Analytical Psychopharmacology ANALYTICAL PSYCHOPHARMACOLOGY OVERVIEW Analytical Psychopharmacology serves 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 collaborates with many academic research centers within and outside of the USA. The Division of Functional Brain Mapping (FBM) is a multidisciplinary group of investigators, dedicated to the study of neurochemical imbalances associated with major neuropsychiatry conditions, with special focus on schizophrenia and drug abuse. A major tool in the investigation of the pathophysiology of major psychiatric conditions is Positron Emission Tomography (PET). PET enables the noninvasive study of the neurotransmitter system in the living human brain. Results of the PET investigations inform the work of preclinical scientists who characterize the emergence and consequence of these abnormalities using animal models. In turn, preclinical research provides hypotheses used to inform clinical research. I. ANALYTICAL PSYCHOPHARMACOLOGY CURRENT RESEARCH New analytical methodology for the determination of therapeutic agents of interest in psychiatry continues to be the focus of Dr. Suckow’s work. During the past year, completion of a highly specific and sensitive procedure for measuring plasma aripiprazole was accomplished, and is currently in use. Data involving the quantitation of significant amounts of a metabolite of quetiapine, N-desalkylquetiapine in patients, is accumulating. The presence of this metabolite in plasma was recently confirmed in our laboratory using a combination of liquid chromatography and mass spectrometry (LC-MS). The clinical implication of this finding is currently being evaluated. A large number of protocols requiring frequent assays for venlafaxine and metabolites, fluoxetine, risperidone, ziprasidone, olanzapine, bupropion and metabolites, and many other drugs and metabolites are ongoing. Analyses of plasma and CSF amino acids (the large neutral amino acids group (valine, leucine, etc.) and the excitatory amino acids (glutamate, glycine) continue to generate useful data in the characterization and management of certain psychiatric disorders. Development of a new procedure for the simultaneous identification and quantitation of D-serine and L-serine has recently been achieved and is currently in use in several animal studies. Dr. Lo and staff continue their efforts in psychoneuroendocrine research developing immunoassay procedures to enhance the capabilities of the department. A special emphasis is on saliva monitoring as a non-invasive approach to study melatonin, cortisol and other neuroendocrine markers in the monitoring of children or adults participating in long- term studies requiring frequent monitoring of compounds of interest in biological psychiatry. Dr. Hungund and staff continue their research on the role of the endogenous cannabimimetic substance anandamide (AEA) and its receptor (CB1) [endocannabinoid system, ES] in the mammalian central nervous system. The fact that AEA is a fatty acid metabolite and alcohol is known to modulate the fatty acid profile of neuronal membrane lipids as a homeostatic neuroadaptation to chronic alcohol exposure, prompted us to investigate the role of ES in alcohol-related behaviors. Unlike other drugs of abuse, alcohol, being smaller in molecular size, does not bind to a receptor to produce its pharmacological and addictive effects. Since AEA is cannabimimetic and produces similar effects as THC, a psychoactive component of marijuana, it was of interest to see if chronic alcohol exposure induces the accumulation of AEA in the brain and if addiction to alcohol could be explained with its increased synthesis. Indeed, this group was the first to report modulation of ES in synaptosomal membranes of chronic alcohol exposed (alcohol-tolerant) mice (Basavarappa et al. 1998). Since then we have established the role of ES in alcohol-dependence and voluntary alcohol consumption using pharmacological (drugs targeted against ES) and genetic manipulation (genetic deletion of CB1 receptors). We have also demonstrated possible utility of drugs targeted against ES system in reducing alcohol tolerance/dependence