One potential explanation of unprecedented efficacy of levodopa in the treatment of Parkinson's disease suggests that levodopa itself or its metabolites may affect targets in the brain in addition to dopamine transmission. Endogenous amines of unknown function, trace amines, that are structurally related to dopamine and other monoamines are normally found at low concentrations in the brain. The recently discovered trace amine receptors (at least 9 known to date) represent attractive candidates for these additional putative targets of levodopa. The best characterized trace amine 1 receptors (TA1R) can be activated by a variety of endogenous and exogenous compounds including trace amines, amphetamines and monoamine metabolites and are associated with the neuronal circuitry that controls movement.
We propose here to use a strain of mutant mice newly established in our laboratory that lack TA1Rs (TA1-KO mice) to analyze the potential role of TA1R in mediating the locomotor promoting or side effects of anitiparkinsonian drugs. First, we will perform general behavioral and pharmacological characterization of motor functions of these mutants. Then we will develop a classical 6-OH-DA model of PD in TA1-KO mice to evaluate the effects of antiparkinsonian drugs and trace amine ligands in these mutants. Furthermore, we will cross TA1-KO mice with DAT-KO mice to perform tests of known antiparkinsonian drugs and putative TA1R ligands in TA1R-deficient dopamine-depleted DAT-KO (DDD) mice. Validation of the involvement of TA1R in the locomotor promoting or side effects of antiparkinsonian treatments may provide a significant breakthrough in the development of better antiparkinsonian treatments.
Final Outcome
Dr. Gainetdinov hypothesized that activation of trace amine receptors in the brain may underlie a non-dopamine pathway mediating some of the beneficial effects of levodopa. He characterized mice deficient for TA1 receptor and found them to be generally hyperactive, an effect mimicked by TAAR1 agonists. Interestingly, levodopa effects are enhanced in mice both deficient for TA1 receptor and also depleted of dopamine, suggesting a suppressing role of TA1 receptor signaling on locomotion. The results did not confirm the original hypothesis and suggested a much more complex role for trace amine signaling with respect to movement control.
Results of this work were published in the journals Neurology, Parkinsonism and Related Disorders and Molecular Pharmacology.
Follow-on funding for additional studies was received from Hoffmann-La Roche Inc. (Basel, Switzerland) and Compania di San Paolo Fondaziona (Torino, Italy).