Numerous studies have demonstrated an antagonistic interaction between specific adenosine A2A receptor (A2AR) and dopamine (DA) D2 receptor (D2R) subtypes. Because of this relationship, it is possible to increase the affinity of D2 receptors and likely activate D2R coupled intracellular cascades via blockade of A2ARs. Therefore the use of A2AR antagonists, which are a treatment target for Parkinson's disease (PD), a disease associated with DA hypofunction, may be a novel therapeutic target for enhancing DA agonist therapy after TBI. We propose to extend our previous findings in the dopaminergic system to hypothesize that persistent functional deficits following TBI may be, at least partially, attenuated by adenosine A2AR modulation of D2R function.
The first Aim will determine whether doses of the D2R agonist bromocriptine, which are lower than that previously shown to be efficacious, can achieve efficacy when combined with selective A2AR antagonists. This will be accomplished by a systematic combination dose-response study of ZM 241385, an A2AR antagonist and bromocriptine, a D2R agonist.
The second Aim will determine the effects of TBI on the interactive relationship between the A2A/D2 receptor systems. The effects of specific A2AR antagonists on DA function will be determined at the extracellular, receptor, and G-protein-mediated signal transduction after TBI.
The third Aim will determine potential mechanisms of action mediated by the combination of adenosine and dopamine agents that wilt be determined in Aim 1 to be most efficacious in attenuating functional deficits, in Aim 3, the pharmacological manipulations of specific adenosine and dopamine receptors will be complimented by using transgenic knockout mice that have the A2A receptor subtypes deleted. The greatest density of the A2A receptors is in the striatum. The striatum and frontal cortex are also involved in cognitive and motor functions that are disturbed in TBI patients. Therefore, all of the proposed tissue studies will be conducted in striatal, hippcampal, and frontal cortical samples. The results of these studies will expand our knowledge of striatal function after TBI and provide initial preclinical evidence to support clinical investigation into adenosine enhanced DA agonist therapies for chronic TBI.
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