Motivation and emotion/Book/2015/Norepinephrine and emotional disorders

Overview
The complexity of the central nervous system has perplexed the scientific mind since time immemorial. It is only in recent years that science has progressed in explaining the operative processes of neuroanatomy, but this remains at the basic level. This advancement transpired through a redirection of analysis, which began at the structural level in the early second millennia, and then advanced to the cellular and molecular level in the 20th century. It was at this point that the break down of how the central nervous system operated became more apparent. The advancements in neurophysiology then expanded into other domains including that of emotion, especially as neural communication turned out to be a key factor in the development of emotional disorders. This book chapter therefore explores the relationship between the neurotransmitter norepinephrine and emotional disorders, and provides a practical guide into how one can improve emotional wellbeing.

Neurotransmitters


Neurotransmitters are endogenous chemicals that act on both the central and peripheral nervous systems by transmitting chemical signals across the synaptic cleft from one neuron to the next (Hardie, 1991). This allows for a directional, bidirectional, or omnidirectional flow of communication as they relay information to and from every structure within the body. Over 50 neurotransmitters have been identified with differing functionality, and as such, are not always referred to as neurotransmitters (Hardie, 1991). Neuromodulators, neurohormones, neurotoxins, and neurotrophic factors are other used terms, however because they all cause some effect on a neuron it can be justified to categorise them under the term neurotransmitter (Elden, 2001).

Among the variation of neurotransmitter function, the central nervous system prominently operates under two classifications (Banich & Compton, 2010). The first, in what is known as an excitatory synaptic transmission, occurs when a presynaptic neuron releases an excitatory neurotransmitter, such as glutamate, that then acts on the postsynaptic neuron and excites an action potential (Banich & Compton, 2010). In essence, this allows the continuation of neuronal communication. By contrast, the second class, in what is known as inhibitory synaptic transmission, occurs when the presynaptic neuron releases an inhibitory neurotransmitter, such as gamma-aminobutyric acid (GABA), that inhibits the postsynaptic neuron from firing an action potential (Golan, 2008). This essentially discontinues neuronal communication or triggers a selective outward current. In short, excitatory neurotransmitters are responsible for an array of normal cognitive function such as memory and attention, as well as bodily processes such as motor activity and increasing the heart rate, whilst inhibitory neurotransmitters regulate sleep, hormone secretion, and mood, as well as having counter effects to excitatory transmissions. (Springer, 2014; Res, 1992).

Norepinephrine


Norepinephrine is an abundant and essential excitatory neurotransmitter that plays multiple roles within the body including that of a functioning hormone (Plowman & Smith, 2007). Norepinephrine is synthesised within the axon and synaptic vesicle of a neuron from the enzyme dopamine-b-hydroxylase, which converts the precursor dopamine into norepinephrine (Nieuwenhuis, Rover, Wildenberg, & Colzato, 2013). Once synthesised, a nerves action potential (as above, the change in a neurons electrical charge that excites communicational action) triggers the release of norepinephrine into the synaptic cleft where it acts on adrenergic receptors that depolarise the postsynaptic cell (Lemke & Williams, 2012). This is most prominent within the sympathetic nervous system (which is responsible for the physiological reaction to threatening stimuli) by accelerating the heart rate, dilating the pupils, dilating essential vesicles, and diverting the flow of blood to skeletal muscle, whilst constricting non-essential vesicles (Goldberg, 2009). As a hormone, norepinephrine is synthesised and secreted by the adrenal medulla in response to threatening stimuli or physiological stress (Brannon & Feist, 2009). In addition, both the hormone and neurotransmitter affect both the cortical and sub-cortical areas of the brain, such as the frontal cortex, amygdala, and hypothalamus that capture attention and control response in such situations (Tanaka, Yoshida, Emoto, & Ishii, 2000).

