Synaptic changes induced by melanocortin signalling

Key Points Plastic structural changes in the melanocortin circuitries that are mediated by melanocortin 4 receptor (MC4R) have been associated with anhedonic behaviours following chronic stress, and there is pharmacological evidence that selective blockade of this receptor in the nucleus accumbens alleviates such behaviour. MC4R signalling in the hippocampus induces morphological synaptic changes that lead to arborization of immature dendritic spines and enhance synaptic strength during long-term potentiation. MC4R activity is associated with enhanced phosphorylation and increased surface expression of AMPA receptors, which may stimulate the transcription of plasticity-associated genes and brain-derived neurotrophic factor synthesis. Mutations of the MC4R gene that lead to reduced receptor function have consistently been associated with obesity. A high occurrence of attention-deficit hyperactivity disorder has been reported in obese patients carrying mutations in MC4R . Aversive emotional and physiological states during drug withdrawal and the drive to compensate these negative states are associated with disruptive changes of synaptic plasticity in MC4R signalling within dopaminergic neurons. MC4R signalling contributes to the sensitization of behavioural responses to drugs of abuse, such as amphetamine, cocaine and heroin. Anatomical characterization of the melanocortin system using in situ hybridization and transgenic green fluorescent protein-expressing mice shows that MC4R is expressed throughout the ascending and descending pain pathways. MC4R agonists have been shown to increase mechanical and thermal hyperalgesia after chronic constriction injury, which suggests that MC4R agonists are pro-nociceptive, whereas antagonists display analgesic properties. Blockade of MC4R may be a new target in the search for strategies to prevent the development of opioid tolerance, to enhance the analgesic effects of opioids and to mitigate morphine withdrawal hyperalgesia. The roles of melanocortins extend well beyond the regulation of energy homeostasis. In this article, the authors review their involvement in different pathophysiological states, which could lead to the development of improved therapeutics for pain and mood disorders, and cognitive impairments. The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Revie