and voluntary alcohol consumption. Voluntary Alcohol Consumption and Dopamine reward circuitry: We have also demonstrated that the mice lacking the gene expressing cannabinoid CB1 receptors (CB1-KO), consumed less alcohol compared to their wild type counterpart when they were offered a two bottle choice of alcohol and tap water. It is suggested that the ES regulates the alcohol-induced dopamine (DA) release in the nucleus accumbens, a neural circuitry implicated in reward mechanism. In our studies we found that the animals lacking CB1 receptors did not have any effect on EtOH-induced DA release in the nucleus accumbens found in the wild type counterparts. This is a significant finding with clinical relevance and may lead to the development of therapies in the treatment of alcohol use and abuse using drugs targeted against the cannabinoid system. As a part of collaborative efforts with the division of Neuroscience, we have investigated the role of ES in human depression and alcoholism using prefrontal cortices of human suicide post-mortem brains (collection from Drs. Arango and Mann’s brain bank). We have confirmed our earlier findings of upregulation of cannabinoid CB1 receptors and CB1 receptor function and endogenous levels of AEA in these tissues. The results of this study suggest that the dysfunctional/hyperactive ES could be one of the factors involved in the etiology of depression/alcoholism. These findings may have far-reaching implications in understanding of the mechanisms involved in the development of depressive illnesses and other psychiatric disorders. GRANTS Principal Investigator: Basalingappa L. Hungund (Senior Independent Investigator
Award). Principal Investigator: Basalingappa L. Hungund Co-Investigator: Basalingappa L. Hungund (P. I.: Csaba Vadasz) Co-Investigator: Cooper, T.B. (P.I. Mann, J.J.) BIBLIOGRAPHY deLeon, J., Odom-White, A., Josiassen, R.C., Diaz, F.Z., Cooper, T.B., and Simpson, G.M.: Serum antimuscarinic activity during clozapine treatment. J. Clin. Psychopharmacol. 23 : 336-341, 2003. Greenhill, L.L., Vitiello, B., Abikoff, H., Levine, J., March J.S., Riddle, M.A., Capasso, L., Cooper, T.B., Davies, M., Fisher, P., Findling, R.L., Fried, J., Labellarte, M.J., McCracken, J.T., McMahon, D., Robinson, J., Skrobala, A., Scahill, L., Varipatis, E., Walkup, J.T., and Zito, J.M.: Developing methodologies for monitoring long-term safety of psychotropic medications in children: report of the NIMH conference, September 25, 2000. J. Am. Acad. Child & Adoles. Psychiatry 42: 651-655, 2003. Greenhill, L.L., Vitiello, B., Riddle, M.A., Fisher, P., Shockey, E., March, J.S., Levine, J., Fried, J., Abikoff, H., Zito, J.M., McCracken, J.T., Findling, R.L., Robinson, J., Cooper, T.B., Davies, M., Varipatis, E., Labellarte, M.J., Scahill, L., Walkup, J.T., Capasso, L., Rosengarten, J.: Review of safety assessment methods used in pediatric psychopharmacology. J. Am. Acad. Child & Adoles. Psychiatry 42: 627-633, 2003. Guilfoyle DN, Suckow RF, Baslow MH, The apparent dependence of the diffusion coefficient of N-acetylaspartate upon magnetic field strength: Evidence of an interaction with NMR methodology, NMR in Biomedicine, 16, 468-474, 2003. Hungund, B. L., Basavarajappa, B. S. Role of endocannabinoid and cannabinoid CB1 receptors in alcohol-related behaviors. Current Status of Dependence/Abuse Studies: Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity, Volume 1025, of the Annals of the New York Academy of Sciences, eds. Syed F. Ali, Toshitaka Nabeshima, and Tomoji Yanagita. 2004. Hungund, B. L., Szakall, I., Adam, A., Basavarajappa, B. S. and Vadasz, C. Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J. Neurochem. 84: 698-704, 2003. Hungund, B.L., Vinod, K.Y., Kassir, S.A., Basavarajappa, B.S., Yalamanchili, R., Cooper, T. B., Mann, J. J. and Arango, V. Upregulation of CB1 receptors and Agonist-stimulated [ 35 S] GTP? S binding in the prefrontal cortex of depressed suicide victims. Mol. Psychiatry. 