Anxiety


As norepinephrine is intrinsically involved in the stress response system, norepinephrine disruption or dysregulation has consequently been linked to the pathogenesis of emotional disorders such as anxiety (Goddard et al., 2010). Indeed, Goldstein (1981) found that elevated levels of norepinephrine at rest was directly associated with increased sympathetic activity, anxiety and hypertension. The role that norepinephrine plays in anxiety however may not be exclusive with common findings throughout the literature suggesting that norepinephrine acts in congruence with the neurotransmitter serotonin (Ressier & Nemeroff, 2000; Koob, 1999). Collective data indicates that increased norepinephrine transmission, in combination with decreased serotonin transmission, mediate anxious symptomatology (Ressier & Nemeroff, 2000; Koob, 1999; Strawn et al., 2015). As the noradrenergic (norepinephrine) and serotonergic (serotonin) systems modulate cortical and sub-cortical areas of the brain, abnormalities in these systems can instigate functional alteration of the ventral pons, medulla, locus coeruleus, hypothalamus, prefrontal cortex, amygdala, and hippocampus (Dell'Osso, Buoli, Baldwin, & Altamura, 2010). The net result is an individual contribution of not only anxiety, but also fear related emotion, as each structure has physiological propensities to such feelings and emotion (Dell'Osso, Buoli, Baldwin, & Altamura, 2010). Consequentially, a range of anxiety disorders can manifest such as generalised anxiety disorder, phobias, obsessive-compulsive disorder, and panic disorder (Ven et al., 2014).



Research in recent years has suggested that one of the root causes to norepinephrine dysregulation may be associated with the norepinephrine transporter gene (Buttenschon et al., 2011). The norepinephrine transporter is responsible for the re-uptake of norepinephrine from the synaptic cleft into presynaptic terminals and, in addition, regulates norepinephrine homeostasis (norepinephrine equilibrium) (Buttenschon et al., 2011). Abnormalities in this process may lead to a homeostatic imbalance resulting in anxious symptomatology. It was theorised that the gene responsible for norepinephrine dysregulation was the norepinephrine transporter gene, which had been subjected to alteration through either genetic inheritance or chemical influence (Buttenschon et al., 2011). Yet, Lee et al. (2005) investigated similar constructs to Buttenschon et al. and no found no association between the norepinephrine transporter gene and anxiety. However Lee et al. also examined the norepinephrine transporter gene in specific relation to agoraphobia, in which the researchers concluded that, although no significant association was found, the development of agoraphobia may still be possible, and therefore warrants further investigation in larger samples.

Depression


The physiological difference between depression and anxiety is difficult to distinguish as depression and anxiety share overlapping origins when the cause relates to norepinephrine dysregulation (Ressier & Nemeroff, 2000). For instance, disturbances in serotonin and norepinephrine transmission within the central nervous system, including the frontal cortex, hypothalamus, amygdala and hippocampus, can lead to depressive symptoms (Moret & Briley, 2011). These cortical and subcortical areas of the brain are some of the structures that comprise of the limbic system, which is involved in learning, memory, behaviour, motivation, and most pertinent to depression, emotion (Ono, 2008). Moret and Briley (2011) explain that there are several lines of evidence to suggest norepinephrine’s importance in the pathophysiology of depression. First, irregularities of the noradrenergic receptors are evident in people who have attempted suicide, and seem to be one of the central causes to depressive symptoms (as also discussed in relation to anxiety). Second, depletion of norepinephrine through experimental procedures results in the return of depressive symptoms. Third, the specific increase of norepinephrine through chemical influence decreases or entirely eradicates depressive symptoms. Last, genetic experiments that enhance norepinephrine function in rodents demonstrate that these rodents have more resistance against depression-like behaviours.



By and large, these findings indicate that norepinephrine plays a crucial role in depression. However, Leonard (2001) explains that these studies only describe the outcomes of norepinephrine dysregulation and clarification in the exact nature of norepinephrine dysfunction in depressive symptoms is required. Leonard argues that depression may be caused by a biochemical legion (a biochemical change) that may specifically relate to (1) a presynaptic decrease in neurotransmitter production or release (2) impaired adrenoreceptor response on the postsynaptic neuron, or (3) abnormal postsynaptic messenger activity. Leonard suggests that genetic abnormalities may be the developmental cause of a biochemical legion and future research may need to be directed or emphasised at such a possibility.

