The existence of sex differences in the response to caffeine

The existence of sex differences in the response to caffeine in young subjects have been studied in humans [8,20] and rodents [21–23], with different conclusions. Soellner et al. [24] reported improved object-discrimination in female rats, following caffeine ingestion. Elkins et al. [20], looking at effects of caffeine in prepubertal boys, concluded that Tariquidar manufacturer memory-impairment associated with caffeine in males was due to increased vigilance and decreased reaction-time with caffeine at lower doses. Fischer and Guillet [25] reported sex-differences in caffeine effect on memory retention in neonatal rats; however Temple et al., [8] reported no sex-differences in cardiovascular response to caffeine in adolescent boys or girls. The differences in the results of these studies would suggest that in the outcomes of tasks involving caffeine administration, the influences of sex are probably task-specific. Sex-differences in drug self-administration was ruled out in the present study, by giving caffeine through gavage; since studies have reported that female rodents are more vulnerable to stimulant self administration [26,27] or drug seeking behaviour [28]. There is a dearth of information on the influence of sex on effects of caffeine on open- field behaviours in rodents or motor activity in humans; and where available, results of studies vary. Uzbay et al. [23] reported the absence of sex-differences with caffeine administration in mice, although a sex-differential response was seen with agmatine on caffeine-induced locomotor response. In an earlier study [21], we reported that male mice (more than females) showed an early locomotor response, although females showed higher basal levels of locomotion. However, the present study differs from our previous study in a few areas: age of animals used, doses of caffeine used and presence of sleep-deprivation. Sleep-deprivation by gentle-handling is a stressor, and has been shown to be associated with elevated corticosterone [29] and alterations in antioxidant activity [30,31]. Oxidative stress occurs due to an imbalance between the production of oxidants and the strength of antioxidant defences. These imbalances can cause structural changes due to oxidation of proteins, lipids, and nucleic acids [32]. A number of studies have reported evidence of oxidative stress following acute or chronic sleep-deprivation [31–34]. An overall effect of sleep-deprivation on the body is a general sympathetic activation.
Methods
Results
Discussion Novelty-induced horizontal locomotion (Fig. 1) and rearing (Fig. 2) showed a general locomotor-stimulating effect of caffeine in both females and males (with or without sleep-deprivation), when compared to their respective vehicle groups. Horizontal locomotion and rearing are well-documented measures of explorative ability; and as seen in our study, caffeine administration (within the range of doses used) resulted in a biphasic effect on locomotion, with enhanced locomotor activity at low doses and suppression at high doses; a result consistent with several studies in adult rodents [41,42]. El Yacoubi et al. [41] also reported a biphasic effect of caffeine on locomotion of wild-type mice not habituated to the open-field, which is similar to the response seen in NSD prepubertal mice in this study. The stimulatory effect of caffeine has been attributed to its effects on adenosine receptors [41,42]. Specifically, the stimulant effect of low doses of caffeine is known to be mediated by A2A receptor blockade [41]. Effects of caffeine on both horizontal locomotion and rearing in the present study, supports the results of a number of other studies [41,43], and the suggestions that these effects are direct consequences of caffeine antagonism at ventral and dorsal striatum adenosine A2A receptors respectively [41]. However, the biphasic effect of caffeine dose on locomotion and rearing seen in NSD groups in this study is blunted by acute sleep-deprivation (regardless of sex); we observed that in the SD mice, excitatory effects seem to persist to the higher doses.