Objective: To understand the molecular basis and function of A2A/D2 receptor (R) interactions in the striatum and their role for the antiparkinsonian actions of A2A antagonists in models of Parkinson’s disease (PD). Background: Studies in rats with unilateral 6-OH lesions of the ascending DA pathways at the nigral level showed that the non-selective adenosine R antagonists caffeine and theophyllamine could markedly enhance the contralateral rotational behavior induced by levodopa and DA agonists indicating an antiparkinsonian potential of these drugs (Fuxe and Ungerstedt, Med Biol, 1974;52,48-54). In 1991-92 the first indications were obtained that these behavioral observations may reflect the existence antagonistic A2A/D2 R interactions at the membrane level in the striatum leading to the proposal that A2A antagonists may represent novel antiparkinsonian drugs (Ferre et al, PNAS 1991;88,7238-41, Ferre and Fuxe, Brain Res 1992;594,124-130). Methods: A combination of in vitro (e.g., biochemical binding assays, cAMP determinations, coimmunoprecipitation, FRET-BRET ) and in vivo (motor behavior, dual probe microdialysis) approaches have been used Results: Constitutive A2A/D2 heteromeric R complexes give the molecular basis for the intramembrane antagonistic A2A/D2 R interaction present in the striatopallidal GABA neurons. A2A agonists counteracted the D2 inhibition of the glutamate drive in the subthalamic neurons. The demonstration of a reciprocal antagonistic D2/A2A interaction at the adenylate cyclase level may underly the ability of A2A antagonists to counteract; e.g., haloperidol induced catalepsy. The antidyskinetic actions of A2A antagonists may be explained by the formation of abnormal receptor mosaics where detrimental synergistic A2A/D2 involving betagamma dimers take place with marked enhancement of A2A signaling causing PKA activation and PP-1 inhibition. This may lead to excessive phosphorylation of the abnormal receptor mosaics formed, causing their stabilization and thus maintenance of the wrong motor programs resulting in dyskinesia development. Conclusion: The therapeutic actions of A2A antagonists may mainly be explained by the counteraction of the antagonistic A2A/D2 interaction and the restoration of balance in A2A and D2 signaling.
Experimental studies and theoretical aspects on A(2A)/D-2 receptor interactions in a rat model of Parkinson's disease. Relevance for treatment and levodopa-induced dyskinesias
TANGANELLI, Sergio;
2006
Abstract
Objective: To understand the molecular basis and function of A2A/D2 receptor (R) interactions in the striatum and their role for the antiparkinsonian actions of A2A antagonists in models of Parkinson’s disease (PD). Background: Studies in rats with unilateral 6-OH lesions of the ascending DA pathways at the nigral level showed that the non-selective adenosine R antagonists caffeine and theophyllamine could markedly enhance the contralateral rotational behavior induced by levodopa and DA agonists indicating an antiparkinsonian potential of these drugs (Fuxe and Ungerstedt, Med Biol, 1974;52,48-54). In 1991-92 the first indications were obtained that these behavioral observations may reflect the existence antagonistic A2A/D2 R interactions at the membrane level in the striatum leading to the proposal that A2A antagonists may represent novel antiparkinsonian drugs (Ferre et al, PNAS 1991;88,7238-41, Ferre and Fuxe, Brain Res 1992;594,124-130). Methods: A combination of in vitro (e.g., biochemical binding assays, cAMP determinations, coimmunoprecipitation, FRET-BRET ) and in vivo (motor behavior, dual probe microdialysis) approaches have been used Results: Constitutive A2A/D2 heteromeric R complexes give the molecular basis for the intramembrane antagonistic A2A/D2 R interaction present in the striatopallidal GABA neurons. A2A agonists counteracted the D2 inhibition of the glutamate drive in the subthalamic neurons. The demonstration of a reciprocal antagonistic D2/A2A interaction at the adenylate cyclase level may underly the ability of A2A antagonists to counteract; e.g., haloperidol induced catalepsy. The antidyskinetic actions of A2A antagonists may be explained by the formation of abnormal receptor mosaics where detrimental synergistic A2A/D2 involving betagamma dimers take place with marked enhancement of A2A signaling causing PKA activation and PP-1 inhibition. This may lead to excessive phosphorylation of the abnormal receptor mosaics formed, causing their stabilization and thus maintenance of the wrong motor programs resulting in dyskinesia development. Conclusion: The therapeutic actions of A2A antagonists may mainly be explained by the counteraction of the antagonistic A2A/D2 interaction and the restoration of balance in A2A and D2 signaling.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