As with anxiety, genetic abnormality has therefore become one of the theoretical focal points that claim genetics as the fundamental predictor in norepinephrine dysregulation and depression (Ryu et al., 2004; Baffa et al., 2010). Ryu et al. (2004) sampled 112 patients with major depression and compared them with 136 healthy control participants. The norepinephrine transporter gene was analysed in relation to depressive symptoms in which a significant association was found. In other words, abnormalities within the norepinephrine transporter gene were suggested to be the cause of major depression (Ryu et al., 2004). Min, Ma, Li, Zhang, and Sun (2009) also found significant differences between the experimental and control group but in specific relation to the susceptibility and onset of depression. Min et al. therefore concluded that alteration or dysfunction of the norepinephrine transporter gene increased susceptibility to depressive symptoms. Likewise with anxiety, however, numerous other researchers have failed to find any associational cause between variables (Buttenschøn, et al., 2013; Hadley, et al., 1995). Chang, et al. (2007) for instance concluded the opposite to Min et al. (2009) when no relationship was found between the norepinephrine transporter gene and depression susceptibility. Evidently, substantial controversy surrounds the genetic responsibility of norepinephrine dysregulation in anxiety and depression and therefore no definitive conclusions can be drawn. As genetic malfunction is one of the only theories that attempt to explain this underlying relationship, the origins of norepinephrine dysregulation in depression and anxiety therefore remain somewhat undetermined.

Pharmacological Treatment
Despite the uncertain origins, there is some understanding in the processes of norepinephrine dysfunction within neuroanatomy, and as such, there are a number of treatment options available.



Benzodiazepines
People with excessive anxiety most commonly seek relief through medication, as medications are the fastest and most convenient method. The most common anxiolytic drugs available are benzodiazepines, which are a class of agents that act on the central nervous system (Fava, Balon, & Rickels, 2015). Several studies indicate that benzodiazepines reduce the norepinephrine and serotonin turnover within areas of the hind, mid and forebrain, pertinently including the amygdala, hippocampus, and hypothalamus (Wise, Berger, & Stein, 1972). Moreover, benzodiazepines bind to several sites on the GABA receptor. This permits chloride irons to cross the membrane into the neuron that then hyperpolarises the cell (inhibiting the cell from firing an action potential). Benzodiazepines thus facilitate the effects of GABA and therefore have an opposing and suppressing effect to norepinephrine.



Although benzodiazepines are effective in the temporary treatment of many types of medical and psychiatric conditions, caution must be exercised with use, as there are a number of negative side effects and associated risks (Stewart, 2005). First, long term use may lead to physical and psychological dependence. People may begin to depend on benzodiazepines for normal day to day activities and have misperceptions of not being able to function or cope without consumption. The cessation of use is commonly accompanied by withdrawal symptoms that include anxiety, depression, insomnia, irritability, aggression, tremors, muscle pain, and cramps (Cheseaux, Monnat, & Zullino, 2003). Second, long term treatment can lead to impairment in many cognitive domains such as verbal learning, information processing, and visuospatial ability (Stewart, 2005). Memory impairment is almost certain whilst under the influence however there is contention surrounding the effects on memory in the long term as some studies find no memory deficits while others do (Barker, Greenwood, & Jackson, 2004). Third, tolerance generally occurs with six or more months of use (Centre for Substance Abuse Research, 2013). Physicians often increase the dosage to counteract the effects of tolerance but this may also lead to or increase negative side effects. Furthermore, research has shown that a cross-tolerance exists between benzodiazepines and other depressants such as alcohol and barbiturates. This may therefore have implications in the amount of alcohol or barbiturates one consumes, as users may not feel the potency as they would otherwise.