9: 184-190, 2004. Javitt DC, Balla A, Burch S, Suckow R, Xie S, Sershen H, Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists, Neuropsychopharmacology, 29, 300-307, 2004. Lindenmayer, J.P., Czobor, P., Volavka, J., Citrone, L., Sheitman, B., McEvoy, J.P., Cooper, T.B., Lieberman, J.A., and Chakos, M.: Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Amer. J. Psychiatry 160: 290-296, 2003. Malone, K.M., Waternaux, C., Haas, G.L., Cooper, T.B., Li, S., Mann, J.J.: Cigarette smoking, suidical behavior, and serotonin function in major psychiatric disorders. Am. J. Psychiatry 160: 773-779, 2003. Oquendo, M.A., Echavarria, G., Galfalvy, H.C., Grunebaum, M.F., Burke, A., Barrera, A., Cooper, T.B., Malone, K.M., and Mann, J.J.: Lower cortisol levels in depressed patients with comorbid post-traumatic stress disorder. Neuropsychopharmacology 28: 591-598, 2003. Oquendo, M.A., Placidi, G.P., Malone, K.M., Campbell, C., Keilp, J., Brodsky, B., Kegeles, L.S., Cooper, T.B., Parsey, R.V., van Heertum, R.L., and Mann, J.J.: Positron emission tomography of regional brain metabolic response to a serotonergic challenge and lethality of suicide attempts in major depression. Arch. Gen. Psychiatry 60: 14-22, 2003. Pelton, G.H., Devanand, D.P., Bell, K., Marder, K., Marston, K., Liu, X., and Cooper, T.B.: Usefulness of plasma haloperidol levels for monitoring clinical efficacy and side effects in Alzheimer patients with psychosis and behavioral dyscontrol. Am. J. Geriatr. Psychiatry 11: 186-193, 2003. Richardson MA, Bevans ML, Read LL, Clelland JD, Chao HM, Suckow RF, Maher TJ, Citrome L, Efficacy of the branched chain amino acids in the treatment of tardive dyskinesia in men, American Journal of Psychiatry, 160, 1117-1124, 2003. Sher, L., Oquendo, M.A., Li, S., Ellis, S., Brodsky, B.S., Malone, K.M., Cooper, T.B., Mann, J.J. : Prolactin response to fenfluramine administration in patients with unipolar and bipolar depression and healthy controls. Psychoneuroendocrinology 28: 559-573, 2003. Suckow RF, Fein M, Correll CU, Cooper TB, Determination of plasma ziprasidone using liquid chromatography with fluorescence detection, Journal of Chromatography, 799, 201-208, 2004. Sziraki, I., Hashim, A., Sershen, H., Allen, D., Cooper, T., Lipovac, M.N., and Lajtha, A.: Strain differences in sensitivity of central dopamine systems to nicotine in Lewis and Fischer 344 rats. Proc. 10th Int. Conf. On In Vivo Methods. pp. 143-145, 2003. Veeranna, Kaji,T., Boland, B., Odrljin, T., Mohan, P., Peterhoff, C. Cataldo, A., Rudnicki, A., Amin, N., Li, B.S., Pant, H.C., Hungund, B.L., Arancio, O., and Nixon, R.A. Caplain mediates calcium-induced activation of the Erk1, 2 MAPK pathway and cytoskeletol phosphorylation in neurons. Am. J. Pathology. 165: 795-805, 2004. Vitiello, B., Riddle, M.A., Greenhill, L.L., March, J.S., Levine, J., Schachar, R.J., Abikoff, H., Zito, J.M., McCracken, J.T., Walkup, J.T., Findling, R.L., Robinson, J., Cooper, T.B., Davies, M., Varipatis, E., Labellarte, M.J., Scahill, L., and Capasso, L.: How can we improve the assessment of safety in child and adolescent psychopharmacology? J. Am. Acad. Child Adolesc. Psychiatry 42(6): 634-641, 2003. Volavka, J., Czobor, P., Cooper, T.B., Sheitman, B., Lindenmayer, J.-P., Citrome, L., McEvoy, J.P., and Lieberman, J.A.: Prolactin levels in schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J. Clin. Psychiatry 65: 57-61, 2004. Xie, S., Aspromonte, J., Balla, A., Sershen, H., Javitt, D.C., and Cooper, T.B. : Sensitive and simple gas chromatographic-mass spectrometric determination for amphetamine in microdialysate and ultrafiltrate samles. J. Chrom. B. 805: 27-31, 2004 II. FUNCTIONAL BRAIN MAPPING DIVISION (FBM)
Development of new radiotracers. This group is involved in the development of new PET radioligands. For example, FBM developed the first radiolabeled D2 receptor agonist, [11C]NPA, an important tool to control for affinity states of D2 receptors in endogenous competition studies; a new SERT ligand, [11C]/[18F]AFM, that allows quantification of SERT in areas of low density, such as neocortical areas; and [11C]GR103545, the first tracer to label kappa opiate receptors. Work is also ongoing to develop probes for the glutamate metabotropic receptors, the D3 and D4 receptors, and 5-HT1B receptors. Some of these efforts are