The Effects of Agmatine on Mice Behavior

Agmatine is a compound derived from the chemical arginine. This neurotransmitter (brain chemical) is found predominantly in nerve cells or neurons. Because it can exert modulatory actions directly and indirectly at multiple receptors in the body, agmatine may benefit a wide array of diseases, including depression, anxiety, schizophrenia, Alzheimer’s disease, cognitive impairment, nicotine withdrawal, and diabetes.

Effect of Agmatine on Age

Agmatine is being studied for its anti-aging effect. Researchers believe that it can counteract certain mechanisms associated with the aging process such as DNA damage, mitochondrial dysfunction, oxidative stress, and impaired stem cell replacement.

DNA damage in a variety of organisms has been proposed to be the primary cause of aging.^[1] This process interferes with cell repair and replication, which ultimately leads to loss of cell function and death. Evidence suggests that agmatine can slow the aging process through its DNA-protective effect. In a study by Wang et al., it was found that agmatine protects cultured rat brain cells from glucocorticoid-induced neurotoxicity by preventing programmed cell death (apoptosis),^[2] suggesting that it can prevent DNA damage and slow the aging process.

Mitochondria are organelles in the cells that help provides energy in order for the body to perform at optimum levels. Their function is vital and any dysfunction can lead to cell death and faster aging.^[3] A study by Arndt et al. found that agmatine protects mitochondrial function and confers resistance to cell death in rats.^[4] This suggests that agmatine may help prevent mitochondrial dysfunction, thereby slowing the aging process.

In another study, El-Awady et al. reported that agmatine administration helps combat oxidative stress in rats.^[5] Researchers observed that intravenous injections of agmatine in rats reduced the levels of oxidative stress, suggesting that it can help prevent cellular damage as well as slow the aging process.

Stem cells are very important for the renewal of cells in an organ. However, aging slows down cell division, resulting in impaired tissue regeneration and stem cell replacement. Interestingly, Li et al. found that agmatine treatment increases the number of stem cells in cultured rat brains, allowing improved cell renewal and tissue regeneration.^[6] This suggests that agmatine exerts its anti-aging effects by increasing the production of stem cells.

Antidepressant Effect of Agmatine

There is increasing evidence that agmatine may help treat depression. A study by Zomkowski et al. was the first one that described the antidepressant-like effects of agmatine in mice.^[7] In this study, the researchers used forced swim test (FST) and tail suspension test (TST) to determine the beneficial effects of agmatine on depression. Antidepressant-like effects were observed in mice injected with 0.01, 0.1, 1, 10 and 50 mg/kg of agmatine, as evidenced by a significant decrease in immobility time both in the forced swim test and tail suspension test.

A subsequent study published by Li et al. found that agmatine produced an antidepressant effect in mice and rats.^[8] Researchers found that oral agmatine supplementation in mice and rats produced an anti-immobility effect at doses of 40 and 80 mg/kg in both forced swim test and tail suspension test.

Anxiolytic Effect

Aside from its antidepressant effect, studies show that agmatine also has an anti-anxiety or anxiolytic effect. In one study, Gong et al. reported that agmatine exerts a significant anxiolytic effect in both rats and mice in a series of tests assessing anxiety.^[9] In the light-dark transition test (a test based on the natural dislike of mice to brightly illuminated areas), both oral and subcutaneous injection of agmatine significantly increased the number of light-dark transitions in mice, which is suggestive of anxiolytic effect.

Furthermore, both oral and subcutaneous agmatine administration in rats significantly increased the number of licks in the Vogel’s drinking conflict test. In this procedure, water-deprived rats are punished by mild electrical shocks whenever they drink, leading to an anxiety-like behavior. The reestablishment of drinking responses in rat subjects led researchers to the conclusion that agmatine has anxiolytic properties.

Finally, in the social interaction test, researchers observed that agmatine administration (10-40 mg/kg three times in 24 hours prior to the test) significantly increased the active social interaction of rats. This behavior suggests that agmatine has anxiolytic effects.

Effect on Learning and Memory

Evidence suggests that agmatine can help protect against learning and memory deficit. In one study, Aricioglu et al. found that agmatine prevents learning and memory deficit associated with morphine withdrawal.^[15] In this study, rats were divided into groups such as Control, Morphine, and Agmatine+Morphine. Researchers observed that agmatine-treated rats were more likely to escape from the large circular pool of water through a hidden platform in the maze compared to controls. This suggests that agmatine treatment prevented learning and memory deficits.

In another study, Rushaidhi et al. reported that agmatine injection significantly improves spatial working memory and object recognition memory in aged rats.^[16] Aged male Sprague-Dawley rats were injected with either saline or agmatine and were subjected to undergo an object recognition test. Researchers observed that agmatine-treated rats displayed increased exploratory activity compared to saline-treated rats, suggesting that the treatment was able to improve spatial working memory and object recognition memory.

Effect on Schizophrenia

Schizophrenia is a chronic and severe mental disorder characterized by impaired thinking skills, disorganized behavior, and loss of attachment to reality. There is increasing evidence that agmatine administration has beneficial effects on this mental condition.

