Neurotransmitters: The significance of balanced and optimized chemistry

Neurotransmitters: The significance of balanced and optimized chemistry

Highlights:

• Neurotransmitters influence many functions, like motor, cognitive, and sensory perceptions
• Aging negatively affects neurons functionality and neurotransmitters levels
• Diet, physical activity, social interaction, and learning impact neurotransmitters levels

Introduction

Neurotransmitters are chemical substances that facilitate communication between nerves throughout the body. Signals are transferred between neurons when neurotransmitters are released from the presynaptic part of one nerve to the postsynaptic part. After performing their actions, neurotransmitters usually undergo degradation and removal. Examples of neurotransmitters include dopamine, serotonin, glutamate, glycine, and others. Their balance plays an intricate role in mental and physical health, as changes in their level could result in several conditions, like Alzheimer's disease (AD), schizophrenia, depression, and Parkinson’s disease (PD). Several factors influence the levels of neurotransmitters, including diet, physical activity, age, genetics, and diseases.      

Image 1

Glutamate: The most abundant neurotransmitter

Glutamate is the main excitatory neurotransmitter in the brain (1). Excitatory neurotransmitters have a stimulating effect on the neuron. In other words, when they are released from the presynaptic part of the nerve, they activate the following part (neuron, muscle, or gland), propagating the signal or “message”. Glutamate is not only the main excitatory neurotransmitter but also the most abundant of all the chemical messengers in the central nervous system (CNS) (2). In the CNS, glutamate receptors are present on over 90% of neurons and 40% of synapses (junctions that facilitate the transmission of signals from one nerve to another or from a neuron to a gland or muscle). This neurotransmitter is involved in learning, memory formation and storage, and synaptic health (3).

Glutamate is synthesized from glutamine, which is the most abundant amino acid found in the body (1). This synthesis process takes place with the help of an enzyme called glutaminase, present in the presynaptic nerves (1, 2). Maintaining proper glutamate homeostasis (balance) is important for healthy brain aging and reducing the risk of neurological disorders like epilepsy, PD, AD, and others (2).

The literature indicates that the aging brain is vulnerable to excitotoxicity (a condition that results from abnormal prolonged receptor activation) (3). Therefore, a malfunction in the glutamatergic system could render the nervous system vulnerable. Clinical studies have revealed that aging causes a drop in glutamate levels across several brain areas involved in motor and sensory functions. For example, evidence from studies shows that glutamatergic neurons and their metabolic activity decrease in cerebral lobes (there are four lobes that have various functions, like cognition, memory, and stimuli processing) and cerebellum (controls and coordinates motor skills) in healthy elderly individuals (3). This was confirmed in a recent meta-analysis, which found that glutamate concentrations were lower in older individuals than in younger adults (4). Also, aging was found to negatively influence the glutamatergic neuron size, dendritic branches, axon length, and glutamate neurotransmission.

Serotonin: A versatile neurotransmitter

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter involved in various physiological, emotional, and cognitive functions (5). It is synthesized from tryptophan, an essential amino acid (it cannot be synthesized by the body and needs to be obtained from external sources) (6). This neurotransmitter is involved in behavior, mood, and memory regulation. The disturbances in its levels have been associated with neurological and psychiatric disorders. For example, research indicates that low tryptophan plasma levels negatively affect serotonin levels, causing depression (6).

There are at least 14 serotonin receptor types and subtypes (5-HT_1A-F, 5-HT_2A-C, 5-HT₃, 5-HT₄, 5-HT_{5A, B}, 5-HT₆, 5-HT₇) across various brain and body regions, explaining its multiple actions (5). Some of these receptors have inhibitory activities, while others are excitatory. For example, the inhibitory receptor 5-HT_1A has been linked to modulating the sleep-wake cycle, anxiety, and long-term memory (5). On the other hand, the excitatory 5-HT_2A receptor has been shown to modulate short and long-term memory.

