Beta-Alanine and its Effect on Mice Behavior

Beta-alanine is a non-essential amino acid, which means that it can be produced naturally by the body. There are three ways in which beta-alanine is produced by the body:

1. It can be released during break-down of histidine dipeptides.
2. As a byproduct of L-alanine to pyruvate conversion.
3. It is released by intestinal microbes during digestion.

Together with other amino acids such as histidine, it forms carnosine, which helps bring down acid levels during vigorous exercise. When consumed as a dietary supplement, it passes from the bloodstream into skeletal muscle and binds with other amino acids to boost the levels of carnosine. Because of this effect, beta-alanine is commonly used to improve athletic performance and exercise capacity. Interestingly, animal studies show that beta-alanine also has other effects on behavior aside from its beneficial effects on muscle endurance during high-intensity exercise.

Effects of Beta Alanine on Spatial Memory

Although there is compelling evidence for the involvement of several naturally occurring amino acids in brain function, there is scarce information supporting the role of beta-alanine in spatial memory. For this reason, Sase et al. investigated the brain levels of beta-alanine in different groups of rats to assess its connection with spatial memory.^[1]

In this study, male Sprague Dawley rats aged between 12 and 14 weeks were used. The rats were then grouped into trained and untrained (used as the control). Prior to the behavioral test, the trained group was allowed to swim and search for the escape platform in the Morris water maze test for 120 seconds for 4 days as part of their training. If the rats were not able to locate the platform, they were manually placed on it for 30 seconds. On day 5, both trained and untrained rats were released and allowed to swim freely in the Morris water maze. Researchers observed that trained rats spent significantly longer times in target quadrants compared to untrained rats, indicating memory formation at retrieval. After the behavioral test, all the rats in each group were sacrificed in order to assess the brain levels of beta-alanine. Researchers found that the brain levels were higher in trained rats compared to untrained rats. This result suggests that beta-alanine may be involved in spatial memory retrieval in rats and that higher levels of this non-essential amino acid is associated with better memory.

Brain-derived neurotrophic factor (BDNF) is an important molecule involved in memory formation. Studies show that higher levels of BDNF are associated with better spatial memory. For instance, Kesslak et al. reported that BDNF production is increased in the hippocampus (the brain region that is mainly associated with memory) of rats following training in the Morris water maze.^[2] Interestingly, there is compelling evidence that shows that beta-alanine has the ability to boost the levels of BDNF.^[3] This suggests that cortisol supplementation may help improve memory by increasing BDNF levels.

Effects of Beta-Alanine on Stress

Exposure to extreme levels of stress can significantly affect behavior and coping mechanisms. In severe cases, this can lead to post-traumatic stress disorder (PTSD). Interestingly, evidence suggests that beta-alanine has an anti-stress effect.

In one study, Hoffman et al. investigated the effects of beta-alanine ingestion on the behavioral response of murine models of post-traumatic stress disorder.^[4] Animals were fed a normal diet with or without beta-alanine supplementation for 30 days. In order to induce extreme stress, animals were exposed to a predator scent. Behaviors were then evaluated using an elevated plus maze test. Researchers observed that animals supplemented with beta-alanine spent significantly more time in the open arms and had more number of entries in the elevated plus maze compared to those who were not fed with beta-alanine. These results suggest that beta-alanine supplementation may help reduce PTSD-like behavior.

Recent evidence also suggests that higher levels of carnosine may increase resilience to stress.^[5] In one study, Tsoi et al. found that carnosine exerts its anti-stress effects by modulating the stress response of the hypothalamus of the brain in mice.^[6] Of note, beta-alanine has been shown to increase carnosine concentrations in skeletal muscle by 20-80%,^[7] suggesting that beta-alanine may have a beneficial effect on the stress response by boosting carnosine levels.

Effects of Beta-Alanine on Anxiety

Beta-alanine also has an anti-anxiety effect. Evidence suggests that beta-alanine exerts this effect by increasing the levels of BDNF. BDNF, which is the most prevalent growth factor in the central nervous system, is thought to play a crucial role in psychiatric diseases, including anxiety disorder.^[8]

A study by Murakami et al. investigated the anti-anxiety effect of beta-alanine in mice under acutely stressful conditions.^[9] Mice were fed with beta-alanine supplements and others were fed with a normal powder diet. In the elevated plus maze test, mice supplemented with beta-alanine displayed a significant increase in the percentage of time spent, and entries in the open arms compared to those who received a normal powder diet, suggesting that beta-alanine has an anti-anxiety effect. After completion of the behavioral test, the mice were sacrificed and their brains were examined. Researchers observed that the brains of the mice fed with beta-alanine have higher levels of a brain-derived neurotrophic factor compared to mice fed with a normal powder diet. This result suggests that beta-alanine exerts its anti-anxiety effect by increasing the levels of a brain-derived neurotrophic factor.

In another study, Hoffman et al. investigated the anti-anxiety effects of beta-alanine in rat models of post-traumatic stress disorder.^[10] In this study, a group of rats was fed with 100 mg of beta-alanine in a powder form and another group was fed with regular food and water for 30 days. After 30 days of ingestion, both groups were exposed to a predator scent. Behaviors were then assessed using an elevated plus maze test. Researchers observed that rats supplemented with beta-alanine had greater time spent in the open arms of the maze and greater number of open arm entries compared to rats fed with regular food and water. These results suggest that beta-alanine has an anti-anxiety effect.

Effects of Beta-Alanine on Cognition

Traumatic brain injury (TBI) can lead to cognitive, behavioral, and emotional difficulties that can be long-lasting. In mice, this type of injury can cause learning and memory impairments.^[11] Evidence suggests that beta-alanine supplementation can significantly reduce cognitive impairments associated with TBI in mice.

