Analytical Psychopharmacology

Thomas B. Cooper, M.A., Chief of Psychiatric Research
Amiram I. Barkai, Ph.D., Research Scientist VI
Basalingappa L. Hungund, Ph.D., Research Scientist V
Ee-Sing Lo, Ph.D., Research Scientist V
Hana Novacenko, M.S., Research Scientist III
Raymond F. Suckow, Ph.D., Research Scientist V
 
FUNCTIONAL BRAIN MAPPING DIVISION
Marc Laruelle, M.D., Research Scientist
Henry Huang, Ph.D., Research Scientist IV
Dah-Ren Hwang, Ph.D., Research Scientist IV
Diana Martinez, M.D., Research Psychiatrist
Mark Slifstein, Ph.D., Research Scientist
Rikki Waterhouse, Ph.D., Research Scientist
Eric Zarahn, Ph.D., Research Scientist
Ning-Ning Guo, Ph.D., Research Scientist
Chris Endres, Ph.D., Research Scientist
 
The department continues to serve as a core facility in two NIMH and one NIDA clinical research centers, a NIDA Medication Development Research Unit, an NIMH Research Unit for pediatric psychopharmacology, and several large multicenter clinical studies. In addition, the department continues collaborations with many academic research centers within and outside of the USA. The Division of Functional Brain Mapping continued to focus on developing several brain imaging methods aimed at studying the living human brain; applying these techniques to study alterations in brain function associated with major mental illnesses and to develop new medications; performing animal studies to better understand the biological significance and consequences of neurochemical alterations observed in patients with imaging studies. Imaging modalities involved PET neuroreceptor imaging, magnetic resonance spectroscopy (MRS) and functional MRI (fMRI).
 
Research Programs: Analytical Psychopharmacology
 We continue our long-established assay development program to explore the pharmacokinetics and pharmacodynamics of new psychotropic drugs and their metabolites and, where appropriate, their enantiomers. Basic work involves investigations at the cellular and molecular level of the interaction of alcohol with the endocannabinoid signaling system, especially membrane-delimited signal transduction research. Faculty members in our department currently have extramural support for their research activities, including the support from NIMH, NARSAD, and NIAAA grants.

Dr. Suckow and staff continue with analyses of plasma and CSF amino acids which continue to generate useful data in the management of certain psychiatric disorders. To determine the role of these substances in specific disorders, an increasing number of research protocols require the determination of either the large neutral amino acids group (valine, leucine, etc), or the excitatory amino acids (glutamate, glycine). Procedures for the quantitation of carnosine, homocarnosine and N-acetylhistidine continue to generate data as part of a collaborative effort in a pilot study to identify the possible functions of the intercellular transport of these substances, as well as that of NAA and NAAG. NAA, and other N-acetylated amino acids implicated in a number of pathophysiological conditions in the brain. Validation of a new analytical procedure for determining the antipsychotic ziprasidone has been completed.
 
Drs. Hungund and Basavarajappa and staff continue their NIAAA funded research elucidating the role of the cannabinoidergic system in alcohol abuse and alcoholism, we have now demonstrated for the first time that the mice lacking the gene expressing cannabinoid CB1 receptors, consumed less alcohol compared to their wild type counterpart when they were offered a two bottle choice of alcohol and tap water. This significant finding may have clinical relevance in the treatment of alcohol use and abuse.
 
Another intriguing finding has been the demonstration of upregulation of cannabinoid CB1 receptors and CB1 receptor function in the prefrontal cortices of human suicide post-mortem brains when compared to the matched control brains (collection from Drs. Arango and Mann’s brain bank). If these results are confirmed they may have impact on our understanding of the mechanisms involved in the development of depressive illnesses and other psychiatric disorders.
 
Dr. Lo and Ms. Novacenko continue their efforts in psychoneuroendocrine research protocols with especial emphasis on saliva monitoring as a non-invasive approach in the study of melatonin in Seasonal Affective Disorder, cortisol monitoring in children and many other compounds of interest in biological psychiatry. This approach holds great promise in enabling frequent sampling over many days which when blood samples were needed made such experiments extremely onerous.
 
We have also completeded analytical procedures for toxicology screens of hair and brain tissue (drugs of use and abuse) using GC with nitrogen detection followed by GC/MS both scan and SIM.
 