Research across the past several decades has shown that the number of 5-HT targets declines with age, including healthy aging (5, 7). This effect was found to be moderate on the 5-HT_1A receptors and large on 5-HT_2A receptors. The age-driven loss of 5-HT neurons and neurotransmitter activity could partially explain the behavioral changes commonly seen in elderly individuals, such as sleep, sexual, and mood alterations (7, 8).

The impact of serotonin extends beyond the brain to the gastrointestinal tract (GIT) (8). Aging has been found to affect various parts of the GIT, and its functions, such as motility, fluids secretion, and general health. Serotonin, through its receptors, has been found to play a role in many of these functions (8). Therefore, factors that affect 5-HT levels likely negatively influence many of the said functions.

Another bodily system where serotonin plays a significant role is the cardiovascular (CV) system. In this context, evidence indicates that excessive serotonin levels are associated with CV diseases, like stroke and heart failure (8). The risk of these diseases has been found to increase with age.

The catecholamine system: Adrenaline, noradrenaline, and dopamine

Catecholamines (CAs) are biogenic amines that act as neurotransmitters in the nervous system and as hormones in the endocrine system. There are three catecholamines, including adrenaline (also called epinephrine), noradrenaline (also called norepinephrine), and dopamine (9). They are slow-acting neurotransmitters that support the function of fast-acting neurotransmitters, like glutamate. They are synthesized from L-tyrosine, a non-essential amino acid (9). Despite having closely related structures, their distribution across the nervous system and their functions vary.

CAs regulate various functions in the body, like motor skills, emotions, fight or flight response, heart rate, blood pressure, and many others (9, 10). Also, disturbance in their levels has been associated with conditions like PD, depression, and schizophrenia (9). Several studies have highlighted the links between CAs imbalance and AD. A meta-analysis by Pan et al. recently confirmed that reduced dopamine and noradrenaline levels were associated with AD (11). Additional literature mentions that dopamine levels decrease by 5-10% per decade across adulthood, affecting cognitive abilities (12, 13).

Image 2

GABA: The main inhibitory neurotransmitter

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain (14). Inhibitory neurotransmitters work by decreasing the likelihood of neuron activation. It is synthesized from glutamate via the action of glutamate decarboxylase enzyme, which uses vitamin B6 as a cofactor (14). GABA is involved in many functions, like voluntary movement, maintenance of respiratory rate, fine-tuning motor skills, and cognitive functioning (14, 15).

With age, GABA concentration decreases in frontal and parietal brain regions (16). These regions are involved in movement, higher executive functions (memory, thinking, and self-control), language processing, and sensory perception, among others. The outcome of aging is compromised motor and cognitive functions (15). Examples of conditions resulting from disturbed GABA levels include depression, anxiety, and AD.

Acetylcholine: The cholinergic neurotransmitter

Acetylcholine (Ach) is one of the earliest identified neurotransmitters (17). Cholinergic (a neuron that uses Ach to send signals) neuron fibers are present in the central and peripheral nervous systems (18). Ach controls many functions, ranging from motor skills, heart rate, blood pressure, and other processes in the respiratory and GIT systems.

Research indicates that Ach system dysfunction is a feature of the aging process. Also, Ach dysfunction is observed in mild cognitive impairment and AD (19). This is likely attributed to reduced cholinergic receptor density or binding affinity. Similarly, the literature suggests that reduced nicotinic Ach receptors (a type of receptors that respond to Ach and the tobacco alkaloid nicotine) play a significant role in developing age-related neurodegenerative disorders (20).  

How to optimize neurotransmitters?  

Exercise is one of the most widely investigated approaches that promote brain function and health. The literature suggests that routine physical activity regulates neurotransmitters levels in the brain and influences its function (21, 22). For example, the literature indicates that exercise improves dopamine and noradrenaline levels, reflected through better memory performance (21). However, preclinical evidence suggests that continuous strenuous physical exercise could have opposite effects.

