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The Effects of D-Aspartic Acid on Mouse and Rat Behaviors

By February 20, 2019October 8th, 2019No Comments

Aspartic acid, also known as asparaginic acid, is a nonessential amino acid. This means that aspartic acid can be produced by our bodies naturally. This amino acid plays a major role in the energy cycle of the body and can be found in milk and dairy products, eggs, meat, fish, legumes, nuts, cereals, citrus fruits, and green leafy vegetables.

Aspartic acid has two forms:

  • L-aspartic acid
  • D-aspartic acid.

The difference between the two is that L-aspartic acid is used by the body to build proteins while D-aspartic acid is used to boost the levels of certain hormones such as testosterone, growth hormone, and insulin-like growth factor 1. Because of this effect, D-aspartic acid is commonly used by athletes and bodybuilders in order to improve athletic performance and body composition. Interestingly, studies conducted on mice and rats show that D-aspartic acid also has a range of effects on behavior.

Effects of D-Aspartic Acid on Learning and Memory

Numerous studies suggest that D-aspartic acid is highly involved in the nervous system by enhancing the transmission of nerve signals and modulating the actions of nerve cells in the brain.[1][2] This suggests that D-aspartic acid has a particular role in learning and memory.

In one study, Topo et al. investigated the effects of oral administration of D-aspartic acid on learning and memory in rats.[3] In this study, the rats were grouped into two:

  1. Rats who received a solution of D-aspartic acid.
  2. Rats who received NaCl (control).

Both groups were fed ad libitum for 12 days and were subjected to undergo a Morris water maze test for three consecutive days. After the test, the rats were sacrificed in order to determine the brain levels of D-aspartic acid. Researchers found that rats treated with D-aspartic acid were more likely to find the hidden escape platform in the Morris water maze compared with rats who received NaCl, suggesting that D-aspartic acid supplementation has beneficial effects on learning and memory. In addition, rats possessing relatively high brain levels of D-aspartic acid were much faster in reaching the hidden platform of the maze compared to control, indicating that their enhanced cognitive capability was associated with the high levels of D-aspartic acid.

In another study, Palazzo et al. investigated the effects of D-aspartic acid on mice with cognitive impairment.[4] In order to induce cognitive impairment, all the mice were injected with sodium pentobarbital, a central nervous system depressant. A group of the mice was then fed with D-aspartic acid solution while another group was given drinking water ad libitum. Both groups were then subjected to undergo a novel object recognition test. The researchers observed that mice fed with D-aspartic acid solution spent more time exploring the new object in the novel object recognition test compared to mice fed with drinking water. This result suggests that D-aspartic acid supplementation in mice may help correct cognitive impairment induced by sodium pentobarbital.

Effects of D-Aspartic Acid on Schizophrenia

Normally, an organism will display a set of reflex behaviors such as the startle response in order to prepare itself to react to certain stimulus. However, certain mental health conditions like schizophrenia can reduce one’s reactivity to moderately intense stimuli. Interestingly, mice studies show that D-aspartic acid supplementation may help reduce schizophrenia-like behaviors through certain mechanisms.

Errico et al. investigated the effects of D-aspartic acid in mice with schizophrenia.[5]  In order to induce schizophrenia-like behaviors, all the mice were injected with amphetamine and were kept in a cage. After a few days, the mice displayed impaired startle response when exposed to background noise. A group of mice was then treated with D-aspartic acid mixed in drinking water and another group was fed with regular food and water ad libitum. Both groups were then subjected to undergo a behavioral test known as acoustic startle response. Researchers observed that mice treated with D-aspartic acid were more likely to exhibit startle response as evidenced by rapid contraction of the facial and skeletal muscles when exposed to loud noise. Of note, this effect was not observed in mice fed with regular food and water. This result suggests that D-aspartic acid supplementation in mice may help alleviate schizophrenia-like behaviors induced by amphetamine.

