This project continues a broad attach on topics pertinent to a better understanding of the organization and function of cerebral dopamine (DA) systems and their receptors, through a collaboration between neuropharmacology and medicinal chemistry programs. Proposed studies seek to continue contributing to a better understanding of the basic neuropharmacology of DA receptors as well as developing principles and lead agents with therapeutic potential for major psychiatric- neuropsychiatric disorders. Approaches continue those proved productive in past years of the project, with additions arising from new methods in DA receptor pharmacology, as well as some attempts to push into unexplored areas. New proposals include greater attention to the role of specific putative DA receptor subtypes D1 and D2 and new agents selective for them. Aporphine and benzazepine systems are used as steroselective, rigid template-probes with which to define chemical features of DA receptor surfaces. In addition, they are yielding novel agents with high affinity and selectivity for D2 or D1 receptors useful as functional probes of receptor mechanisms, including the study of receptor-based regulation of Da metabolism, for labeling specific receptor sites in vitro and histologically, and as leads to potential new medicinal agents. Studies include a developmental perspective on the regulation of DA metabolism and seek to clarify striking changes in the receptor-related regulation of DA metabolism during maturation in rat. Critical attempts are made to separate receptor-mediated from direct biochemical actions of DA agonists on DA metabolism by use of novel monohydroxy D2 agonists, and development of similar agents for D1 receptors, Further attempts will be made to understand the basis on which novel S(+) aporphines exert apparently limbic-selective anti-DA activity and so suggest themselves as potential antipsychotic agents with a low risk of acute extrapyramidal side effects. Leads include recent observations of steroselective neurotensin-elevating effects in limbic cerebral cortex not shared with current typical neuroleptics. An alternative strategy that may lead to functionally anti-DA agents with a reduced risk of neurological side effects is the development of mixed agonist-antagonists, including partial-ergoline aporphine analogs. Other work continues on the discovery that a clinically used anti-inflammatory agent may stabilize DA and adrenergic receptors and so modify their super- or subsensitization by prolonged antipsychotic or antidepressant treatment-a suspected source of late side effects or loss of efficacy. Finally, new consideration is given to the possibility that """"""""transporter"""""""" macromolecules associated with monoamine uptake across neuronal membranes may share some plastic- adaptive characteristics with receptors, such as in response to prolonged treatment with mood-elevating or other psychotropic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH034006-11
Application #
3375482
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1980-04-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Bois, Frederic; Baldwin, Ronald M; Amici, Louis et al. (2008) Synthesis, radiolabeling and baboon SPECT imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl)tropane ([(123)I]YP256) as a serotonin transporter radiotracer. Nucl Med Biol 35:53-9
Bois, Frederic; Baldwin, Ronald M; Kula, Nora S et al. (2006) Synthesis and monoamine transporter affinity of 2beta-carbomethoxy-3beta-(4'-p-substituted phenyl)-piperidine analogs of cocaine. Bioorg Med Chem Lett 16:5222-5
Davids, Eugen; Zhang, Kehong; Tarazi, Frank I et al. (2003) Animal models of attention-deficit hyperactivity disorder. Brain Res Brain Res Rev 42:1-21
Frazier, Jean A; Cohen, Louise Glassner; Jacobsen, Leslie et al. (2003) Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia. J Clin Psychopharmacol 23:87-91
Davids, Eugen; Zhang, Kehong; Tarazi, Frank I et al. (2002) Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology (Berl) 160:92-8
Zhu, Meng-Yang; Kim, Chun-Hyung; Hwang, Dong-Youn et al. (2002) Effects of desipramine treatment on norepinephrine transporter gene expression in the cultured SK-N-BE(2)M17 cells and rat brain tissue. J Neurochem 82:146-53
Zhang, Kehong; Davids, Eugen; Tarazi, Frank I et al. (2002) Serotonin transporter binding increases in caudate-putamen and nucleus accumbens after neonatal 6-hydroxydopamine lesions in rats: implications for motor hyperactivity. Brain Res Dev Brain Res 137:135-8
Fu, Xing; Tan, Ping-Zhong; Kula, Nora S et al. (2002) Synthesis, receptor potency, and selectivity of halogenated diphenylpiperidines as serotonin 5-HT2A ligands for PET or SPECT brain imaging. J Med Chem 45:2319-24
Davids, Eugen; Zhang, Kehong; Kula, Nora S et al. (2002) Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats. J Pharmacol Exp Ther 301:1097-102
Zhang, Kehong; Davids, Eugen; Tarazi, Frank I et al. (2002) Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions. Psychopharmacology (Berl) 161:100-6

Showing the most recent 10 out of 98 publications