Diet has also been suggested as an important tool to optimize neurotransmitters (23). The value of diet and nutritional supplements is important because many neurotransmitter precursors are derived from everyday diet components. For example, glutamine is an amino acid that acts as a precursor of glutamate (1). The latter also acts as a precursor for GABA synthesis. The average daily intake of glutamine from dietary protein sources is about 3-6 grams, given that the daily intake is 0.8–1.6 g/kg bm for a 70-kg individual (24). Food containing glutamine includes seafood, dairy products, nuts, meat, and eggs (25). Tryptophan is the amino acid precursor of serotonin. The recommended daily allowance of this amino acid to maintain neurotransmitter levels and sustain bodily functions is 3.5 to 6 mg/kg of body weight (26). Examples of food types containing tryptophan include turkey, oats, tuna, banana, cheese, and chocolate.

Supplements also provide means to optimize neurotransmitters levels. For example, glutamine is supplied as a powder, tablet, or capsule containing 250mg up to 1000mg (24). Tryptophan is another neurotransmitter precursor that is available as a supplement. A meta-analysis by Kikuchi et al. that assessed studies in which healthy individuals received 0.14-3 grams of tryptophan found that it improved mood quality (27). However, it highlighted the need for further research to identify the optimal dose.

In addition to the above, social interaction has been shown to influence brain health and neurotransmitters. For example, research has suggested that higher serotonin levels could possibly promote more constructive social interaction with other individuals (28). The latter effect is attributed to the impact of serotonin on individuals’ general mood.

Another way to optimize neurotransmitter health is to engage in learning activities. This is important because evidence suggests that individuals with conditions like attention deficit hyperactivity disorder (ADHD) have been found to have low levels of dopamine (29). ADHD individuals have a short attention span, greater impulsiveness, and responsiveness to external stimuli.  

Image 3

Tips: What to suggest to your clients

There is a lot of information that has been suggested above. Putting this information into action could potentially help your clients balance and optimize their neurotransmitters.

• Highlight the importance of neurotransmitters to the overall physical and mental health.
• Discuss the value of daily physical activity to reduce the age-associated decline in neurotransmitters levels. However, suggest avoiding continuous strenuous exercise, as it could produce opposite effects.
• Discuss the importance of maintaining social interaction with others, as it helps the brain and neurotransmitters.
• Suggest engaging in learning activities, as they promote neuronal health and improve neurotransmitter function.
• Suggest genetic tests to detect disorders associated with neurotransmitter metabolism, receptors, and transporters.

Collective neurotransmitter’s experience

Neurotransmitters play an important role in various functions, including cognitive and motor skills and neuroplasticity. The latter term encompasses the brain’s capacity to modify and adapt its structure and function in response to experiences. Most of the abovementioned neurotransmitters are affected by age, causing outcomes linked to an increased risk of developing age-related changes. The same changes pave the road to diseases like AD and PD. Fortunately, lifestyle modification could optimize the levels of neurotransmitters and slow down the impact of aging on them. Pharmacological options that work on various neurotransmitters exist today, helping treat many conditions, like PD.

References

1.            Marsman A, Mandl RCW, van den Heuvel MP, Boer VO, Wijnen JP, Klomp DWJ, et al. Glutamate changes in healthy young adulthood. European Neuropsychopharmacology. 2013;23(11):1484-90.

2.            Cox MF, Hascup ER, Bartke A, Hascup KN. Friend or Foe? Defining the Role of Glutamate in Aging and Alzheimer’s Disease. Frontiers in Aging. 2022;3.

3.            Gasiorowska A, Wydrych M, Drapich P, Zadrozny M, Steczkowska M, Niewiadomski W, et al. The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain. Frontiers in Aging Neuroscience. 2021;13.

4.            Roalf DR, Sydnor VJ, Woods M, Wolk DA, Scott JC, Reddy R, et al. A quantitative meta-analysis of brain glutamate metabolites in aging. Neurobiol Aging. 2020;95:240-9.

