23. López JF, Vázquez DM, Chalmers DT, Akil H and Watson SJ: Regulation of 5-HT receptors and the Hypothalamic-Pituitary-Adrenal axis: Implications for the neurobiology of suicide. Ann NY Acad Sci 836:106-134, 1997.

24. López JF, Chalmers DT, Little KY and Watson SJ : Regulation of 5-HT1A receptor, Glucocorticoid and Mineralocorticoid receptor in rat and human hippocampus: Implications for the Neurobiology of Depression. Biological Psychiatry 43:547-573, 1998.

25. Vázquez DM, López JF, Morano MI, Kwak SP, Watson SJ and Akil, H: Alpha, Beta and Gamma mineralocorticoid receptor mRNA splice variants: Differential expression and rapid regulation in the developing hippocampus. Endocrinology 139:3165-3177, 1998.

26. Young EA, López JF, Weingberg-Murphy V, Watson SJ and Akil H: The role of mineralocorticoid receptors in HPA axis regulation in humans. J Clin Endocrinol & Metab 83:3339-3345, 1998.

27. Liberzon I, López JF, Flagel SB, Vázquez DM and Young EA: Differential regulation of hipppocampal glucocorticoid receptors and negative feedback: Relevance to PTSD. Journal of Neuroendocrinology 11:11-17, 1999.

28. López JF, Liberzon I, Vázquez DM,Young EA and Watson SJ: Serotonin 1a receptor mRNA regulation in the hippocampus after acute stress. Biological Psychiatry 45:943-947, 1999.

29. López JF, Akil H and Watson SJ: Neural circuits mediating stress and anxiety. Biological Psychiatry (In press), 1999.

1. López JF, Little KY, Zimmer CA and Watson SJ: Chronic unpredictable stress and antidepressant modulation of serotonin 2a, mineralocorticoid, and glucocortioid receptors: The role of endogenous corticosteroids. (Submitted).

2. Vázquez DM, López JF, Watson SJ and Levine S: The effect of maternal separation on 5-HT receptors in rat brain. (Submitted).

3. Vázquez DM, Eskandari R, Levine S and López JF: The effect of maternal separation and desipramine administration on CRF receptors in the developing rat. (Submitted).

1. Watson SJ, Kelsey JE, López JF and Akil H: Neuropeptide biology: Basic and clinical lessons from the opioids. In APA Annual Review, Vol. 4, Chapter 6, 1985.

2. López JF, Young EA, Herman JP, Akil H and Watson SJ: The Regulatory Biology of the HPA Axis: An Integrative Approach. In CNS Peptide Mechanisms in Stress and Depression, S. Risch ed. American Psychiatric Press, Inc. 1991, pp. 1-52.

3. Greden JF and López JF: Treatment of Major Depression. In Current Psychiatric Therapy II, D. Dunner ed. American Psychiatric Press, Inc. 1997.

4. Vázquez DM and López JF: Developmental Neuroendocrinology. In The Handbook of Child and Adolescent Psychiatry, Basic Psychiatric Science and Treatment. Joseph D. Noshpitz, Editor-in-Chief; Norman E. Alessi, Joseph T. Coyle, Saul Isaac Harrison and Spencer ETH, editors; John Wiley & Sons, Inc. Vol 6: 3-31. 1998.

5. Mansour A, Meador-Woodruff JH, López JF and Watson SJ: Biochemical Anatomy: Insights Into the Cell Biology and Pharmacology of the Dopamine and Serotonin Systems in the Brain. In Textbook of Psychopharmacology. American Psychiatric Press, Inc. 1998.

1. The hypothalamic-pituitary-adrenal axis: Birth, Life and Death. Psychiatry Department Grand Rounds, Ann Arbor, Michigan. April 16, 1990.

2. Regulation of the Serotonin 1A Receptor. Post-Baccalaureate Pre-Medical Fellowship Program, University of Michigan, February 19, 1993.

3. Steroid and Antidepressant Regulation of the 5HT1A System in the Hippocampus: Implications for the Pathophysiology and Treatment of Anxiety and Depressive Disorders. Department of Psychiatry Preclinical-Clinical Neuroscience Seminar Series. January 7, 1994.

4. Brain Banks and Brain Research in Mental Illness. Invited Speaker for the Detroit Chapter of the National Alliance for the Mentally Ill. April 25, 1994.

