**3. Neurotransmitters in the Enteric Nervous System (ENS)**

The enteric nervous system (ENS) can be considered the body's second brain with more than 100 million neurons of different types. Neural signals may be transmitted from gut to the CNS by neural connection and by humoral mechanisms. The afferent fibers of the gut-brain neural are vagal (parasympathetic) and (ortho)sympathetic. Different sensors respond also to distension of stomach and contractions of the intestine. Chemical stimuli (e.g. spices), gut hormones, neurotransmitters, neuromodulators, cytokines and inflammatory mediators produced by the bacterial flora in the gut-are all important. In the brainstem most afferent vagal fibers terminate on the nucleus tractus solitarius (NTS). There is a viscerotopic repre‐ sentation of different parts of the enteric system in the NTS. The NTS is in connection with hypothalamus and amygdala, which also plays a role in regulation of hunger and satiety. We should not forget the emotional aspects of eating (smell, taste, and situational factors during eating).

Cholecystokinin is secreted by duodenal and jejunal cells after eating food. CCK acts on vagal neurons projecting to the brainstem, giving a signal of satiety inhibiting further need for eating.

Ghrelin is secreted when a person is hungry and it increases appetite. It acts on the hypothal‐ amus stimulating feeding, counteracting the inhibitory effects of leptin.

Leptin is manufactured mainly in fat cells in adipose tissue. Leptin counteracts the effects of neuropeptide Y and inhibits secretion of alpha-MSH (alpha melanocyte-stimulating hormone). Leptin decreases appetite and inhibits food intake contrary to ghrelin.

Alpha-MSH is in the arcuate nucleus in the brain where it acts to suppress appetite. Alpha-MSH may have also some function in the sleep-wake regulation.

Serotonin is an important neurotransmitter in the central nervous system (CNS) with impor‐ tant effects on sleep-wake regulation. Serotonin also has an important role in regulation of the gastrointestinal (GI) function through an interaction with the ENS. Up to 60-90 % of the total body amount of serotonin is in the GI tract, and 2-20% of all enteric neurons express serotonin. Stimulatory receptors include β-adrenoceptors, muscarinic and nicotinic Ach receptors and 5- HT3 receptors. Inhibitory receptors include alpha2-adrenceptors, histamine H3, GABA-B, adenosine A2, and 5-HT4 receptors. In the GI tract 5-HT is eliminated mainly by monoamine oxidase metabolism. [8]

Hypocretin (orexin) was originally considered to be important especially in central control of food intake [9, 10] but it is essential also in control of sleep and wakefulness. There are about 70 000 hypocretin neurons in the lateral hypothalamus. Narcolepsy, a central hypersomnia with excessive daytime sleepiness and cataplexy, is characterized by destruction of the hypocretin neurons. [11, 12] Hypocretin is involved also in energy homeostasis, nociception, reward seeking behavior, and drug addiction. [13-19] In addition to brain, hypocretins are also widely present in the gastrointestinal tract12 where they have a role in regulation of peristaltic GI motility, and in gastric, intestinal and pancreatic secretions. The hypothalamic hypocretin cells are intermingled with MCH neurons. Both hypocretin-and MCH-cells are glucosesensing neurons. Decrease of glucose increases activity of hypocretin neurons and decreases activity of the MCH cells, producing wakefulness. Respectively, increase of glucose decreases activity of hypocretin and increases activity of MCH, producing sleepiness. These interactions explain at least partly the alerting effects of fasting and the observations that eating rapidly absorbing carbohydrates, provoking fast increase of blood glucose, increase sleepiness.