The N-methyl-D-aspartate receptor (NMDAR) is a group of proteins that help regulate the transmission of signals from one nerve cell to another. This receptor is believed to play a major role in learning and memory formation. Studies show that dysregulation in NMDAR is strongly linked with the development of schizophrenia.[6] Interestingly, Krashia et al. reported that higher levels of D-aspartic acid are associated with improved NMDAR activity in mice.[7] The researchers examined the brains of mice treated with D-aspartic acid and found higher levels of this compound compared to untreated mice. It was found that high D-aspartic levels increase NMDAR numbers, which in turn cause dopamine neurons to build a protective uptake mechanism. This mechanism may help reduce schizophrenia-like symptoms and prevent its development.

Another study by Errico et al. investigated the effects of D-aspartic acid supplementation on schizophrenia-like behaviors in mice.[8] In order to induce schizophrenia-like behaviors, the mice were injected with phencyclidine (PCP). An increase in locomotor activity and inhibition of the startle response were observed after PCP injection. After producing PCP-induced schizophrenia-like behaviors, the mice were grouped into two:

  1. D-aspartic acid-treated mice
  2. H2O-treated mice (control)

Both groups were then observed and subjected to undergo magnetic resonance imaging (MRI). Interestingly, while D-aspartic acid failed to produce statistically significant effects on schizophrenia-like behaviors, MRI results showed that the brains of mice treated with D-aspartic acid have increased cortico–hippocampal connectivity (which is usually reduced in schizophrenia patients) compared to control. These results suggest that D-aspartic acid supplementation may help improve impaired cortico–hippocampal brain network organization in mice with schizophrenia-like behaviors induced by PCP.

Effects of D-Aspartic Acid on Pain Perception

Pain related to nerve injury or trauma can significantly affect mice and rat behavior. Evidence suggests that D-aspartic acid may help improve mice behavior through its analgesic properties.

In one study, Onat et al. investigated the effects of D-aspartic acid on mice suffering from nerve injury.[9] A group of mice received D-aspartic acid injections at a dose of 115-230 mg/kg and another group did not receive any injections. In order to assess behavior, the tail flick test was used. This test is a measure of the animal’s pain response and involves focusing an intense light on the animal’s tail in order to observe its reaction to heat. The moment that the light is focused on the tail, a timer starts. When a tail flick is observed, the timer stops, and the recorded time (latency) is considered as a measure of the pain threshold. Typically, drugs that are used for relieving pain increase the latencies observed in this test. Interestingly, researchers observed that mice treated with D-aspartic acid had a significant increase in tail flick latency compared to untreated mice, suggesting that D-aspartic acid has pain-relieving properties.

In another study, D’aniello et al. investigated the effects of D-aspartic acid in a mouse model of neuropathic pain.[10] In order to induce pain, the mice underwent a surgery to cause trauma to the sensory nerves. A group of mice with nerve injury was then given repeated injections with D-aspartic acid for 12 months, while another group did not receive any injections. Researchers observed that D-aspartic acid-treated mice displayed lesser pain-associated behaviors such as protection of the injured hindlimb, compared to untreated mice, suggesting that D-aspartic acid has analgesic properties.

Effects of D-Aspartic Acid on Male Sexual Behavior

Sexual dysfunction can be caused by several factors. Evidence suggests that D-aspartic acid levels are strongly associated with the degree of sexual function.

Xia et al. investigated the relationship between D-aspartic acid levels and ejaculatory behavior of rats.[11] In this study, female rats were paired with male rats in a steel cage for copulation (30 minutes daily for 6 weeks). Copulation behavior such as ejaculation frequency (EF) was then recorded with a high-definition digital video processing system. Based on the EF values, the male rats were grouped as “rapid,” “normal,” or “sluggish” ejaculators. The male rats were then sacrificed in order to determine the brain levels of D-aspartic acid. Results of the study showed that D-aspartic acid levels were highest in rapid ejaculators, followed by normal ejaculators, and lowest in sluggish ejaculators, indicating that higher D-aspartic acid levels are associated with improved sexual performance.

In another study, Melis et al. reported that D-aspartic acid administration may help improve copulatory behavior in rats.[12] In this study, a group of male rats was injected with D-aspartic acid and another group of male rats was injected with Lactated Ringer’s solution (control). Each male rat was placed on a cage near an inaccessible female rat (also placed on a separate cage) in order to assess non-contact erections. After 40 minutes, both rats were placed in one cage to allow copulation and observe for the quality of penile erections. The male rats were then sacrificed in order to assess the brain levels of D-aspartic acid. Results showed that rats injected with D-aspartic acid displayed more potent erections during the pre- and copulatory period compared to rats treated with Lactated Ringer’s solution. In addition, their brain levels of D-aspartic acid were significantly higher compared to control.

