Ghrelin and aggressive behaviours—Evidence from preclinical and human genetic studies

•Central ghrelin infusion, but not ghrelin administered systemically, increases aggressive behaviours in male mice.•Aggressive behaviour is decreased by pharmacological suppression of the growth hormone secretagogue receptor-1A by JMV2959.•Ex vivo biochemical data shows that serotonin in amygdala may have central roles for the ability of JMV2959 to reduce aggression.•JMV2959 cannot decrease aggression following depletion of central serotonin signalling.•In men displaying hazardous alcohol use the Leu72Leu variant in the pre-pro-ghrelin gene are associated with higher aggression. Aggressive behaviour is of crucial importance in the defence for limited resources including food and mates and involves central serotonin as well as dopamine signalling. As ghrelin modulates food intake and sexual behaviour we initially investigated the hypothesis that central ghrelin signalling regulates aggressive behaviour in the resident intruder paradigm in male mice. Moreover, interaction between ghrelin signalling and serotonergic, noradrenergic as well as dopaminergic neurotransmission in aggression was investigated. The relevance of ghrelin for human aggression per se as well as for aggression induced by alcohol was evaluated in a human genetic association study comprising young men (n = 784) from the normal population assessed for anti-social behaviours. The present study demonstrates that central ghrelin infusion, but not ghrelin administered systemically, increases aggression. Moreover aggressive behaviour is decreased by pharmacological suppression of the growth hormone secretagogue receptor-1 A (GHSR-1A) by JMV2959. As indicated by the ex vivo biochemical data serotonin, rather than dopamine or noradrenaline, in amygdala may have central roles for the ability of JMV2959 to reduce aggression. This link between central serotonin, GHSR-1A and aggression is further substantiated by the behavioural data showing that JMV2959 cannot decrease aggression following depletion of central serotonin signalling. The genetic association study demonstrates that males carrying the Leu72Leu genotype of the pre-pro-ghrelin gene and displaying hazardous alcohol use are more aggressive when compared to the group carrying the Met-allele. Collectively, this contributes to the identification of central ghrelin pathway as an important modulator in the onset of aggressive behaviours in male mice.