Although caffeine is the most widely used central nervous system stimulant, the neuronal populations and pathways mediating its stimulant effects are not well understood. Using c-Fos protein as a marker for neuronal activation, the present study investigated the pattern of c-Fos induction at 2 hours after low locomotor-stimulant doses (1, 5, 10, and 30 mg/kg, i.p.) of caffeine and compared them with those after a higher dose (75 mg/kg, i.p.) or saline injection in adult male rats. Fos-immunoreactive neurons were counted in selected nuclei across the entire brain. Caffeine induced an increase in locomotor activity in a dose-dependent manner up to doses of 30 mg/kg and a decline at 75 mg/kg. Quantitative analysis of Fos-immunoreactive neurons indicated that no structures showed significant Fos expression at doses below 75 mg/kg or a biphasic pattern of Fos expression, as in locomotion. In contrast, caffeine at 75 mg/kg induced a significant increase compared with the saline condition in the number of Fos-immunoreactive neurons in the majority of structures examined. The structures included the striatum, nucleus accumbens, globus pallidus, and substantia nigra pars reticulata and autonomic and limbic structures including the basolateral and central nuclei of the amygdala, paraventricular and supraoptic hypothalamic nuclei, periventricular hypothalamus, paraventricular thalamic nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract. The locomotor-enhancing effects of low doses of caffeine did not appear to be associated with significant Fos expression in the rat brain.

In order to identify the mechanisms that would lead to increased levels of the inhibitory neuromodulator adenosine in the brain, we tested metabotropic glutamate receptor agonists for their ability to increase extracellular adenosine in the cortex of unanesthetized rat using in vivo microdialysis. The group I/II metabotropic glutamate receptor agonist trans-(+/-)- 1-amino-(1S,3R)-cyclopenyanedicarboxylic acid (I mM) increased extracellular adenosine as did the specific group I agonist (S)- 3,5-dihydroxyphenylglycine (DHPG; 1 mM). The evoked increase of adenosine by 1 mM DHPG was reduced by the group I antagonist (RS)- 1-aminoindan-1,5,-dicarboxylic acid. Activation of group II or III metabotropic receptors did not affect extracellular adenosine. These results suggest that activation of group I metabotropic receptors contributes to elevated extracellular adenosine levels in vivo.

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