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Anxiety-Inducing Neurotransmitters

  • 7 min read

The whole world is getting more anxious by the day. According to recent statistics, up 33.7% of people will be affected by an anxiety disorder during their lifetime [2] and there are currently 264 million people impacted globally [3].  

In 2019, the percentage of patients taking anti-anxiety medication was around 10% in females over 45, and around 5% in males, according to Statista.com. And since the pandemic, these rates have skyrocketed. Currently there are 50 million Americans taking mental health medications. This was an increase in 20% in just one year, from 2020 to 2021 according to theCDC

In today’s article, we will take a look at the different neurotransmitters are involved in the anxiety response.

But first…    

What is Anxiety? 

Anxiety is a powerful and frequent negative emotional state that is most often associated with feelings of worry and apprehension [1]. It is closely related to fear, which is our usual response to perceived or real threats – the ‘fight or flight’ response – but involves some expectation of future harm or insult.  

Anxiety is a very normal human emotional response, yet it can become excessive or chronic under certain conditions and wreak havoc on your physiology. Evidence from neuroscience seems to suggest that these ‘anxiety disorders’ arise from a dysfunction in the brain circuits responsible for how we emotionally respond to threatening situations [1].  

Consequences of Chronic Anxiety 

When chronic, anxiety can cause a range of biological and psychosocial issues, mostly likely due to chronic sympathetic activation. For example, the presence of anxiety disorders such as post-traumatic stress disorder, panic disorder and/or social phobia can reduce health-related quality of life, and result in more sick days from work [4].  

Anxiety can result in problems with family relationships and impaired physical and cognitive functioning. In adolescents, anxiety seems to worsen these psychosocial outcomes by the age of 30 [5].   

So what neurotransmitters are involved?  

GABA 

In both normal and disordered anxiety, the neurotransmitter GABA (γ-aminobutyric acid) plays a key role in the anxiety response, especially in the brain circuits of the amygdala [1]. The amygdala is a region of the brain that forms the core of a processing network that deals with fearful and threatening stimuli, and activates fear-related behavior [2].  It is located in the medial temporal lobe, just anterior to (in front of) the hippocampus. 

Research in several animal species has shown that when GABA is infused into the amygdala, measures of fear and anxiety decrease. Conversely, when GABA antagonists are infused, it brings about the opposite effect [1,3]. 

GABA has been associated with anxiety for a long time, and the drugs used to target disordered anxiety, such as benzodiazepines, are geared towards this neurotransmitter system [1]. Human studies show that when benzodiazepines are provided, the activation of the amygdala in the presence of negative emotional stimuli is reduced [4].  There are supplements that directly increase the amount of GABA in the brain or increaseGABA activity…but be careful, oral GABA does not cross the blood brain barrier. Seethis blog for more details on the GABA in the brain. 

Serotonin 

Serotonin, or 5-hydroxytryptamine (5-HT), plays an essential role in the regulation of our emotions.  

It is involved in a wide range of neurological activities and modulates virtually all human behavioral processes, to the degree that drugs targeting serotonin receptors are used extensively in the psychiatry and neurology disciplines [5]. It is the use of these drugs that have revealed a key role for this neurotransmitter in anxiety settings [6]. 

Research in mice shows that serotonin from the dorsal raphe nucleus (located on the midline of the brainstem) actuallyenhances fear and anxiety [7]. This at least partly explains why early adverse events may occur when selective serotonin reuptake inhibitors (SSRIs) – drugs that block the reuptake of serotonin into the synapse – are provided to some patients with anxiety disorders. Reduced serotonin transporter availability in the thalamus is associated with high anxiety in a study of patients with major depression [8], further underlining the importance of this neurotransmitter although there is now recent evidence that there serotonin by and large isnot depleted in most patients with depression. 