5.            Karrer TM, McLaughlin CL, Guaglianone CP, Samanez-Larkin GR. Reduced serotonin receptors and transporters in normal aging adults: a meta-analysis of PET and SPECT imaging studies. Neurobiol Aging. 2019;80:1-10.

6.            Bamalan OA, Al Khalili Y. Physiology, serotonin. 2019.

7.            Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY, et al. Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging. Neuropsychopharmacology. 1998;18(6):407-30.

8.            Fidalgo S, Ivanov DK, Wood SH. Serotonin: from top to bottom. Biogerontology. 2013;14(1):21-45.

9.            Nagatsu T. The catecholamine system in health and disease -Relation to tyrosine 3-monooxygenase and other catecholamine-synthesizing enzymes. Proc Jpn Acad Ser B Phys Biol Sci. 2007;82(10):388-415.

10.          Amano A, Tsunoda M, Aigaki T, Maruyama N, Ishigami A. Age-related changes of dopamine, noradrenaline and adrenaline in adrenal glands of mice. Geriatrics & Gerontology International. 2013;13(2):490-6.

11.          Pan X, Kaminga AC, Jia P, Wen SW, Acheampong K, Liu A. Catecholamines in Alzheimer's Disease: A Systematic Review and Meta-Analysis. Frontiers in Aging Neuroscience. 2020;12.

12.          Karrer TM, Josef AK, Mata R, Morris ED, Samanez-Larkin GR. Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis. Neurobiol Aging. 2017;57:36-46.

13.          Berry AS, Shah VD, Baker SL, Vogel JW, O'Neil JP, Janabi M, et al. Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility. J Neurosci. 2016;36(50):12559-69.

14.          Jewett BE, Sharma S. Physiology, GABA. 2018.

15.          Cuypers K, Maes C, Swinnen SP. Aging and GABA. Aging (Albany NY). 2018;10(6):1186-7.

16.          Hermans L, Leunissen I, Maes C, Verstrawelen S, Cuypers K, Edden RA, et al., editors. The aging brain and changes in GABA concentrations2017.

17.          Brown DA. Acetylcholine and cholinergic receptors. Brain Neurosci Adv. 2019;3:2398212818820506.

18.          Sam C, Bordoni B. Physiology, Acetylcholine.  StatPearls [Internet]: StatPearls Publishing; 2022.

19.          Sultzer DL, Lim AC, Gordon HL, Yarns BC, Melrose RJ. Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia. Alzheimer's Research & Therapy. 2022;14(1):25.

20.          Utkin YN. Aging affects nicotinic acetylcholine receptors in brain. Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents). 2019;19(2):119-24.

21.          Lin TW, Kuo YM. Exercise benefits brain function: the monoamine connection. Brain Sci. 2013;3(1):39-53.

22.          Meeusen R, De Meirleir K. Exercise and brain neurotransmission. Sports Med. 1995;20(3):160-88.

23.          Briguglio M, Dell'Osso B, Panzica G, Malgaroli A, Banfi G, Zanaboni Dina C, et al. Dietary Neurotransmitters: A Narrative Review on Current Knowledge. Nutrients. 2018;10(5).

24.          Gleeson M. Dosing and Efficacy of Glutamine Supplementation in Human Exercise and Sport Training. The Journal of Nutrition. 2008;138(10):2045S-9S.

25.          Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients. 2018;10(11).

26.          Richard DM, Dawes MA, Mathias CW, Acheson A, Hill-Kapturczak N, Dougherty DM. L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. Int J Tryptophan Res. 2009;2:45-60.

27.          Kikuchi AM, Tanabe A, Iwahori Y. A systematic review of the effect of L-tryptophan supplementation on mood and emotional functioning. J Diet Suppl. 2021;18(3):316-33.

28.          Young SN, Leyton M. The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav. 2002;71(4):857-65.

29.          Gold MS, Blum K, Oscar-Berman M, Braverman ER. Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children? Postgrad Med. 2014;126(1):153-77.

‍