Locomotor activity has been frequently used in animal models to characterize and assess a wide variety of drugs, including neuroleptics and central stimulants. Dopamine (DA) has been implicated in the central processes involved in the regulation of locomotor activity and related psychomotor behaviors. There is a good deal of evidence implicating the nucleus accumbens, a major component of the ventral striatum rich in DA, in the neuronal mechanisms mediating locomotor activity, reward processes, drug addiction, and psychiatric disorders. Adenosine has been shown to modulate neuronal function in the central nervous system (CNS) through a variety of receptor-mediated mechanisms involving second messenger systems, ion fluxes, and modulation of transmitter release. Alkylxanthines, such as caffeine, act as competitive antagonists at extracellular adenosine receptors. Recent work in the applicant's laboratory has shown that intra-nucleus accumbens microinjections of selective adenosine A(2a) receptor agonists potently suppress locomotor activity in mice. The nucleus accumbens exhibits the highest densities of A(2a), receptors in the brain. In light of numerous studies indicating a functional linkage and colocalization of adenosine and DA receptors in specific CNS regions, the proposed studies are designed to examine the functional interaction between adenosine and DA receptor subtypes in the nucleus accumbens involved in the mediation of locomotor activity. Specifically, the proposed studies will assess the effects of both central (intra-nucleus accumbens) and peripheral drug administrations designed to alter adenosinergic, dopaminergic, and combined adenosinergic and dopaminergic receptor function, on locomotor activity in mice. In addition, the proposed studies will incorporate three inbred mouse strains differing in baseline locomotor activity, methylxanthine-sensitivity, and A(2a), receptor density, as tools to characterize the specific interactions of adenosine and DA receptor subtypes in nucleus accumbens-mediated mechanisms of locomotor control.
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