Dopamine 

Alongside the amygdala, baseline and stress-induced anxiety states are also governed by other brain regions, such as the prefrontal cortex and hippocampus [9]. Each of these regions is influenced by signals from dopamine-rich areas of the midbrain that help shape anxiety-like behavior [10].  

Dopamine is a neurotransmitter that plays a central role in reward behavior, sleep, mood, attention, learning, and pain processing, to name a few [11]. In the ventral mibrain, dopamine neurons innervate several limbic structures that are implicated in how we process emotions [12].  

Some evidence has revealed that the mesolimbic, mesocortical, and nigrostriatal dopaminergic systems are all involved in anxiety, and underpinned by dopamine D1 and D2 receptor mechanisms [13]. The activity of the dopaminergic system is also influenced by other neurotransmitters discussed in this article (notably GABA and glutamate) in the medial prefrontal cortex and nucleus accumbens, respectively.  

Evidence seems to suggest that for social anxiety in particular, dopaminergic brain circuitry might underpin these often challenging symptoms [14].  

Norepinephrine 

Norepinephrine, also known as noradrenaline, is a neurotransmitter and hormone involved in the ‘fight or flight’ response (i.e. oh sh*t there is a bear!). It modulates the activity of brain regions relevant to anxiety, such as the amygdala, and anxiety states are associated with the release of noradrenaline into the bloodstream and cerebrospinal fluid [15].  

From a functional standpoint, norepinephrine is involved in a range of processes, including arousal, cognition, learning and sleep regulation, as well as the regulation of the stress response [16].   

Given the relationship between the serotonin and noradrenaline systems, so-called ‘dual-reuptake inhibitors’ such as venlafaxine, milnacipran, and duloxetine were developed and may have an advantage over SSRIs in the treatment of certain anxiety disorders, such as post-traumatic stress disorder [15]. 

Can Anxiety be a good thing? 

There is no doubt that some anxiety is can be improve motivation, focus, and even heighten senses. These benefits are directly related to the neurotransmitters above, especially dopamine and norepinephrine. But when anxiety becomes constant--and these neurotransmitters are continuous released--these same neurotransmitters can lead to pathology that runs the gamut from mental health disorders (anxiety, obviously but also depression, violence and more), to heart attacks, hypertension, strokes, and other physical ailments. So too much of a helpful thing isn’t so helpful after all. Just like bananas. Or Christmas.  

Tro Calm

At Troscriptions, we developed Tro Calm for those of us (i.e. all of us) who have times of stress and anxiousness where calming down on demand is vital. It is formulated with N-Nicotinoyl GABA and Kava Kava that both enhance the GABA system as wells CBD and CBG which modulate your endocannabinoid system to calm you down too. Like all of our buccal troches, it is titratable so you can find your optimal dose. On average, ¼ troche will take the edge off without letting you lose your focus or concentration (i.e. perform better when you’re less anxious!). ½ troche will relax you and you’ll be less focused and ¾ to 1 full troche for deeper relaxation and deeper sleep.  


Try Tro Calm today and save 10% on your order using code CALM10 

References 

[1]        P. Nuss, Anxiety disorders and GABA neurotransmission: a disturbance of modulation, Neuropsychiatr Dis Treat. 11 (2015) 165–175.https://doi.org/10.2147/NDT.S58841

[2]        M.G. Baxter, P.L. Croxson, Facing the role of the amygdala in emotional information processing, Proc. Natl. Acad. Sci. U.S.A. 109 (2012) 21180–21181.https://doi.org/10.1073/pnas.1219167110

[3]        C.A. Barbalho, R.L. Nunes-de-Souza, A. Canto-de-Souza, Similar anxiolytic-like effects following intra-amygdala infusions of benzodiazepine receptor agonist and antagonist: Evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus-maze test, Brain Research. 1267 (2009) 65–76.https://doi.org/10.1016/j.brainres.2009.02.042

