Literature review suggests a strong presence of

Literature review suggests a strong presence of central histaminergic transmission in the angiogenic areas targeted by caffeine to induce its behavioral actions. Interestingly, it is reported that caffeine administration increases the histamine neuronal activation and release of histamine in the brain [15]. The main locus for the origin of histaminergic neuronal activity in the brain is the tuberomammillary nucleus (TMN) wherein, it is reported that endogenous adenosine promotes non-REM sleep by suppressing the histaminergic system via the A1 receptor [16]. Moreover, a sleep-promoting A2A receptor agonist, CGS 21680, increases GABA release in the TMN [17], which during REM sleep is linked to the suppressed activity of histamine neurons [15]. Thus, accumulating evidence supports for an existence of functional interaction between the targets of caffeine action i.e. adenosine A1 or A2A receptor with the central histaminergic system. Furthermore, similar to caffeine, the ability of central histaminergic neurotransmission to induce CNS stimulation like activity i.e. arousal and wakefulness have been already reported. This is well supported by the evidence that activity of posterior hypothalamus (PH) histamine neurons remains high during waking and is reduced or absent in sleep states [16,18]. Incidentally, Adeno-associated virus (AAV)-encoding humanized Renilla green fluorescent protein to trace long axonal pathways, it was found that adenosine A2A receptors in the NAc shell (an important brain area involved in the reward) projected to the arousal nuclei, including histaminergic TMN [19]. Moreover, direct modulations of reward pathway; VTA and NAc neuronal activity by histaminergic transmission have been also demonstrated [20]. Considering the above reports, the role of central histaminergic transmission in the caffeine induced locomotor sensitization seems to be worth investigating. It is important to note that histaminergic neurons project from the TMN to most of the central nervous system and is reported to promote locomotion or wakefulness mainly through histamine H1 receptors activation rather than other histamine receptors [28,[21], [22], [23], [24], [25]]. Thus, present study addressed the contribution of histamine H1 receptor in the caffeine induced development phases of sensitization i.e. during induction of locomotor sensitization and as well as expression to locomotor sensitization in mice using actophotometer test. Sensitization of locomotor activity is the most commonly studied paradigm, which reflects the incentive motivational properties of drugs believed to contribute to the intensification of drug craving and compulsive drug-seeking behavior [26].
Materials and methods
Results
Discussion The results of the present study demonstrated that repeated intermittent intraperitoneal (i.p.) administration of caffeine (15 mg/kg) on day 1st, 3rd,5th,7th,9th,11th and 13th, progressively increased the total locomotor count of mice on each day as compared to saline treated group (Fig. 1A), indicative of development of locomotor sensitization (induction phase) to caffeine. On the other hand, challenge with less stimulant dose of caffeine (10 mg/kg, i.p.) to the mice left untreated after 13th day for next 3 days i.e. on day 17th (expression phase) exhibited higher locomotor stimulation as compared to the tretament of same challenge dose of caffeine to the group of mice treated with saline during the induction phase, indicating the expression of locomotor sensitization to caffeine (Fig. 1[B]). These results are in concordance with the previous reports demonstrating the locomotor sensitizing effect of caffeine [7,8,32]. The observed behavioral sensitization with caffeine might be ascribed to the neuroadaptation and could be implicated in the development of drug addiction as well as in the relapse to drug-seeking behavior as seen with many psychostimulants [33,34]. However, it is reported that inconsistency observed with caffeine consumption patterns makes it difficult to describe it as addictive agent [35]. Considering the results of the present study it is reasonable to speculate that consistent spaced administration of caffeine can induce locomotor sensitization in mice, indicative of its addictive property.