Interactions between chemically different neurotransmitter systems provide the mechanisms responsible for maintaining homeostatic balance and for appropriate responses within the central nervous system (CNS) to changes in both the internal and external environment. The purpose of this proposal is to use positron emission tomography (PET) as a tool for further characterizing neurotransmitter interactions within the extrapyramidal motor system Specifically, we will examine interactions between the cholinergic, dopaminergic, GABAergic, and serotonergic systems in order to more completely understand the consequences of how a drug-induced perturbation in one of these neurotransmitter systems can manifest itself through any other neuroanatomically and/or functionally-linked system. Specific deficits in any one of these neurotransmitters have been implicated in abnormalities in motor coordination and psychiatric disorders. While PET studies have examined each one of these systems separately, studies designed to examine interactions between these neurotransmitters will provide a more complete understanding of the mechanisms responsible for these disorders. Previously we synthesized and measured the binding characteristics of a dopaminergic and cholinergic ligand and demonstrated that interactions between acetylcholine and dopamine can be measured with PET (Dewey, et al., 1991). The studies in this proposal will further our understanding of the role that GABA and serotonin play in these interactions. Pharmacologic intervention with drugs of known receptor specificity will be used in conjunction with the appropriate radiotracer to measure these effects. This unique strategy for studying neurotransmitter interactions in vivo has widespread clinical applications and may lead to a more complete understanding of many CNS disorders that have classically been attributed to a single neurotransmitter system (ie. schizophrenia, affective disorders, Parkinson's disease, Huntington's chorea, etc.). Furthermore, this approach takes full advantage of the unique capabilities of PET and the selective radiotracers 11C-benztropine (cholinergic), 11C-raclopride (dopamine D2), and 18F-altanserin (serotonergic, 5-HT2) for assessing dynamic neurotransmitter relationships and the consequences of their interactions-in the living brain. These studies will serve as the impetus for future investigations that will provide insight into the adaptive or responsive changes that occur in one neurotransmitter system following alterations in another. Finally, these studies can be used to assess the ability of a specific neurotransmitter system to adapt to drug-induced or pathological changes in the internal environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049165-02
Application #
3388633
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1992-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Associated University-Brookhaven National Lab
Department
Type
DUNS #
City
Upton
State
NY
Country
United States
Zip Code
11973
Marsteller, Douglas A; Gerasimov, Madina R; Schiffer, Wynne K et al. (2002) Acute handling stress modulates methylphenidate-induced catecholamine overflow in the medial prefrontal cortex. Neuropsychopharmacology 27:163-70
Gerasimov, M R; Schiffer, W K; Gardner, E L et al. (2001) GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine. Eur J Pharmacol 414:205-9
Schiffer, W K; Gerasimov, M R; Marsteller, D A et al. (2001) Topiramate selectively attenuates nicotine-induced increases in monoamine release. Synapse 42:196-8
Schiffer, W K; Gerasimov, M; Hofmann, L et al. (2001) Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission. Neuropsychopharmacology 25:704-12
Gerasimov, M R; Schiffer, W K; Brodie, J D et al. (2000) gamma-aminobutyric acid mimetic drugs differentially inhibit the dopaminergic response to cocaine. Eur J Pharmacol 395:129-35
Gerasimov, M R; Franceschi, M; Volkow, N D et al. (2000) Comparison between intraperitoneal and oral methylphenidate administration: A microdialysis and locomotor activity study. J Pharmacol Exp Ther 295:51-7
Gerasimov, M R; Franceschi, M; Volkow, N D et al. (2000) Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse 38:432-7
Schiffer, W K; Gerasimov, M R; Bermel, R A et al. (2000) Stereoselective inhibition of dopaminergic activity by gamma vinyl-GABA following a nicotine or cocaine challenge: a PET/microdialysis study. Life Sci 66:PL169-73
Dewey, S L; Brodie, J D; Gerasimov, M et al. (1999) A pharmacologic strategy for the treatment of nicotine addiction. Synapse 31:76-86
Gerasimov, M R; Dewey, S L (1999) Gamma-vinyl gamma-aminobutyric acid attenuates the synergistic elevations of nucleus accumbens dopamine produced by a cocaine/heroin (speedball) challenge. Eur J Pharmacol 380:1-4

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