2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Parkinson-Disease--Secondary

In Parkinson's disease a degeneration of dopaminergic neurons of the nigrostriatal pathway is observed. Loss of dopaminergic regulation of striatal neuron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neurons. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordinated movements. This indicates that absence of dopamine in Parkinson's disease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have anti- parkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore the possibility that an A2AR antagonist might reestablish their motor impairment. Interestingly, blockade of A2AR rescues the behavioral parameters altered in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to normal levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia. They also provide evidence that selective A2AR antagonists can exhibit their anti-parkinsonian activities through a nondopaminergic mechanism.

Topics: Adenosine; Animals; Antihypertensive Agents; Antineoplastic Agents; Enkephalins; Gait; Gene Expression; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Parkinson Disease, Secondary; Phenethylamines; Purinergic P1 Receptor Antagonists; Purines; Radioligand Assay; Receptor, Adenosine A2A; Receptors, Dopamine D2; Receptors, Purinergic P1; RNA, Messenger; Substance P; Tritium

To determine the functions of striatal adenosine A2a receptors in vivo, the effects of a selective agonist, 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamidoaden osi ne hydrochloride (CGS 21680), and an antagonist, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837), on acetylcholine release were investigated in the striatum of awake freely moving rats using microdialysis. Intracerebroventricular injection of CGS 21680 (10 micrograms) increased acetylcholine release in striatum and KF17837 (30 mg/kg p.o.) antagonized the CGS 21680-induced acetylcholine elevation. To investigate the contribution of dopaminergic and GABAergic neurons on A2a receptor-mediated acetylcholine release, the effects of CGS 21680 were studied by using dopamine-depleted rats in the presence or absence of GABA antagonists. In the dopamine-depleted striatum, the intrastriatal application of CGS 21680 (0.3-30 microM) increased extracellular acetylcholine, which was significantly greater than that in normal striatum. The CGS 21680-induced elevation of acetylcholine release was still observed in the presence of GABA antagonists bicuculline (30 microM) and 2-hydroxysaclofen (100 microM) and was similar in both normal and dopamine-depleted striatum. These results suggest that A2a agonist stimulates acetylcholine release in vivo, and this effect of A2a agonist is modulated by dopaminergic and GABAergic neurotransmission.

Topics: Acetylcholine; Adenosine; Animals; Corpus Striatum; Drug Combinations; GABA Antagonists; Male; Muscimol; Oxidopamine; Parkinson Disease, Secondary; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Reference Values