Hypocretin: the 6 functions of this neurotransmitter

When we think of neurotransmitters, names like serotonin, dopamine, norepinephrine, glutamate, GABA or acetylcholine. Histamine and melatonin are also widely known.

However, there are many other substances that act as neurotransmitters and that are highly relevant to our functioning as human beings. Among them we can find a type of neuropeptide that was not identified until 1998: hypocretins or orexins. In this article we are going to briefly introduce what they are and some of the multiple functions in which they participate.

• Related article: "Types of neurotransmitters: functions and classification"

What is a hypocretin?

Hypocretins or orexins are peptides, small molecules composed of chains of amino acids that are found in large amounts in most animals. These are substances discovered relatively recently (specifically in 1998) and that have been found to have a great influence on a wide variety of functions. The fact that it can be called in two ways is due to the fact that this neurotransmission system was discovered in a practically simultaneously by two different research teams, observing the correspondence between both subsequently.

Within the hypocretins we can find mainly two neuropeptides, hypocretins 1 and 2 (or orexins A and B), which have their corresponding receptors on the membranes of some of the cells of the nervous system.

As with other hormones such as dopamine, the neurons that synthesize and use this type of neurotransmitter make up a system, called the hypocretinergic system.

Although the location of the neurons of this system occurs only in the hypothalamus later, the hypocretinergic system has a broad effect on the whole brain since the neurons that start from it have a large number of connections with different areas of this set of organs. Among them, those existing with the limbic system, with hypocretin being closely related to emotional processes. It is also linked to reticular system ascending, being very relevant in processes such as sleep and wakefulness.

Functions of these peptides

Although relatively little known by most of the population, hypocretins play a very important role in a large number of relevant functions and processes in our behavior. Let's see what they are.

1. Regulation of emotions and mood

One of the best known functions of hypocretins has to do with emotion and mood. And it has been proven that there are dense connections of hypocretinergic neurons between the hypothalamus and the limbic system. Although it does not generate the emotions itself, this neurotransmitter works by maximizing the emotional experience.

In this sense, the presence of hypocretin seems to be linked to the experience of emotions that suppose an upturn of energy, either positive such as joy or more negative ones such as anger. Similarly, in depressed or stressed patients, a decrease in the level of these neurotransmitters has been observed.

• You may be interested in: "Are there different types of depression?"

2. Regulation of sleep/wake cycles

Wakefulness and sleep are also mediated to a large extent by hypocretins or orexins, specifically affecting the activation of the wakefulness system and the maintenance of the alert state. This, in turn, is involved in attention capacity and the use of energy and physical and mental resources.

A lower concentration than necessary will generate alterations in said maintenance, being this factor linked to the disorder known as narcolepsy (In fact, it is one of the possible biological explanations for the disorder).

3. Forgetting and remembering: hypocretin in memory

Another of the multiple tasks associated with hypocretins is found in memory. Specifically, in experiments carried out with rodents it is observed that the blockade of the receptors of this type of peptides cause the disappearance of aversive memories. In other words, hypocretins help us to consolidate and maintain unpleasant memories in memory (an aspect that, although experientially it may seem aversive, it is functionally useful in allowing us to move away from the source of such stimulation).

• Related article: "Types of memory: how does the human brain store memories?

4. Learning

Directly derived from the previous point, we can consider that hypocretins have important role in the establishment of learning and conditioning, especially with regard to learning from fear.

5. intake

Another of the basic functions in which hypocretins participate is in intake. It has been observed that these molecules play a relevant role in explaining why do we look for food and have the craving to eat. The synthesis of hypocretins is activated by the action of ghrelin and inhibited by leptin, which are known for their role in generating hunger or satiety, respectively. It is also suspected that it is their actions that generate the link between food and sleep.

6. gratification and pleasure

Orexin or hypocretin is strongly linked to emotions and the sensation of pleasure, as well as the desire to achieve it. This is what happens with the numerous existing addictions, both at the level of drugs and at the level of sex or food.

Disorders to which they are linked

As we have said, hypocretins have multiple functions of great relevance to humans. Therefore, the dysfunction of the hypocretinergic system can bring relevant consequences to our behavior, there is a certain link between the action of this neurotransmitter and some disorders. Some of them are as follows.

1. narcolepsy

One of the main investigations related to hypocretins has to do with their effect on circadian rhythms and wakefulness. Low or insufficient hypocretins make it difficult to stay awake, a deficiency of these substances having been related to the origin of narcolepsy (although much more research is required on this).

2. addictions

Another of the great investigations that has been carried out reflects that hypocretins are related to addiction and relapses. The hypocretins are linked to craving and motivation to obtain the elements that make us feel pleasure and well-being, being a biological substrate that has a certain influence when it comes to facilitating the possibility of relapse into addictions.

3. Depression

Different investigations seem to reflect that the presence of a high level of hypocretins corresponds to energetic moods, which could be used in the future to develop drugs against passivity and lack of energy characteristic of depression.

4. Anxiety and stress-related disorders

Likewise, it has been observed that hypocretins are related to the encoding and maintenance of aversive memories and fear regulation. High levels make it difficult to extinct fear, for example, in a phobia or post-traumatic stress disorder.

Bibliographic references:

• Baumann, C.R. & Bassetti, C.L. (2005). Hypocretins (Orexins): Clinical Impact of the Discovery of a Neurotransmitter. Sleep Medicine Reviews 9(4): 253-268.
• Flowers, A.; Valls-Comamala, V.; Costa, G.; Saravia, R.; Maldonado, T.; Berrendero, F. (2014). The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology. 39: 2732-2741.
• Plaza-Zabala, A.; Martin-Garcia, E.; de Lecea, L.; Maldonado, R.; Berrendero, F. (2010). Hypocretins Regulate the Anxiogenic-Like Effects of Nicotine and induce Reinstatement of Nicotine-Seeking Behavior. Journal of Neuroscience, 30: 2300-2310.
• Siegel J.M. (1999). Narcolepsy: A key role for hypocretins (orexins). Cell, 98: 409–412.
• Siegel, J.M.; Moore, M.D.; Thannickal, T. & Nienhuis, R.S. (2001) A brief history of hypocretin/orexin and narcolepsy. Neuropsychopharmacology, 25: 514-520.
• Schwartz JR, Roth T. (2008). Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 6: 367-78.