Previous studies have attributed the changes that

Previous studies have attributed the changes that occurs during the behvioral sensitization to many psychostimulants with neuroadaptation in dopaminergic cell bodies of the VTA (induction phase) along with alteration in dopamine axon terminal field transmission of NAc during the expression to sensitization [36,37]. Interestingly, apart from the ubiquitous presence of the dopaminergic system in the Tie2 kinase inhibitor mg areas involved in locomotion (striatum) especially in mesolimbic reward area (VTA and NAc), a strong presence of histaminergic transmission is also reported. Thus, it is reasonable to contemplate that histamine might play a cardinal role in the behvioral sensitization induced by caffeine. However, the role of central histaminergic transmission in the behavioral effect of caffeine is still obscure. Therefore, intrigued by the reports that caffeine administration increases the histamine neuronal activation along with release of histamine in brain [15] and that histamine plays a cardinal role in the modulation of locomotion or arousal mainly via H1 receptor activation [[22], [23], [24], [25]], the present study attempted to investigate the role of the central histaminergic transmission via H1 receptor in the caffeine induced locomotor sensitization. In order to address the above objectives, protocols were designed by central (i.c.v.) administration of H1 receptor agonist or antagonist in mice concomitantly with caffeine (15 mg/kg, i.p) during the induction phase of sensitization. Moreover, the influence of H1 receptor modulation during induction phase on expression to caffeine-induced sensitization was also evaluated using actophotometer test in male Swiss mice. The results of the present study demonstrated that simultaneous pharmacological stimulation of H1 receptor during induction phase by i.c.v. administration of H1 receptor agonist, FMPH (6.5 μg/mouse, i.c.v.), (Fig. 2[A]) along with caffeine (15 mg/kg, i.p.) significantly potentiated the locomotor sensitization induced by caffeine from day 1st to 13th day as compared to FMPH naïve caffeine treated group (aCSF + caffeine). Similarly, FMPH treated group (FMPH + saline) per se also shown some locomotor sensitizing effect but only from day 9th to day 13th. Moreover, the group of mice treated with FMPH + caffeine or FMPH + saline during induction phase (for 13 days) on challenge with low dose of caffeine (10 mg/kg, i.p.) on 17th day [FMPH + caffeine (ch-caff)], exhibited enhanced expression to locomotor sensitization as compared to aCSF + caffeine (ch-caff) treated group (Fig. 3[A]). These results directly points towards the development of H1 receptor up-regulation during the induction as well as expression phase after caffeine treatment. These results of the H1 receptor agonist protocols on caffeine induced locomotor sensitization points towards a prominent contributory role of endogenous histamine via activation of histamine H1 receptors in the locomotor sensitizing effect of caffeine. Indeed, this premise is also supported by the report that mice lacking histamine H1 receptor exhibited reduced locomotor and exploratory activity, suggesting the role of central endogenous histamine in locomotion via H1 receptor stimulation [25]. It is noteworthy that i.c.v. administration of histamine or H1 agonists induces behavioral arousal [22]. Literature review shows the existence of some reports that corroborates with our proposed contributory role of histamine in caffeine induce locomotor sensitization. Indeed, previous reports have identified that endogenous adenosine in TMN suppresses the histaminergic transmission via the adenosine A1 receptors to promote the non- REM sleep. Moreover, it is have also reported that adenosine A1 receptors are expressed on histamine neurons of the rat TMN [16]. 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 behvioral senstizating effect of abuse drugs like caffeine) projected to the arousal nuclei, including histaminergic TMN [19]. Moreover, a sleep-promoting A2A receptor agonist, CGS21680, increases GABA release in the TMN [17], which during REM sleep is linked to the suppressed activity in histamine neurons [15]. Therefore, it can be hypothesized that caffeine by disinhibit the tonic effects of adenosine via A1 or A2A receptor on TMN neurons that innervates the reward center i.e. VTA and NAc and results in activation and release of histamine therein. Thus, it is reasonable to contemplate that increased histamine neuronal activation and release of histamine after caffeine administration [38] might subsequently activate the H1 receptor probably in VTA and NAc to contribute in the development caffeine’s addiction by participating in its locomotor sensitizing effect.