5. Strategies for the Study of the Disinhibition of Hypothalamo-Pituitary-Adrenal Axis in Affective Disorders. Symposium at the CINP International Congress. Washington D.C., June 29, 1994.

6. Advances in Office Psychiatry III: Mood and Anxiety Disorders. University of Michigan CME Course. Mackinac Island, Michigan. July 8-10, 1994.

7. Mood Disorders: Diagnosis and Psychobiology. Advances in Psychiatry for Practicing and General Psychiatrists (CME Course). Ann Arbor, Michigan. November 14, 1994.

8. Recent Research Advances in Depression. Invited Speaker for the Oakland County Depressive and Manic Depressive Association. Livonia, Michigan. November 28, 1994.

9. The Relationship Between Stress and Depression. North Oakland Medical Center, Dept. of Psychiatry Grand Rounds. Pontiac, Michigan. March 24, 1995.

10. Brain Circuits and Antidepressant Action. Michigan Alliance for the Mentally Ill Meeting. Novi, Michigan. May 6, 1995.

11. Stress and the Neurobiology of Depression. School of Nursing, University of Michigan. Ann Arbor, Michigan. February 28, 1996.

12. Advances in Office Psychiatry V: Mood and Anxiety Disorders. University of Michigan CME Course. Mackinac Island, Michigan. July 18-20, 1996.

13. Advances in Dysthymic and Atypical Depressions. Invited Lecture Sponsored by Eli Lilly. Sands Hotel, San Juan, Puerto Rico. April 19, 1996.

14. CRF in Mood and Anxiety Disorders. Symposium Chairperson and Discussant. Society of Biological Psychiatry Annual Meeting. May 17, 1997.

15. Stress Hormones and the Brain. Invited speaker for the Dearborn Alliance for the Mentally Ill. October 5th, 1997.

16. The Neurobiology of Stress, Implications for the Treatment of Depression. Mental Health Grand Rounds, Dallas V.A. Medical Center, Dallas Tx. March 19, 1998.

17. The Relationship Between Stress, Mood, and Antidepressant Treatment. Psychiatry Grand Rounds, Henry Ford Health System, October 15, 1998.

17. Depression, Serotonin, and the Neurobiology of Stress. Psychiatry Grand Rounds, Michigan State University, Kalamazoo Center for Medical Studies. December 8, 1998.

The neurobiology of mood disorders and of suicide.

The effects of stress on the serotonin system and the hypothalamic-pituitary-adrenal axis.

The mechanisms of action of antidepressant medications.

SCIENTIFIC AND ACADEMIC ACCOMPLISHMENTS

Research Interests:

Over the past few years, my research interests have focused on Depressive Disorders, Serotonin, the Limbic-Hypothalamic-Pituitary-Adrenal (LHPA) axis and Stress. Abnormalities of serotonin receptors have been postulated to mediate both suicidal behavior and depression. It is also believed that serotonin receptors mediate the therapeutic action of some antidepressant medications. One of my research focus is to understand what particular serotonin receptors and what specific brain areas are affected by antidepressants and by stress. In collaboration with Stanley Watson, I have also been investigating if the same molecules are altered in the same brain regions of people who have committed suicide.

To study the interaction between serotonin receptors and the LHPA axis we use endocrinological, neuroanatomical and molecular biology methods, and focus on the brain pathways thought to be involved in mood disorders. In situ hybridization, receptor autoradiography and radioimmunohistochemistry allow us to visualize both the receptor itself and the mRNA that encodes for that receptor. Hormonal measurements (e.g. corticosterone and ACTH) help us correlate peripheral endocrinological activity and central nervous system changes. For example, one of my research paradigms consists in stressing rats and in administering several types of antidepressant medications, to analyze the response of the serotonin receptors and the LHPA axis to these maneuvers. We also study the same molecules in the brains of suicide victims and compare them to non-suicide subjects. Using this experimental approach, we have demonstrated that stress decreases the receptor number and mRNA levels of the serotonin 1a receptor subtype (5-HT1a) in rat hippocampus. We have also found that chronic stress increases the protein and mRNA levels of the serotonin 2a receptor (5-HT2a) in the prefrontal cortex. Antidepressant administration prevents these 5-HT receptor changes. Interestingly, the same receptor changes have been described (by us, and others) to be present in the brains of suicide victims with a history of depression. Therefore, it is possible that changes in 5-HT receptors within this brain structures may be mediating the stress-induced mood changes in humans.

