Caffeine and the Regulation of Locomotor Activity / Summary

In addition to modulating dopaminergic processes, caffeine shows neuroprotective efficacy in animal models of PD. In mice with neurotoxin-induced damage, caffeine acts in a dose-dependent manner to reduce the loss of endogenous dopamine and the dopamine transporter in mouse striatum. Striatal A_2AAR has been proposed to promote glutamate release and glia-mediated inflammation, which contribute to the pathogenesis of PD. Studies showing a significant reduction in risk of PD in populations with regular caffeine intake support a neuroprotective effect of caffeine against the development or exacerbation of PD. In an animal model, the neuroprotective effects of caffeine were mimicked by A_2AAR but not A₁AR antagonists, suggesting that A_2AAR blockade predominates in the antiPD effect of caffeine.

Caffeine and the Regulation of Locomotor Activity / Caffeine and PD

The influence of caffeine on locomotion is dose-dependent. High doses of caffeine (100 mg/kg) are either ineffective or reduce locomotor activity in both rats and mice; this effect has been attributed to rapid development of tolerance. A₁AR blockade promotes D₁R-mediated enhancement of locomotion in rats, and this effect is attenuated by prior chronic treatment with caffeine but not with a selective A_2AAR antagonist. Furthermore, long-term administration of a specific A_2AAR antagonist did not induce tolerance to caffeine. These findings led to the proposal that tolerance to caffeine is associated with chronic occupancy of A₁AR and that A₁AR activity is reduced and A_2AAR function is retained during the generation of caffeine tolerance.

Caffeine and the Regulation of Locomotor Activity / part 2

Other mechanisms also contribute to the general behavioral stimulation induced by caffeine. Studies with adenosine receptor KO mice indicate that A_2AAR, but not A₁AR, are involved in the sleep-promoting effect of adenosine. Caffeine administration reduces the hypnotic effects of alcohol in mice by means of A_2AAR blockade,and caffeine-induced psychomotor stimulation is deficient in A_2AAR KO mice, supporting the contention that caffeine-induced psychomotor stimulation occurs through A_2AAR antagonism. Finally, by blocking A₁AR, caffeine attenuates adenosine-mediated inhibition of mesopontine cholinergic neurons in the brainstem, thereby increasing neuronal firing rate, stimulating prefrontal cortex, and promoting arousal.

Caffeine and the Regulation of Locomotor Activity / part 1

The methylxanthine drug caffeine is a well-known psychostimulant chemical that promotes behaviors such as vigilance, attention, arousal, and locomotor activity. Caffeine is a competitive inhibitor of cyclic nucleotide phosphodiesterase (an enzyme that catalyzes cAMP degradation). However, caffeine's major mechanism of action in brain is nonselective blockade of adenosine re-ceptors.³⁰ Caffeine blocks postsynaptic A₁AR and A_2AAR, causing attenuation of adenosinergic neurotransmission and relative amplification of dopaminergic neurotransmission. These effects enhance both D₁R-mediated inhibition (via the direct pathway) and D₂R-mediated attenuation in stimulation (via the indirect pathway) on GPi-SNr-mediated inhibition of thalamus, thereby increasing thalamic stimulation of cortex and promoting locomotion.

Adenosine-dopamine Receptor Interactions in the Regulation of Locomotor Activity

Psychomotor activation is regulated in striatum via both the direct and indirect pathways. A₁AR-D₁R and A_2AAR-D₂R colo-calize as heterodimers on the MSN of the direct and indirect pathways, respectively. Molecular interactions within the complex allow one receptor of the pair to readily affect its counterpart. DR-mediated neurotransmission ultimately promotes behavioral activation, as reflected by increased voluntary locomotor activity. Stimulation of A₁AR and A_2AAR respectively counteracts D₁R- and D₂R-mediated neurotransmission, tending to reduce locomotor activity, and antagonism of either of these 2 AR promotes locomotor activity.

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.

Adenosine and Dopamine: Dopamine / part 2

Therefore, somatodendritic and nerve terminal autoreceptors act synergistically to reduce dopaminergic transmission, and both are more sensitive to agonists than are postsynaptic dopamine receptors. Stimulation of D₂ autoreceptors reduces AC activity, calcium influx, and neuronal excitability and promotes membrane hyperpolarization and potassium efflux.Functions of autoreceptors include inhibition of dopaminergic neuronal firing, inhibition of dopamine synthesis, promotion of dopamine uptake by DAT located on neuronal membranes and cytosolic vesicles, and enhanced DAT expression.