.   Kabbaj M (2006): Individual vulnerability to drug abuse: the high responders/low responders model. CDT-CNS Neurological Disorders special issue on the effects of Stress on brain function. Review. Volume 5, No.5: 513-520.   SM. Clinton, DM. Vázquez, M Kabbaj, MH Kabbaj, SJ. Watson, and H Akil (2007) Individual differences in novelty-seeking and emotional reactivity correlate with variation in maternal behavior. Hormones and Behavior 51 (5): 655-64.   M Kabbaj, S. Morley-Fletcher, M. Le Moal, PV. Piazza and S. Maccari (2007) Individual differences in the effects of chronic prazosin treatment on hippocampal mineralocorticoid and glucocorticoid receptors. European Journal of Neurosciences 25(11):3312-8.   Dietz D and H. Wang and Kabbaj M (2007) Corticosterone fails to produce conditioned place preference or place aversion. Behavioral Brain Research: 18 (2): 287-291.   Kabbaj M and C Isgor (2007) Effects of chronic environmental and social stimuli during adolescence on mesolimbic dopaminergic circuitry markers. Neuroscience Letters: 422: 7-12.