carried out in partnership with the pharmaceutical industry. Biological foundations of PET molecular imaging. The group is studying biological factors that affect the binding of CNS PET radiotracers. Long standing areas of interest are the interactions between endogenous transmitters and PET neuroreceptor radiotracers. The discovery of these interactions enabled the use of PET molecular imaging techniques, not only to measure receptors and enzymes, but also to measure intrasynaptic concentration of neurotransmitters in a dynamic way. The availability of combined PET and microdialysis experiments in rodents and primates is a fundamental resource for these investigations. Other areas of investigation include the impact of receptor internalization on the binding of radioligands (studies performed in collaboration with Stephen Rayport, M.D., Ph.D., from the Department of Neuroscience, and Jonathan Javitch, M.D., Ph.D., in the Center for Molecular Recognition), and the study of modulation of drug blood-brain barrier (BBB) penetration by PgP proteins using PET (studies performed in collaboration with Dr. Margaret Wood, Chair of the Anesthesiology Department). Development of imaging analysis methods. FBM has published comprehensive papers on kinetic modeling of several PET ligands, such as the SERT ligands [11C]McN 5652 and [11C]DASB, the D1 ligand [11C]NNC 112, the 5-HT1A ligand [11C]WAY 100635, the D2 ligands [11C]raclopride and [18F]fallypride, on statistical analysis of imaging data, and improved image processing methods for CNS PET (improved between modalities registration methods and partial voluming correction methods). Pathophysiology of neuropsychiatric disorders. Beyond development of methods and tracers, FBM uses PET molecular imaging to assess the pathophysiology of neuropsychiatric disorders. These include schizophrenia, addiction, anxiety and mood disorders, autism, and personality disorders. FBM has made fundamental contributions to the dynamic mapping of dopaminergic alterations in schizophrenia and substance abuse. The studies investigate the neuroscience of the disease entity under study and have contributed to construction of circuitry models for normal and pathological effects observed. These studies are carried out under a multimodality combination of PET molecular imaging with MRS and fMRI. Neurochemical imbalances described with PET are correlated with clinical presentation and response to treatment.
Drug Development. The collaboration between the Division and the pharmaceutical industry using PET to accelerate drug development is ongoing. These studies include both occupancy studies in nonhuman primates, healthy volunteers or psychiatric patients using known and established radiotracers such as [11C]raclopride, [11C]NNC 112, [11C]WAY 100635, [11C]MDL 100907 or [11C]DASB, as well as joint development of new radiotracers to label target sites for which no radiotracers are currently available. Animal Model Program. Research in the Rodent Models Core and Moore laboratory within the Division of Functional Brain Mapping encompasses the examination of cerebral cortical regulation of limbic forebrain and ascending monoaminergic systems across development and characterization of relationships between changes in radioligand binding and the temporal dynamics of neurotransmitter release and receptor activation. The goal of these experiments is to increase the power of PET imaging in characterizing neurochemical abnormalities in psychiatric disease. These lines of research are applied to candidate rodent models of the neuropathology of schizophrenia. The models include: gestational and juvenile nutrient depletion, midgestational disruptions of methylation, mutations of genes regulating cortical interneuron development and a genetic model of striatal upregulation of the dopamine D2 receptor. Each of these experimental manipulations in a rodent models a hypothesized etiologic pathway and/or prominent pathophysiological phenotypes that have been observed in schizophrenia. We apply behavioral, in vivo neurochemical (including functional imaging) and anatomical techniques to evaluate these models.
