Involvement of the central melanocortin system in the effects of caffeine on anxiety-like behavior in mice

Aims: To investigate the role of the melanocortin (MC) system in the framework of the central nucleus of the amygdala (CeA) in the differential effects of the adenosine receptor blocker caffeine on anxiety-like behavior, using the social interaction (SI) test. Main methods: Caffeine was injected intraperitoneally, alone or in combination with alpha-melanocyte stimulating hormone (alpha-MSH), the MC4 receptor agonist R027-3225 or the antagonist HS014 via the intra-CeA route. The effects of chronic (21 days) caffeine, given alone or concurrently with alpha-MSH, or R027-3225, were investigated. The effects of withdrawal of these treatments on SI time were also evaluated. Furthermore, the acute effects of HS014 were investigated in different sets of caffeine-withdrawn mice. Key findings: Acute injection of caffeine, R027-3225, or alpha-MSH produced anxiety-like behavior. Prior treatment with alpha-MSH, or R027-3225 potentiated the caffeine-induced anxiety-like behavior. Subchronic treatment with HS014 increased the SI time, which was attenuated by caffeine. Chronic administration of caffeine resulted in tolerance to caffeine's anxiogenic effect, while abrupt discontinuation of the treatment produced peak anxiety-like behavior at 72 h post-withdrawal. Concurrent administration of alpha-MSH, or R027-3225 with chronic caffeine delayed the development of tolerance and prevented withdrawal-induced anxiety-like behavior. Moreover, acute treatment with HS014 at 72 h post-withdrawal attenuated the anxiety-like behavior. Significance: alpha-MSH, possibly via MC4 receptor in the neuroanatomical framework of the CeA, may contribute to the acute, chronic and withdrawal actions of caffeine associated with anxiety-like behavior in the neuroanatomical framework of the CeA. (C) 2013 Elsevier Inc. All rights reserved.