Biphasic changes in locomotor behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration

Abstract

The time course of expression of mRNA for NGFI-A and NGFI-B after a single intraperitoneal injection of saline or caffeine was examined using in situ hybridization. Administration of a high dose of caffeine (100 mg/kg) decreased locomotor behavior and increased NGFI-A and NGFI- B mRNA in the entire striatum. A lower dose of caffeine (50 mg/kg) caused a weak enhancement of both messages, which was confined to the lateral part of caudate-putamen. This dose increased horizontal, but not vertical, movement. In rats treated with the lowest dose of caffeine (25 mg/kg), the expression of both investigated genes tended to be lower than for saline-treated rats and both horizontal and vertical locomotor activity increased markedly. The reduction in the number of labeled neurons seemed to occur predominantly in enkephalin- containing neurons, which coexpress adenosine A2A receptors and dopamine D2 receptors. The decrease of mRNA for NGFI-A, NGFI-B, and jun B caused by caffeine (25 mg/kg) could be mimicked by the D2 agonist quinpirole (1 and 3 mg/kg). Moreover, caffeine could significantly decrease the expression seen following treatment with the D2 antagonist raclopride (2 mg/kg). In addition, in the parietal cortex, 25 mg/kg of caffeine caused a significant elevation of both examined immediate early genes. Thus, biphasic changes in locomotion induced by caffeine are paralleled by biphasic changes in mRNA for NGFI-A, NGFI-B, and jun B. The results also provide additional support for a functionally important interaction between adenosine and dopamine D2 receptors.

Dopamine–Adenosine Interactions in the Striatum and the Globus Pallidus: Inhibition of Striatopallidal Neurons through Either D2or A2AReceptors Enhances D1Receptor-Mediated Effects onc-fosExpression

“…Conversely, the D 2 agonist effect on c-fos in D 1 -containing neurons might be related to activation of presynaptic D 2 autoreceptors located on dopaminergic terminals, because this strongly decreases striatal dopamine release (Imperato et al, 1988;Suaud-Chagny et al, 1991) and thereby the D 1 -mediated activity in striatonigral neurons. Decreases of mRNA coding for the immediate early gene NGFI-A (zif 268) have been described after treatment with drugs acting on D 2 or A 2A receptors (Gerfen et al, 1995;Svenningsson et al, 1995), but we describe here for the first time the D 2 -mediated inhibition of c-fos expression in the two striatal output neurons.…”

Modulation of the hypothalamo–pituitary–adrenocortical axis by caffeine

“…The higher corticosterone and ACTH release induced by the 10 mg/kg caffeine dose, especially in the background (60 dB) noise condition is likely a reflection of the ability of caffeine at this dose to induce HPA axis activation basally, as shown in Experiment 3, but not by reducing the threshold to stressful events. A number of prior results suggested that a low dose of caffeine may produce an attenuation of the HPA axis response to stressful stimuli: first, because of the biphasic effects of caffeine reported in some responses (Svenningsson et al, 1995;Garrett and Holtzman, 1995); second, the finding that a similar low dose (2 mg/kg) attenuated the restraint-induced elevations in hippocampal serotonin and dopamine release (Yamato et al, 2002), despite the fact that caffeine alone elevated these neurotransmitters in the hippocampus (Carter et al, 1995); and finally, the existence of a putative mechanism whereby antagonism at adenosine A2a receptors might produce different effects than antagonism at the A1 receptors (Fredholm et al, 1999), as indicated by the findings that only high doses of caffeine (10 mg/kg and above) induce anxiety in rodents (Lister, 1987;Baldwin et al, 1989;Jain et al, 1995;Bhattacharya et al, 1997), while selective blockade of A1 receptors (Florio et al, 1998) but not A2a receptors (El Yacoubi et al, 2000) was reported to induce anxiety. These central actions of caffeine might have been expected to generalize to regulation of the hypothalamic paraventricular nucleus.…”

“…For example, in rats, caffeine has biphasic effects on locomotor activity (Svenningsson et al, 1995) and rotation behavior (Garrett and Holtzman, 1995), with low doses displaying an activating effect and high doses producing inhibitory effects. Additional evidence also suggests that caffeine may produce biphasic effects related to stress and anxiety.…”

Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

“…Indeed, with low caffeine doses (25 mg͞kg or lower) in wild-type animals, it has been hypothesized that A 2A receptors instead of A 1 receptors are preferentially blocked, and hyperlocomotion is induced by net elevation of efficacy of D 2 receptor signaling and depression in G olf activity in striatopallidal neurons (17,23). Higher caffeine doses (75-100 mg͞kg) elicit different responses that involve other pharmacological targets in addition to adenosine receptors, and these higher doses induce striatal immediate-early gene expression (23)(24)(25)(26)(27)(28)(29)(30). Finally, the effects of caffeine in mutants were only marginally inhibited by a combination of dopamine receptor antagonists that substantially reduced L-dopa-activated locomotor activity and feeding, suggesting that most of caffeine's effects are not mediated by release of residual dopamine.…”