We have also found that components of the LHPA axis, such as the glucocorticoid (GR) and mineralocorticoid (MR) receptors, are altered in the brains of suicide victims with a history of depression. Interestingly, these same abnormalities are found in rats subjected to chronic and severe stress. These findings demonstrate that there is an intimate link between the serotonergic system and the LHPA axis. It also suggests that the serotonin and LHPA abnormalities that exist in depression may share a common pathophysiology. We are expanding our investigation into other molecules thought to be involved in stress, such as the CRH receptors, CRH binding protein and the neurotrophic factors. Studies of these molecules are in progress in rat, monkey and human brain tissue.

Over the past two years, I have also started a collaboration with Delia Vázquez, from the Department of Pediatrics, investigating the immediate and long term effects of early life stress, on these same systems. We have found, for example, that neonatal rats subjected to 24 hours of maternal separation show anatomically specific changes in GR, MR, 5-HT and CRF receptors. Unlike the adult rats, however, these receptor changes are not reversed by antidepressant administration. We have also discovered that subjecting rats to mild stress after the weaning period, results in a decrease in growth hormone secretion, and growth retardation (independent of their food consumption). However, administering CRF receptor antagonists to these developing rats prevents the growth problems caused by stress. We are actively replicating and characterizing this observation, because of its potential therapeutic application in children who suffer from psychosocial growth failure (i.e. "psychosocial dwarfs").

More recently, in collaboration with Dr. Robert Thompson (Department of Psychiatry and Reproductive Sciences Program), I have been using gene array technology to investigate 1) whether we can identify novels genes regulated by antidepressant treatment, 2) whether there is a common set of genes regulated by different types of antidepressants and, 3) whether genes altered by stress can be "normalized" by the administration of these medications. Dr. Robert Thompson and I have recently discovered several novel genes that are commonly regulated by antidepressants from three different "classes": bupropion (a dopamine reuptake inhibitor), fluoxetine (a serotonin reuptake inhibitor), and desipramine (a potent norepinephrine reuptake inhibitor). The (future) development of pharmaceutical agents targeting these molecules may result in novel, and perhaps faster acting, antidepressant agents.

It is hoped that these studies will help us understand the molecular brain mechanisms underlying the actions of antidepressants, and how stress can trigger depressive episodes in vulnerable individuals. These studies will also increase our knowledge of the biochemical abnormalities that may contribute to suicide and depression. This knowledge can eventually lead to the design of better and more specific medications to treat and/or to prevent mood disorders.

Scientific Accomplishments:

My work on stress, serotonin, and the LHPA axis, has begun to receive recognition at the national and international levels. In the past few years, I have been invited to participate in national and international symposia to present my work, to chair sessions, and/or to be the discussant (e.g. the International Congress on Brain, Hormone and Behavior in 1996, the CINP meeting in 1994, and in 1997, Biological Psychiatry Meeting in 1997, ACNP meeting in 1998). I have also been invited by several Departments of Psychiatry to deliver "Grand Rounds" lectures. In 1997, I was awarded the A.E. Bennet Award from the Society of Biological Psychiatry. I have been asked to be an ad hoc reviewer for several NIMH and NSF grants, and I was recently asked to participate as a reviewer for the NIMH Board of Scientific Counselors.

I am the P.I. of a Scientist Development Award grant, which will end on June 2000, and which I am planning to resubmit as a Career Scientist Award next October. I am currently resubmitting an R01 to NIMH entitled "The Impact of Stress on Serotonin and the LHPA Axis". I am also the P.I. of two Nancy Pritzker Network grants, and a Co- P.I. in a Program Project grant (Stanley J. Watson, P.I.).

Educational Accomplishments:

I have been the Co-director (together with Stephan Taylor) of the Neuroscience Core Curriculum for psychiatric residents the past four years. I am also a frequent lecturer to medical students, residents of other medical specialties, primary physicians, and practicing psychiatrists, both within and outside the Medical School. I have a graduate student doing her thesis work with me (Carrie Zimmer) and I frequently mentor undergraduate students. I also give frequent talks to community organizations, like the National Alliance for the Mentally Ill, National Alliance for Research in Schizophrenia and Depression, Depressive and Manic-Depressive Association, Depression Awareness Week, etc.

To summarize. I am overworked, overstressed, and chronically behind. But hey, it’s supposed to be fun.