Research Programs and Research Projects: Functional Brain Mapping
Clinical Studies in Schizophrenia In collaboration with Drs. Abi-Dargham, Gorman, Gill and Kegeles, the Division continues to explore alterations of cortical and subcortical dopamine function in schizophrenia. The major result published during this period is the observation that schizophrenia is associated with a regionally selective upregulation of dopamine D1 receptors in the dorsalateral prefrontal cortex, and that this upregulation is very predictive of poor performance at cognitive tasks involving working memory. This result suggests that a deficit in prefrontal dopamine function might be involved in the cognitive deficits presented by these patients. Further studies of prefrontal function in schizophrenia are ongoing using fMRI and MRS.
 
Cocaine Abuse In collaboration with Drs. Kleber, Fishman and Foltin, PET studies have demonstrated that chronic cocaine abuse is associated with both a loss of dopamine D2 receptors in the ventral striatum, and a very marked decrease in dopamine release in this region. These alterations might explain the deficit presented by these patients at experiencing natural rewards, and the need to stimulate dopamine function with potent pharmacological agents, such as cocaine.
 
Alcoholism In collaboration with Dr. Abi-Dargham and Dr. Krystal (Yale), the Division continues to explore alterations of dopamine and serotonin transmission in alcoholism. Subjects from the Yale alcoholism Center are being scanned here at Columbia. The study is ongoing.
 
Anxiety Disorders In collaboration with Drs. Simpson and Liebowitz, the Division completed the first study of the distribution of serotonin transporters (SERT) in drug-free patients with obsessive compulsive disorders. No abnormalities of SERT density were observed in these patients, suggesting that the efficacy of SSRIs in this condition might not be linked to correcting a presynaptic serotonin deficit. In collaboration with Drs. Schneier and Liebowitz, the Division expanded on previous results suggesting abnormalities of dopamine D2 receptors in social phobia. The current study combines imaging of dopamine transporters, dopamine receptors and dopamine release. A study of SERT in social phobia, in collaboration with Drs. Kent and Gorman failed to detect abnormalities of SERT distribution.
 
Personality Disorders and Autism In collaboration with Dr. L. Siever at Mt. Sinai. Both pre- and post-synaptic markers of serotonin function are studied in subjects with impulse/aggressive personality disorders. Initial results suggest that this condition might be associated with deficits in serotonin function in orbito-frontal cortex. In people with schizotypal personality disorder (SPD), a study of striatal dopamine release indicated that people with SPD share with those with schizophrenia a dysregulation of presynaptic function, although less severe. Collaboration with Dr. E. Hollander at Mt. Sinai demonstrated marked alteration of 5-HT function in Asperger’s syndrome.
Collaborations with several drug companies for the development of ligands targeting the glutamatergic system should facilitate and accelerate the development of new glutamatergic based therapy for anxiety disorders and schizophrenia. The Division is also involved in testing the target occupancy achieved by new drugs in patients. For example, the Division evaluated in collaboration with Eli Lilly the duration of occupancy of D2 receptors associated with treatment with olanzapine depot.
 
Several new PET ligands have been successfully developed in our laboratory, such as the first F18 labeled SERT ligand, the first ligand to image the high affinity state of the D2  receptors, and the first ligand to image the kappa opiate receptors. Additional targets of a vigorous development effort include glutamatergic receptors, 5HT1A and 5HT  1B  receptors, and D3 receptors. New approaches to image synaptic levels of GABA are also developed with a combined PET-MRS effort.
 
The data analysis and instrumentation core of the Division develops sophisticated techniques for image analysis, including original methods for head motion and partial voluming corrections. These techniques enable us to derive more accurate measurements of biological processes in small regions of the brain, such as the nucleus accumbens, that are critical regions involved in the pathophysiology of psychiatric conditions.
 
Animal Model of Schizophrenia The generous support of the Lieber Center enabled the recruitment of Holly Moore, Ph.D., from the University of Pittsburgh. Dr. Moore has developed a very interesting rodent model of schizophrenia that displays many biological features seen in patients in our imaging program. In addition to this important translational collaboration, the presence of Dr. Moore will allow us to perform combined microdialysis and imaging studies in nonhuman primates. In collaboration with Dr. Javitt, from the Nathan Kline Institute (NKI), we continue to explore the glutamatergic model of schizophrenia
 
Cell Biology In collaboration with Drs. Rayport and Javitch, the Division is studying the cellular localization of the binding of PET radiotracer in order to evaluate the effect of receptor trafficking on the binding of these agents. This critical collaboration should enable a better understanding of the biological foundation of the signal recorded by the PET camera.