In one study, Hoffman et al. investigated the benefit of beta-alanine supplementation on behavioral and cognitive responses relating to mild TBI in rats.^[12] In this study, rats were exposed to a low-pressure blast wave in order to induce mild TBI. Some of these rats were then fed with a diet supplemented with beta-alanine (100 mg per kg of body mass) while others were fed with a normal diet (regular food and water) for 30 days. The rats were initially assessed in the elevated plus maze test, followed by the acute startle response test, an hour later. Spatial memory performance was also assessed using the Morris water maze 8 days after exposure to low-pressure blast wave. Researchers observed that rats supplemented with beta-alanine had increased entries and spent more time in the open arms of the elevated plus maze compared to those who received a normal diet. In addition, rats supplemented with beta-alanine displayed lesser facial and skeletal muscle contractions (lesser startle response) compared to rats fed with a normal diet. In the Morris water maze test, rats supplemented with beta-alanine spent less time finding and climbing onto the escape platform of the maze compared to the group fed with a normal diet. These results suggest that beta-alanine can help counter cognitive deficits associated with traumatic brain injury induced by low-pressure blast wave.

Carnosine, which is synthesized in skeletal muscle from the amino acids histidine and beta-alanine, is known to exert a neuroprotective effect that can help prevent and treat cognitive deficits. In one study, Rajanikant et al. reported that carnosine can help improve cognitive function by preventing nerve damage to the brain caused by lack of oxygen supply.^[13] Interestingly, an overwhelming body of evidence suggests that beta-alanine supplementation in mice can significantly increase the levels of carnosine, suggesting that beta-alanine can be beneficial in treating cognitive decline.^[14][15]

Effects on Locomotor Activity

Beta-alanine also has an effect on locomotor activity in mice. Studies show that beta-alanine affects the activity of mice through various important mechanisms.

In one study, Mena gomez et al. investigated the effects of beta-alanine supplementation on rat behavior.^[16] In this study, a group of rats received beta-alanine injections and another group did not receive any injections. In order to assess behavior, the researchers used the open field test. During the behavioral test, rats injected with beta-alanine displayed decreased exploratory behavior compared to those who did not receive the injections. This result suggests that beta-alanine might alter locomotor behavior in rats by decreasing exploratory behavior.

In another study, Nishigawa et al. investigated the effects of beta-alanine on growth and behavior of mice.^[17] In this study, pregnant mice were separated into 3 groups:

1. Control group (saline)
2. Taurine group
3. Beta-alanine group

During the lactation periods, the mice received injections of saline, taurine, and beta-alanine. Interestingly, researchers observed that the taurine concentration in milk was decreased by beta-alanine administration, but was not altered by the taurine or saline treatment. In addition, the body weight of offspring was lower in the beta-alanine group compared to the taurine and control group. Of note, the beta-alanine treatment caused a significant reduction in the concentration of taurine in the brains of offspring, which in turn induced hyperactivity. The researchers, therefore, concluded that beta-alanine administration during lactation period can significantly decrease taurine concentration in the brain of offspring, which can result in decreased body weight and hyperactivity.

Itch-associated Behavior

Beta-alanine induces itch and tingling after consumption, but the exact mechanism on how beta-alanine exerts this effect is unknown.

In order to determine how beta-alanine induces itch-associated behavior, Liu et al. investigated the effects of oral and intradermal administration of beta-alanine in mice.^[18] In this study, mice were grouped into five:

1. Mice who were given oral beta-alanine.
2. Mice who were fed with 5% sucrose in water.
3. Mice who received an intradermal injection of beta-alanine.
4. Mice who received an intradermal injection of histamine dihydrochloride.
5. Mice who received an intradermal injection of saline.

After administration, each group was observed using a video recorder to assess the number of bouts of scratching of the cheek with the hind paw and the number of wipes of the cheek with the forepaw (itch-associated behaviors). Researchers observed that mice who received both oral and intradermal injections of beta-alanine displayed increased itch-associated behaviors compared to other groups. In order to determine the mechanism involved with itch-like behavior, mice were anesthetized and their epineuriums (outermost layer of connective tissue) were surgically removed and were observed under a microscope. Interestingly, researchers observed that the levels of Mas-related G-protein coupled receptor member D (MRGPRD) were higher in mice who received both oral and intradermal beta-alanine compared to other groups. This result suggests that beta-alanine administration induces itch-associated behavior by increasing MRGPRD levels in mice.

Conclusion

The benefits of beta-alanine go beyond improving athletic performance and exercise capacity. Higher levels of this powerful amino acid are strongly linked with better spatial memory in rats. Beta-alanine also has an anti-stress effect which can help combat extreme levels of stress, and even reduce post-traumatic stress disorder-like behaviors. By increasing brain-derived neurotrophic factor, beta-alanine exerts its anti-anxiety effect. In addition, beta-alanine can also help improve cognitive deficits associated with traumatic brain injury and lack of oxygen supply by increasing the levels of carnosine. With all these benefits, beta-alanine may potentially be a therapeutic option in patients with cognitive impairment, anxiety, and stress disorders.

While beta-alanine may have beneficial effects, it can negatively affect locomotion in rats by decreasing exploratory behavior. Furthermore, beta-alanine administration in mice during lactation period can significantly bring down the levels of taurine in the brain of offspring, which in turn decreases body weight and causes hyperactivity. Finally, a beta-alanine administration can also induce itch-associated behavior in mice by increasing MRGPRD levels. Therefore, beta-alanine must be used with caution in order to avoid unwanted side effects and achieve therapeutic goals.

References:

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2. Kesslak J. P., So V., Choi J., Cotman C. W., Gomez-Pinilla F. (1998). Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance? Behav. Neurosci. 112, 1012–101910.1037/0735-7044.112.4.1012.
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