GRANTS
Moore Grants 2003-2004
BIBLIOGRAPHY Abi-Dargham A, Kegeles LS, Zea-Ponce Y, Mawlawi O, Martinez D, Mitropoulou V, O'Flynn K, Koenigsberg HW, Van Heertum R, Cooper T, Laruelle M, Siever LJ (2004) Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide. Biol Psychiatry 55:1001-1006. Dumont F, Waterhouse RN, Montoya JA, Mattner F, Katsifis A, Kegeles LS, Laruelle M (2003) Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors. Nucl Med Biol 30:435-439. Frankle WG, Lerma J, Laruelle M (2003) The synaptic hypothesis of schizophrenia. Neuron 39:205-216. Frankle WG, Huang Y, Hwang DR, Talbot PS, Slifstein M, Van Heertum R, Abi-Dargham A, Laruelle M (2004) Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med 45:682-694. Frankle WG, Gil R, Hackett E, Mawlawi O, Zea-Ponce Y, Zhu Z, Kochan LD, Cangiano C, Slifstein M, Gorman JM, Laruelle M, Abi-Dargham A (2004) Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications. Psychopharmacology (Berl) 175:473-480. Guo N, Hwang DR, Lo ES, Huang YY, Laruelle M, Abi-Dargham A (2003) Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia. Neuropsychopharmacology 28:1703-1711. Huang Y, Hwang DR, Bae SA, Sudo Y, Guo N, Zhu Z, Narendran
R, Laruelle M (2004) A new positron emission tomography imaging agent
for the serotonin transporter: synthesis, pharmacological characterization,
and kinetic analysis of [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine
([11C]AFM). Nucl Med Biol 31:543-556 Hwang DR, Narendran R, Huang Y, Slifstein M, Talbot PS, Sudo Y, Van Berckel BN, Kegeles LS, Martinez D, Laruelle M (2004) Quantitative analysis of (-)-N-(11)C-propyl-norapomorphine in vivo binding in nonhuman primates. J Nucl Med 45:338-346. Jentsch, J.D., Olaussen, P., and Moore, H. (2003) Animal models of psychosis. In J.C. Soares and S. Gershon, Handbook of Medical Psychiatry, New York, Marcel Dekker, Inc., pp 317-333. Kegeles L, Laruelle M (2003) Neuroimaging findings in schizophrenia: from mental to neuronal fragmentation. In: Handbook of Medical Psychiatry (Soares JC, Gershon S, eds), pp 237-238. New York: Marcel Dekker. Laruelle M (2003) Dopamine transmission in the schizophrenic brain. In: Schizophrenia, Second Edition (Weinberger DR, Hirsch S, eds), pp 365-387: Blackwell Publishing, Oxford, U.K. Laruelle M, Slifstein M, Huang Y (2003) Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol 5:363-375. Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, Dopamine, and Schizophrenia: From Pathophysiology to Treatment. Ann N Y Acad Sci 1003:138-158. Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, Cooper T, Kegeles L, Zarahn E, Abi-Dargham A, Haber SN, Laruelle M (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23:285-300. Martinez D, Broft A, Foltin RW, Slifstein M, Hwang DR, Huang Y, Perez A, Frankle WG, Cooper T, Kleber HD, Fischman MW, Laruelle M (2004) Cocaine dependence and D2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology 29:1190-1202. Narendran R, Hwang DR, Slifstein M, Talbot PS, Erritzoe D, Huang Y, Cooper TB, Martinez D, Kegeles LS, Abi-Dargham A, Laruelle M (2004) In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse 52:188-208. Rosenkranz, JA. Moore, H. Grace, AA. (2003). The prefrontal
cortex regulates lateral Simpson HB, Lombardo I, Slifstein M, Huang HY, Hwang DR, Abi-Dargham A, Liebowitz MR, Laruelle M (2003) Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652. Biol Psychiatry 54:1414-1421. Slifstein M, Narendran R, Hwang DR, Sudo Y, Talbot PS, Huang Y, Laruelle M (2004) Effect of amphetamine on [(18)F]fallypride in vivo binding to D(2) receptors in striatal and extrastriatal regions of the primate brain: Single bolus and bolus plus constant infusion studies. Synapse 54:46-63. Slifstein M, Hwang DR, Huang Y, Guo N, Sudo Y, Narendran R, Talbot P, Laruelle M (2004) In vivo affinity of [18F]fallypride for striatal and extrastriatal dopamine D2 receptors in nonhuman primates. Psychopharmacology (Berl) 175:274-286. Waterhouse RN, Schmidt ME, Sultana A, Schoepp DD, Wheeler WJ, Mozley PD, Laruelle M (2003) Evaluation of [(3)H]LY341495 for labeling group II metabotropic glutamate receptors in vivo. Nucl Med Biol 30:187-190. Waterhouse RN, Slifstein M, Dumont F, Zhao J, Chang RC, Sudo Y, Sultana A, Balter A, Laruelle M (2004) In vivo evaluation of [(11)C]N-(2-chloro-5-thiomethylphenyl)-N'- (3-methoxy-phenyl)-N'-methylguanidine ([(11)C]GMOM) as a potential PET radiotracer for the PCP/NMDA receptor. Nucl Med Biol 31:939-948. Zhu Z, Guo N, Narendran R, Erritzoe D, Ekelund J, Hwang
DR, Bae SA, Laruelle M, Huang Y (2004) The new PET imaging agent [(11)C]AFE
is a selective serotonin transporter ligand with fast brain uptake kinetics.
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