Strategies for Evaluating Adenosine and Dopamine Interactions in Brain

Pharmacologic manipulation and genetic deletion of adenosine and dopamine receptors frequently are used in rodents to investigate the specific physiologic functions and interactions of adenosine and dopamine receptor subtypes. Agents that bind to but do not stimulate receptors (that is, antagonists) prevent or reduce the binding of endogenous stimulatory ligands, thereby allowing behavioral studies under the condition of temporary deficiency of receptor-mediated physiologic activity. The duration of antagonist occupancy of the receptor depends on the combined effects of the drug concentration and its receptor binding affinity as compared with those of endogenous ligands. Receptor function resumes after the antagonist dissociates, thereby allowing binding of the endogenous ligand. Based on their binding affinities for specific receptors, antagonists can be categorized as selective or nonselective. For example, caffeine is a nonselective adenosine receptor antagonist, with similar binding affinities for both AjAR and A_2AAR. In contrast, as a result of their higher affinities, the chemicals 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH58261 are selective antagonists for A₁AR and A_2AAR, respectively.

Gene deletion techniques can be used to generate mice with complete and chronic loss of a specific receptor subtype (that is, knockout [KO] mice). Such mice offer valuable insights into receptor functions and interactions. For example, as compared with genetically intact mice, A₁AR KO mice show hyperalgesia and greater signs of anxiety, whereas A_2AAR KO mice show hypoalgesia, greater aggressiveness, and an attenuated response to psychostimulant challenge. Furthermore, locomotion is reduced both in D₂R KO mice and in mice treated with a selective D₂R antagonist.
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The availability of neurotransmitters in the brain can also be manipulated by pharmacologic and genetic approaches. Endogenous dopamine is synthesized in neurons of the SNc and VTA and stored in vesicles located in nerve terminals. Depletion of vesicular dopamine by impaired synthesis or storage reduces extracellular dopamine availability, thereby reducing DA release and stimulation of DA receptors. For example, the tyrosine analog a-methylparatyrosine (aMPT) competes with tyrosine as a substrate for TH and thereby reduces or prevents dopamine synthesis, whereas the drug reserpine depletes vesicular DA by inhibiting monoamine re-uptake by vesicular membrane transporter.
In contrast to the drug-induced reversible reduction of dopamine availability, the neurotoxins 6-hydroxydopamine (6-HDA) and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) kill dopaminergic neurons via production of free radicals. Both toxins have been used to create rodent models of Parkinson's disease. Striatal injections of 6-HDA can be performed unilaterally to create a hemiparkinsonian animal that demonstrates some Parkinsonian symptoms (for example, rigidity of the contralateral limb) and can be used to study of the therapeutic and detrimental effects of drug therapy (for example, L-DOPA-induced dyskinesia). MPTP accumulates in dopaminergic SNc neurons, where it is metabolized by monoamine oxidase-B into 1-methyl-phenylpyri-dinium, which interferes with mitochondrial metabolism, leading to the accumulation of free radicals and eventual cell death. Administration of MPTP to primates and some mouse strains produces a comprehensive repertoire of Parkinsonian symptoms and has been used to model the pathogenesis of PD and to study the associated behaviors.