[4]        M.P. Paulus, J.S. Feinstein, G. Castillo, A.N. Simmons, M.B. Stein, Dose-Dependent Decrease of Activation in Bilateral Amygdala and Insula by Lorazepam During Emotion Processing, Arch Gen Psychiatry. 62 (2005) 282.https://doi.org/10.1001/archpsyc.62.3.282

[5]        M. Berger, J.A. Gray, B.L. Roth, The Expanded Biology of Serotonin, Annu. Rev. Med. 60 (2009) 355–366.https://doi.org/10.1146/annurev.med.60.042307.110802

[6]        J.A. Gordon, R. Hen, The Serotonergic System and Anxiety, NMM. 5 (2004) 027–040.https://doi.org/10.1385/NMM:5:1:027

[7]        C.A. Marcinkiewcz, C.M. Mazzone, G. D’Agostino, L.R. Halladay, J.A. Hardaway, J.F. DiBerto, M. Navarro, N. Burnham, C. Cristiano, C.E. Dorrier, G.J. Tipton, C. Ramakrishnan, T. Kozicz, K. Deisseroth, T.E. Thiele, Z.A. McElligott, A. Holmes, L.K. Heisler, T.L. Kash, Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala, Nature. 537 (2016) 97–101.https://doi.org/10.1038/nature19318

[8]        M. Reimold, A. Batra, A. Knobel, M.N. Smolka, A. Zimmer, K. Mann, C. Solbach, G. Reischl, F. Schwärzler, G. Gründer, H.-J. Machulla, R. Bares, A. Heinz, Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study, Mol Psychiatry. 13 (2008) 606–613, 557.https://doi.org/10.1038/sj.mp.4002149

[9]        G.G. Calhoon, K.M. Tye, Resolving the neural circuits of anxiety, Nat Neurosci. 18 (2015) 1394–1404.https://doi.org/10.1038/nn.4101

[10]      S.R. DeGroot, R. Zhao-Shea, L. Chung, P.M. Klenowski, F. Sun, S. Molas, P.D. Gardner, Y. Li, A.R. Tapper, Midbrain Dopamine Controls Anxiety-like Behavior by Engaging Unique Interpeduncular Nucleus Microcircuitry, Biological Psychiatry. 88 (2020) 855–866.https://doi.org/10.1016/j.biopsych.2020.06.018

[11]      G. Ayano, Dopamine: Receptors, Functions, Synthesis, Pathways, Locations and Mental Disorders: Review of Literatures, J Ment Disord Treat. 2 (2016).https://doi.org/10.4172/2471-271X.1000120

[12]      L.S. Zweifel, J.P. Fadok, E. Argilli, M.G. Garelick, G.L. Jones, T.M.K. Dickerson, J.M. Allen, S.J.Y. Mizumori, A. Bonci, R.D. Palmiter, Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety, Nat Neurosci. 14 (2011) 620–626.https://doi.org/10.1038/nn.2808

[13]      M.-R. Zarrindast, F. Khakpai, The Modulatory Role of Dopamine in Anxiety-like Behavior, Arch Iran Med. 18 (2015) 591–603.https://doi.org/0151809/AIM.009

[14]      T. Lawn, O. Dipasquale, A. Vamvakas, I. Tsougos, M.A. Mehta, M.A. Howard, Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD, Psychopharmacology (Berl). (2022).https://doi.org/10.1007/s00213-022-06117-5

[15]      D.S. Baldwin, Serotonin noradrenaline reuptake inhibitors: A new generation of treatment for anxiety disorders, International Journal of Psychiatry in Clinical Practice. 10 (2006) 12–15.https://doi.org/10.1080/13651500600637056

[16]      N. Brunello, P. Blier, L.L. Judd, J. Mendlewicz, C.J. Nelson, D. Souery, J. Zohar, G. Racagni, Noradrenaline in mood and anxiety disorders: basic and clinical studies:, International Clinical Psychopharmacology. 18 (2003) 191–202.https://doi.org/10.1097/00004850-200307000-00001

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