A study by Unal et al. found that agmatine treatment improves cognitive deficits and increases socialization in rats with negative and cognitive symptoms of schizophrenia.^[10] In this study, researchers administered MK-801, a substance that is known to cause schizophrenia-like behaviors in rats. On day 14, rats received agmatine injections and others were grouped as the control. In order to assess the benefits of agmatine on schizophrenia-like behaviors, social interaction test and novel object recognition test were performed. Researchers observed that agmatine-treated rats displayed increased social interaction and time spent exploring new objects than the familiar objects, compared to the control group. These results suggest that agmatine treatment can improve cognitive deficits and increase socialization in rats with schizophrenia-like behaviors.

Effect on Diabetes

Diabetes can lead to nerve damage, which ultimately affects pain sensation. There is evidence that agmatine may help suppress increased sensitivity to pain caused by non-painful stimuli in diabetic rats.

A study by Courteix et al. investigated the effects of agmatine injection in diabetic rats with impaired pain sensation.^[11] In this study, agmatine-treated diabetic rats have undergone paw pressure test. This test involves an application of a uniformly increasing mechanical pressure on the animal paw, leading to an escape reaction. Researchers observed that the diabetic rat subjects treated with agmatine displayed an increased pain threshold, indicating that the treatment was able to suppress increased pain sensitivity associated with diabetes.

Effect on Alzheimer’s Disease

Alzheimer’s disease results in memory impairment and death of neurons in the brain.^[12] Evidence suggests that agmatine does have neuroprotective effects which can help improve cognitive decline associated with this disease.^[13]

A study by Song et al. found that agmatine improves cognitive dysfunction and prevents cell death in a streptozotocin-induced Alzheimer rat model.^[14] In this study, rats were given anesthesia followed by a single injection of streptozotocin to induce pathological and behavioral alterations similar to those observed in Alzheimer’s disease. Rats were then injected with agmatine (100 mg/kg) daily up to two weeks and others were grouped as the control. In order to assess the beneficial effects of agmatine, the Morris water maze was performed. Researchers observed that the agmatine-treated rats were more likely to escape from the large circular pool of water through a hidden platform in the maze compared to the control group. Furthermore, when the researchers examined the brains of the agmatine-treated rats using the Western blot test, they found that agmatine was able to suppress the accumulation of amyloid beta (the causative agent of Alzheimer’s disease).

Effects on the Behavioral Manifestations of Nicotine Withdrawal

Nicotine abstinence following chronic exposure can lead to memory and cognitive impairments, which can significantly impact the quality of life. Interestingly, studies show that agmatine does have beneficial effects on the symptoms of nicotine withdrawal.

A study by Kotagale et al. found that agmatine treatment prevents behavioral manifestations of nicotine withdrawal in mice.^[17] In this study, subjects experienced abrupt withdrawal of daily nicotine injections which led to a significant increase in withdrawal symptoms. Mice were then injected with agmatine and others were grouped as the control. Results of the study showed that repeated injections of agmatine led to decreased immobility in forced swim test and increased number of entries and time spent in open arm in elevated plus maze, compared to the control group. Of note, the agmatine-treated mice experienced lesser symptoms of nicotine withdrawal, including rearing, grooming, jumping, genital licking, leg licking, and head shakes, which is suggestive of antidepressant and anti-anxiety effect.

The same researchers also found that agmatine inhibits nicotine withdrawal-induced cognitive deficits in rats.^[18] In this study, rats received daily nicotine injections for 14 days and its abrupt withdrawal led to significant impairment in cognitive function. Rats were then injected with agmatine and were subjected to undergo inhibitory avoidance task. In this test, rats typically receive a single aversive footshock whenever they step from a lighted compartment into a darkened compartment. Researchers observed that agmatine-treated rats showed increased step. This result suggests that agmatine treatment attenuates nicotine withdrawal-induced memory impairment in rats.

Conclusion

Because agmatine can exert modulatory actions directly and indirectly at multiple receptors in the body, this compound can benefit a wide array of diseases. An overwhelming body of research suggests that agmatine exerts its anti-aging properties by fighting certain mechanisms associated with the aging process such as DNA damage, mitochondrial dysfunction, oxidative stress, and impaired stem cell replacement. Evidence also suggests that agmatine has potent antidepressant and anti-anxiety effect which can improve mood. Furthermore, agmatine has also beneficial effects on chronic medical conditions. In rats with schizophrenia-like behaviors, agmatine administration may help improve cognitive deficits and increase socialization. In diabetic rats with impaired pain sensation, agmatine administration improves nerve damage by suppressing increased pain sensitivity.

There is also evidence that agmatine may help prevent Alzheimer’s disease and improve its related cognitive deficits. In mice with Alzheimer’s disease, agmatine administration restores the levels of the insulin signal molecules in the brain, which in turn reduces the accumulation of brain amyloid beta proteins, which are known to cause Alzheimer’s disease. In rats with memory and learning deficits, agmatine improves spatial working memory and object recognition memory. Moreover, treatment with agmatine prevents behavioral manifestations of nicotine withdrawal in mice. With its anti-aging effect and benefits on mood, memory, and cognitive function, agmatine can be considered as a potential therapeutic option for patients with chronic, debilitating medical conditions such as depression, anxiety, schizophrenia, Alzheimer’s disease, nicotine withdrawal, and diabetes.

References

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