Hypothalamic neuropeptides and the endocannabinoid system

The hypothalamus plays a critical role in regulating the body homeostasis. This area of the brain works by setting the values of set point, integrates metabolic input information and adjusts the output control via the autonomic and endocrine systems. The endocannabinoid system is composed of cannabinoid receptor types 1 and 2 (CB1 and CB2) and two major endogenous ligands, N-arachidonyl ethanolamine (anandamide) and 2-arachidonoyl glycerol, have been found to exert pronounced regulatory effects on hypothalamic neuroendocrine functions especially those controlling feeding behavior, sleep and stress response. The endocannabinoids, as a retrograde messenger, activate presynaptic CB1 receptors, leading to decreased release of other neurotransmitters such as GABA and glutamate. In the hypothalamus, endocannabinoids reduce GABA release and disinhibit melanocortin-concentrating hormone neurons, leading to an increase in food intake. The orexigenic effect of endocannabinoids is also mediated via modulating the release of other neurotransmitters including neuropeptide Y, melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript and ghrelin. Endocannabinoid system modulates the activity of hypothalamic-pituitary-adrenocortical axis under both basal and stress-related conditions. Presynaptic CB1 receptor signaling regulates the release of corticotropin-releasing hormone from hypothalamic paraventricular neurons and plays a role in stress response. Endocannabinoids also promote rapid-eye-movement sleep by interacting with melanin-concentrating hormone neurons in the lateral hypothalamus. Based on these effects, endocannabinoids have potential therapeutic benefit for several conditions. On the other hand, dysfunction of this system could be involved in the development of several psychiatric disorders.