In order to further determine the exact mechanism by which D-aspartic acid improves sexual behavior, the same researchers studied its effects on rats.[13] In this study, the rats were grouped into two:

  1. D-aspartic acid-treated rats
  2. Untreated rats

Both groups were then sacrificed and their brains were examined. Researchers observed that D-aspartic acid-treated rats had increased brain levels of nitric oxide (a substance that induces penile erection) compared to untreated rats. The researchers, therefore, concluded that the potent erections observed in D-aspartic acid-treated rats can be attributed to high D-aspartic acid levels.

Another mechanism by which D-aspartic acid influences sexual behavior in rats has been reported by D’aniello et al.[14] In this study, a group of rats was injected with D-aspartic acid and another group was not given any injections. The rats were then sacrificed in order to assess the blood levels of testosterone, a hormone that is known to play a major role in sexual arousal and penile erections. Data from the study showed that D-aspartic acid-treated rats have higher blood levels of testosterone compared to untreated rats. This result suggests that D-aspartic acid may help improve sexual behavior in rats by boosting testosterone levels.

Conclusion

The benefits of D-aspartic acid go beyond improving athletic performance and body composition. In mice and rats, this naturally-occurring amino acid can improve learning and memory as well as help correct cognitive impairment induced by sodium pentobarbital. It can also help treat schizophrenia-like behaviors by improving the startle response, causing dopamine neurons to build a protective uptake mechanism in the brain, and enhancing cortico–hippocampal brain network organization. Moreover, D-aspartic acid has analgesic properties that can help relieve pain associated with nerve injury. In addition, D-aspartic acid can also improve copulatory behavior by enhancing the quality of penile erections and ejaculation frequency via increased nitric oxide and testosterone production. These results suggest that D-aspartic acid can potentially be a therapeutic option for patients suffering from cognitive impairment, mental disorders, nerve pain, and sexual dysfunction.

References:

  1. Fisher GH, Petrucelli L, Gardner C, Emory C, Frey WH II, Amaducci L, Sorbi S, Sorrentino G, Borghi M, D’Aniello A (1994) Free Damino acids in human cerebrospinal fluid of Alzheimer’s, multiple sclerosis, and healthy control subjects. Mol Chem Neuropathol 23:115–124.
  2. D’Aniello A (2007) D-Aspartic acid, an endogenous amino acid with an important neuroendocrine role. Brain Res Rev 53:215–234.
  3. Topo E, Soricelli A, Di maio A, D’aniello E, Di fiore MM, D’aniello A. Evidence for the involvement of D-aspartic acid in learning and memory of rat. Amino Acids. 2010;38(5):1561-9.
  4. Palazzo E, Luongo L, Guida F, et al. D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice. Amino Acids. 2016;48(7):1553-67.
  5. Errico F, Rossi S, Napolitano F, et al. D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci. 2008;28(41):10404-14.
  6. Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?. Brain Res Bull. 2010;83(3-4):108-21.
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  11. Xia JD, Chen J, Yang BB, et al. Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior. Asian J Androl. 2018;20(4):355-359.
  12. Melis MR, Succu S, Mascia MS, Cortis L, Argiolas A. Extracellular excitatory amino acids increase in the paraventricular nucleus of male rats during sexual activity: main role of N-methyl-d-aspartic acid receptors in erectile function. Eur J Neurosci. 2004;19(9):2569-75.
  13. Melis MR, Succu S, Iannucci U, Argiolas A. N-methyl-D-aspartic acid-induced penile erection and yawning: role of hypothalamic paraventricular nitric oxide. Eur J Pharmacol. 1997;328(2-3):115-23.
  14. D’aniello A, Di cosmo A, Di cristo C, Annunziato L, Petrucelli L, Fisher G. Involvement of D-aspartic acid in the synthesis of testosterone in rat testes. Life Sci. 1996;59(2):97-104.
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