Caffeine modulates voluntary alcohol intake in mice depending on the access conditions: Involvement of adenosine receptors and the role of individual differences.

Caffeine is the most consumed psychoactive stimulant and the main active ingredient of energy drinks. Epidemiology studies have shown a positive correlation between the consumption of energy drinks and that of ethanol. The popular belief is that caffeine antagonizes the intoxicating effects of alcohol. Both drugs act on the adenosine system but have opposite effects. Caffeine is a methylxanthine that acts as a nonselective adenosine receptor antagonist, binding to A1 and A2A receptor subtypes. In contrast, ethanol increases extracellular adenosinergic tone. The purpose of this study was to examine the impact of a broad range of doses of caffeine and of selective adenosine A1 and A2A receptor antagonists on voluntary ethanol intake under different ethanol access conditions. C57BL/6 J male mice had access to ethanol (10% w/v) under different conditions: restricted (2 h in the dark), unrestricted (24 h access), or after 4 days of alcohol removal following several periods of unrestricted access. Mice reduced ethanol intake in the restricted access condition after receiving caffeine (20.0 mg/kg), or theophylline (20.0 mg/kg), another methylxanthine. Selective A1 and A2A adenosine receptor antagonists, or their combination, did not have any effect. However, under unrestricted access conditions caffeine and the adenosine A2A receptor antagonist increased ethanol intake. After splitting animals into high, moderate and low ethanol consumers, caffeine (2.5-20.0 mg/kg) significantly increased ethanol consumption in moderate consumers with no effect on low or high consumers. In addition, after reintroducing ethanol access, caffeine (5.0 mg/kg) decreased ethanol consumption among moderate consumers. Thus, caffeine produced different effects on ethanol intake depending on the access condition and the baseline consumption of ethanol.

The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor.

Tetrabenazine (TBZ) is a reversible inhibitor of vesicular monoamine storage that is used to treat Huntington's disease. TBZ preferentially depletes striatal dopamine (DA), and patients being treated with TBZ often experience parkinsonian side effects. The present studies were conducted to investigate the ability of TBZ to induce tremulous jaw movements (TJMs), which are a rodent model of parkinsonian tremor, and to determine if interference with adenosine A2A receptor transmission can attenuate TJMs and other motor effects of TBZ. In rats, TBZ (0.25-2.0mg/kg) significantly induced TJMs, which primarily occurred in the 3.0-7.5-Hz frequency range. The adenosine A2A antagonist MSX-3 (1.25-10.0mg/kg) significantly attenuated the TJMs induced by 2.0mg/kg TBZ in rats, and also significantly reduced the display of catalepsy and locomotor suppression induced by TBZ. In mice, TBZ (2.5-10.0mg/kg) dose dependently induced TJMs, and adenosine A2A receptor knockout mice showed significantly fewer TJMs compared to wild-type controls. MSX-3 (2.5-10.0mg/kg) also significantly reduced TBZ-induced TJMs in CD1 mice. To provide a cellular marker of these pharmacological conditions, we examined c-Fos expression in the ventrolateral neostriatum (VLS). TBZ (2.0mg/kg) significantly increased the number of c-Fos-positive cells in the VLS, which is indicative of reduced DA D2 receptor transmission, and 10.0mg/kg MSX-3 significantly attenuated the TBZ-induced c-Fos expression. These results indicate that TBZ induces tremor as measured by the TJM model, and that pharmacological antagonism and genetic deletion of adenosine A2A receptors are capable of attenuating this oral tremor.

Effect of subtype-selective adenosine receptor antagonists on basal or haloperidol-regulated striatal function: studies of exploratory locomotion and c-Fos immunoreactivity in outbred and A(2A)R KO mice.

Behavioral activation is regulated by dopamine (DA) in striatal areas. At low doses, while typical antipsychotic drugs produce psychomotor slowing, psychostimulants promote exploration. Minor stimulants such as caffeine, which act as adenosine receptor antagonists, can also potentiate behavioral activation. Striatal areas are rich in adenosine and DA receptors, and adenosine A2A receptors are mainly expressed in the striatum where they are co-localized with DA D2 receptors. Adenosine antagonists with different receptor-selectivity profiles were used to study spontaneous or haloperidol-impaired exploration and c-Fos expression in different striatal areas. Because A2A antagonists were expected to be more selective for reversing the effects of the D2 antagonist haloperidol, A2A receptor knockout (A2ARKO) mice were also assessed. CD1 and A2ARKO male mice were tested in an open field and in a running wheel. Only the A1/A2A receptor antagonist theophylline (5.0-15.0 mg/kg) and the A2A antagonist MSX-3 (2.0 mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0-15.0 mg/kg), and MSX-3 (1.0-3.0 mg/kg) reversed haloperidol-induced suppression of locomotion. The A1 antagonist CPT was only marginally effective in reversing the effects of haloperidol. Although adenosine antagonists did not affect c-Fos expression on their own, theophylline and MSX-3, but not CPT, attenuated haloperidol induction of c-Fos expression. A2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1 mg/kg) in the open field and in the running wheel. A2A receptors are important for regulating behavioral activation, and interact with D2 receptors in striatal areas to regulate neural processes involved in exploratory activity.

Adenosine A2A receptor antagonism and genetic deletion attenuate the effects of dopamine D2 antagonism on effort-based decision making in mice.

Brain dopamine (DA) and adenosine interact in the regulation of behavioral activation and effort-related processes. In the present studies, a T-maze task was developed in mice for the assessment of effort-related decision making. With this task, the two arms of the maze have different reinforcement densities, and a vertical barrier is positioned in the arm with the higher density (HD), presenting the animal with an effort-related challenge. Under control conditions mice prefer the HD arm, and climb the barrier to obtain the larger amount of food. The DA D(2) receptor antagonist haloperidol decreased selection of the HD arm and increased selection of the arm with the low density of reinforcement. However, the HD arm was still the preferred choice in haloperidol-treated mice trained with barriers in both arms. Pre-feeding the mice to reduce food motivation dramatically increased omissions, an effect that was distinct from the actions of haloperidol. Co-administration of theophylline, a nonselective adenosine receptor antagonist, partially reversed the effects of haloperidol. This effect seems to be mediated by the A(2A) receptor but not the A(1) receptor, since the A(2A) antagonist MSX-3, but not the A(1) antagonist CPT, dose dependently reversed the effects of haloperidol on effort-related choice and on c-Fos expression in the dorsal striatum and nucleus accumbens. In addition, adenosine A(2A) receptor knockout mice were resistant to the effects of haloperidol on effort-related choice in the maze. These results indicate that DA D(2) and adenosine A(2A) receptors interact to regulate effort-related decision making and effort expenditure in mice.