Antidepressants
People who suffer major depression or bouts of depressive symptoms often turn to antidepressant medication for treatment, because similarly with anxiety or other psychological conditions, antidepressant medication provides moderately fast and convenient relief. Antidepressant drugs fall into several categories, including tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and atypical antidepressants (Frazer, 1997). Because serotonin, norepinephrine and dopamine are involved in almost all cases of depression, antidepressant drugs work by targeting the specific neurotransmitter in play or target other neurotransmitters or proteins that influence the causal neurotransmitter(s) (Bateman, 2007). Tricyclics operate by blocking transporter proteins that reabsorb serotonin, norepinephrine, and dopamine into the presynaptic neuron. Serotonin, norepinephrine and dopamine thus accumulate within the synaptic cleft and continue to exert their effects on the postsynaptic neuron (Sattler, Dech, Sandermann, & Kick, 1996). Selective serotonin reuptake inhibiters operate in a similar manner to tricyclics but specifically target serotonin. It is now possible however to target both serotonin and norepinephrine reuptake through a new availability of drugs (Sattler et al., 1996). Monoamine oxidase inhibitors block the monoamine oxidase enzyme, which is released by the presynaptic neuron to metabolise catecholamines and serotonin into inactive forms (CIBA Foundation Symposium, 2009). This allows greater transmitter availability for the presynaptic neuron to release. Last are the miscellaneous group of antidepressants called atypical antidepressants. Atypical antidepressants do not fall into any other class with each administering unique effects. Bupropion for instance inhibits the reuptake of both dopamine and norepinephrine but not serotonin (Brayfield, 2013).

It may be assumed from the mechanistic action of antidepressants that the cause of depression is due to low levels of neurotransmitter release or sustainment within the synapse. However studies show that depressed people have a normal or even an increased level of neurotransmitter activity (Neumeister, Hu, Luckenbaugh, Schwarz, Nugent, & Bonne, 2004). Furthermore, there is no clear evidence that any antidepressant drug produces different or better psychological effects from any other (Rothschild, 2012). Thus, research has failed to recognise the underlying cause(s) of depression as well as decipher why the mechanistic actions of antidepressants work to treat symptoms.

Despite the limited understanding, antidepressants have proven to be very effective in the treatment of not only depression, but anxiety disorders as well. As with many pharmaceutical drugs however there are a number of negative side effects that can vary from one antidepressant to the next. Treatment with tricyclic antidepressants may cause dizziness, difficulty urinating, tremors, nervousness, blurred vision, headaches, constipation, fatigue, nausea, insomnia, and impotence. More serious problems can emerge however that involve, jaundice, seizures, complications with the heart such as arrhythmia, tachycardia, and palpitations, as well as psychological implications such as the contemplation of suicide (American Psychiatric Association, 2006). Selective serotonin reuptake inhibitors, and also serotonin and norepinephrine reuptake inhibitors, are generally more tolerable than other antidepressants. However people still may experience anxiousness, nausea, diarrhoea or constipation, loss of appetite and weight loss, dizziness, burred vision, insomnia, headaches, and low libido. Seizures, paraesthesia, and changes in liver function can also transpire (Marchand, 2012). Monoamine oxidase inhibitor side effects are similar to the above but additionally involve intense daytime fatigue and low blood pressure (Gard, 2002). There are patients however that have used monoamine oxidase inhibitors for more than 40 years with no indication to suggest that long-term use causes any additional, or more intense side effects than mentioned above.

As the literature suggests, benzodiazepines and antidepressants are effective in the treatment of anxiety and depressive disorders. Unfortunately however, side effects are numerous and range in severity from uncomfortable muscle pain through to life threatening seizures and heart complications. Furthermore, treatment with these drugs produces effects that are only temporary. Upon cessation, anxious and or depressive symptoms can, and usually do return, accompanied by severe symptoms of withdrawal. It is therefore apparent that drug therapy is a potentially harmful and dangerous option for the treatment of anxiety and depression from norepinephrine dysregulation.

Diet


Diet is important for the synthesis and regulation of all neurotransmitters (Berntson & Cacioppo, 2009). Amino acids are the precursors, or building blocks, that are required for neurotransmitter production and can only be sufficiently obtained through an optimal diet. For the syntheses of norepinephrine to occur the mammalian brain requires the amino acid tyrosine. Cofactors from folic acid, vitamins B and C, as well as minerals such as copper, zinc, magnesium, and iron must also be present. Tyrosine, vitamins, and minerals are abundant in fish, red meat, dairy, and nuts, as well as in certain fruits and vegetables. Protein is especially important as a deficiency can result in an enhancement of the norepinephrine metabolic rate and accelerate norepinephrine turnover (Kevonian, Tuig, & Romsos, 1894). Thus, a severe reduction or a complete absence of protein rich foods may lead to the dysregulation of norepinephrine.

