This project outlines studies designed to lead to the development of chemical molecules which have the ability specifically to release endogenous serotonin from brain serotonin neurons. The target compounds will not produce long-term deficits in central serotonin markers, as is typical of other such agents such as parachloroamphetamine or fenfluramine. This project has immediate application, as the drugs which are developed will be useful as pharmacological tools to study the role of brain serotonin systems in a variety of behaviors. These molecules should have significance to the study of serotonin systems comparable to that of amphetamine for studying dopaminergic systems. The long range significance of this work will lie in a better understanding of the role serotonin plays in emotion and behavior. In addition, serotonin-releasing agents may prove to have utility in the treatment of conditions such as depression and anxiety disorders which are now effectively treated with serotonin uptake inhibitors. This proposal targets several types of chemical structures, including para-alkylthioamphetamine derivatives, 5- alkylthio-2-aminoindans, ring-methylated 3,4-methylenedioxyamphetamine derivatives, and 5-trifluoromethyl-2-aminoindan and its N-ethyl derivative, the latter which are rigid analogues of fenfluramine and norfenfluramine. Following synthesis, new compounds will be screened in a battery of assays, initially including ability to inhibit monoamine accumulation into rat brain synaptosomes and to induce the overflow of transmitter from prelabeled superfused synaptosomes. In addition, tests for cross-substitution in the two-lever drug discrimination paradigm will assess whether the compounds are more similar in vivo to serotonin releasing agents, hallucinogens, or psychostimulants. Acute and long-term effects on brain monoamines will be assessed using HPLC-EC, with a particular emphasis on acute and long-term effects on serotonin neuron markers as an indication of potential serotonergic neurotoxicity of new compounds. This will provide data to continue our testing of the hypothesis that substituted amphetamines must release both serotonin and dopamine to induce long-term serotonergic deficits. Compounds will be evaluated for reinforcing effects using conditioned place preference, to assess the validity of the hypothesis that only compounds with dopaminergic activity will induce place preference. In vivo microdialysis will be used to measure changes in extracellular dopamine in the rat nucleus accumbens to test further the hypothesis that increased accumbens dopamine levels are correlated with ability to induce place preference.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004758-10
Application #
2770059
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1988-08-01
Project End
2001-08-31
Budget Start
1998-09-17
Budget End
2001-08-31
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Selken, Jennifer; Nichols, David E (2007) Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats. Pharmacol Biochem Behav 86:622-30
Kanthasamy, A; Sprague, J E; Shotwell, J R et al. (2002) Unilateral infusion of a dopamine transporter antisense into the substantia nigra protects against MDMA-induced serotonergic deficits in the ipsilateral striatum. Neuroscience 114:917-24
Sprague, J E; Worst, T J; Haynes, K et al. (2001) The pharmacodynamic characterization of an antisense oligonucleotide against monoamine oxidase-B (MAO-B) in rat brain striatal tissue. Cell Mol Neurobiol 21:53-64
Parker, M A; Marona-Lewicka, D; Kurrasch, D et al. (1998) Synthesis and pharmacological evaluation of ring-methylated derivatives of 3,4-(methylenedioxy)amphetamine (MDA). J Med Chem 41:1001-5
Marona-Lewicka, D; Nichols, D E (1998) Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology (Berl) 138:67-75
Cozzi, N V; Frescas, S; Marona-Lewicka, D et al. (1998) Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. Pharmacol Biochem Behav 59:709-15
Sprague, J E; Everman, S L; Nichols, D E (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine. Neurotoxicology 19:427-41
Marona-Lewicka, D; Nichols, D E (1997) 5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat. Neuropharmacology 36:1471-5
Marona-Lewicka, D; Rhee, G S; Sprague, J E et al. (1996) Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol Biochem Behav 53:99-105
Sprague, J E; Nichols, D E (1995) The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 273:667-73

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