As mismanaging the diet leads to nutrient deficiencies, and consequently, norepinephrine dysregulation, the opposite is true whereby managing one’s diet correctly results in optimum nutrition and norepinephrine regulation. Diet is arguably the most important factor to norepinephrine homeostasis because it is responsible for the synthesis and regulation of not only norepinephrine but also all other neurotransmitters within the body (Desai, 2000). This is important because neurotransmitters affect one another through synthesis and or biological processes (Lemke & Williams, 2012). Adenosine, histamine, serotonin, and dopamine for instance can influence or inhibit the release of norepinephrine within synapses. Thus, if one or more of these neurotransmitters is excessively high or disproportionately low this may impact the synthesis and regulation of norepinephrine. A balanced diet therefore maintains a state of homeostasis among almost all neurotransmitters and is consequently an efficient, safe, and healthy option for treating or preventing minor to moderate forms of anxiety and depression.

Sodium Chloride Evidence from numerous studies has suggested that sodium chloride may play an important role in neurohormonal and hemodynamic regulatory mechanisms (Friberg, Meredith, Jennings, Lambert, Fazio, & Esler, 1990; Nicholls, Kiowski, Zweifler, Julius, Schork, & Greenhouse, 1980; Vitello, Prinz, & Halter, 1983). Indeed, Nicholls et al. found that plasma norepinephrine levels were altered by sodium intake when within the 10-300mEq (milliequivalents per litre) per day range. Nicholls et al. observed when norepinephrine levels were the highest dietary sodium was most restricted. When norepinephrine levels were intermediate or low, intake of dietary sodium was moderate to high, respectively. Thus, a sodium-restricted diet has been shown to activate plasma (blood) norepinephrine concentration, which therefore increases the activity of the sympathetic nervous system. Consequently, this may have an impact on emotional disorders by provoking or enhancing symptoms, or increasing the risk of disorder development. Furthermore, Vitello, Prinz, and Halter found a low sodium diet was associated with disturbances in sleeping patterns. Because low dietary sodium increases plasma norepinephrine, which subsequently alters the sympathetic nervous system, an increase in wakefulness often occurs. In short, being cognisant of one’s sodium intake may assist in the regulation of norepinephrine and therefore prevent or reduce symptoms of anxiety or depression.

Exercise
Exercise is abundant with the benefits it can provide in not only physical terms, but psychologically as well. Exercise has been known to alleviate symptoms of anxiety and depression by affecting the processes of neurotransmission that regulate stress responses (Dishman, Renner, White-Welkley, Burke, & Burke, 2000). Endorphin neurotransmitters have been the popular explanation in the psychological effects of exercise but little evidence supports this theory. In fact, strong evidence suggests the contrary whereby Markoff, Ryan, and Young (1982) found that ‘runners high’, a phenomenon accredited to endorphin release, could not be blocked by injections of naloxone, an opiate (or endorphin) antagonist (as cited by Craft & Perna, 2004). Instead, many researchers have turned to norepinephrine as norepinephrine plays a key role in the body’s stress response system. In addition, because norepinephrine is intrinsically involved in the mechanics of anti-depressants, researchers have predicted that this combination may position norepinephrine as the instigator in the psychological effects of exercise.



Norepinephrine plasma concentration has been found to increase in proportion to exercise intensity (Greiwe, Hickner, Shah, Cryer, & Holloszy, 1999). Norepinephrine rapidly increases when a person begins to exercise, and once a particular anaerobic threshold has been reached, norepinephrine continues to increase but at a steady rate (The University of Mississippi Medical Centre, 2015). Researchers at the University of Mississippi Medical Centre found that when the heart rate reached its maximum value, norepinephrine was at peak concentration. Moreover, it is at this point where the hormonal form of norepinephrine comes into effect succeeding from the spilled neurotransmitter mechanisms of lower anaerobic intensities. In other words, the high concentrations that are required within the blood stream are now released from the adrenal medulla (involved in the endocrine system) as opposed to the sympathetic nervous system. An important note to clarify, however, is that elevated norepinephrine levels due to exercise differs substantially from norepinephrine dysregulation as dysregulation has a chronic effect on sympathetic activity, as well as having underlying biological defects.

It rationally appears that exercises neurochemical puzzle for wellbeing, may primarily feature the norepinephrine neurotransmitter. A number of studies conducted on animals have supported this theory but additionally found that serotonin plays an equally important role (Wang, Chen, Zhang, & Ma, 2013; Dishman, 1997). Indeed, Wang et al. found that both the norepinephrine and serotonin systems were responsible for exercise-induced positive effects that particularly involved neural pathways within the hippocampus and frontal cortex. The researchers concluded that serotonin not only had a stress reducing effect but also mediated the high activation of norepinephrine within the brain. Some psychologists and psychiatrists, however, do not believe that more norepinephrine and serotonin simply equates to less stress, anxiety, and enhanced feelings of wellbeing. The argument is that exercise enhances the body’s ability to cope with stress. In essence, physical activity exercises the body’s stress response system forcing communication and collaboration between the stress response systems physiological components (i.e. the endocrine system, the renal system, the cardiovascular system, and the central and peripheral nervous systems). Thus, the more active the person, the more efficient that person is in responding to stress, and likewise with the contrary (the less active, the less efficient) (Dishman & Sothmann, 2015). Either way, it therefore seems that exercise training might be one behavioural intervention to either treat or alleviate the symptoms of emotional disorders such as anxiety and depression.

Practical Guide
To improve health and wellbeing without the use of drugs, a brief practical guide on diet and physical training has been included. The aim of this guide is to assess whether the combination of diet and physical training has a positive effect on your psychological wellbeing, and thus, norepinephrine regulation. Alternatively, either diet or exercise can be trialled separately however the benefits will most likely be greatest in combination. A word of caution must be exercised, however, that before undertaking any form of diet and exercise that the approval from a physician be obtained. Moreover, if severe symptoms of anxiety and or depression are currently experienced it is recommended that a physician be consulted as soon as possible.

Diet
Diet throughout must include a variety of fruit and vegetables, dairy, both red and white meat, and an assortment of nuts. Furthermore, sodium intake is recommended at approximately 1600mg per day (or the equivalent of 0.24% of a tablespoon), and refined sugar intake should be minimised. As an example, consider:

Table 1.

Recommended four week diet to improve norepinephrine regulation, anxiety, and wellbeing. Note: Nuts should be consumed throughout the day for snacking.

Exercise
Physical training should start at low intensity (week 1) and should slowly increase as each week passes. As an example, consider:

Table 2.

Recommended four week exercise program to improve norepinephrine regulation, anxiety, and wellbeing. On conclusion of the four-week period, it is anticipated that norepinephrine, as well as other neurotransmitters, will be near or at normal regulation. Therefore, one can expect to feel less anxious and have a greater sense of wellbeing.

Conclusion
On the completion of reading this book chapter, one may reflect on the ambiguous nature of this topic and be left wondering what definitive conclusions can be drawn between the relationship of norepinephrine and emotional disorders. The short and simplistic answer - very little. The underlying mechanisms of why neurotransmitter dysregulation affects emotion are largely unknown. The use of benzodiazepines and antidepressants provide some insight for the sole and simple reason that they effectively work in relieving symptoms. But understanding the neurochemical process only illuminates the effect and not the underlying cause. Nevertheless, knowledge of this process allows for neurochemical manipulation through diet, exercise, and medicine, although the use of drugs is associated with a number of physical and psychological problems that have the potential to put health and life at risk. Overall, attending to one’s health by eating correctly, and conducting exercise on a regular basis, will ensure the optimal regulation of norepinephrine and therefore assist in the prevention or in the treatment of emotional disorders.