RELATIONSHIP BETWEEN NEUROTRANSMITTERS, BEHAVIOR, AND MALTREATMENT: A REVIEW

This review paper examined the following eight neurotransmitters: dopamine, norepinephrine, epinephrine, serotonin, histamine, phenylethylamine (PEA), glutamate, and gamma-aminobutyric acid (GABA).  Specifically, we examined the relationship between these neurotransmitters and psychopathological behaviors that indicate underlying psychological problems or histories of maltreatment. Awareness of these links can provide a deeper understanding of these behaviors as well as assist practitioners in making more informed treatment decisions.

INTRODUCTION

This review paper examined the following eight neurotransmitters: dopamine, norepinephrine, epinephrine, serotonin, histamine, phenylethylamine (PEA), glutamate, and gamma-aminobutyric acid (GABA). The relationship between behavior and these neurotransmitters is discussed below. Some of the neurochemicals listed above are not consistently defined as “neurotransmitters” in the literature due to ambiguity as to whether they affect the central or peripheral nervous system. However, to facilitate reading of this article we will address them all as neurotransmitters.

Neurotransmitters, described as chemical messengers of the nervous system, support the transmission of signals from one neuron to another and ultimately allow the signal to be carried throughout all organs within the body. Neurotransmitters are present in body fluids such as serum, cerebral spinal fluid (CSF), saliva, and urine (Ailts, Ailts, & Bull, 2007). Though present throughout the body, neurotransmitters are primarily synthesized, stored, and released by specialized neurons within the central nervous system (CNS). Most of the essential neurotransmitters are synthesized from amino acids obtained from dietary intake and therefore neurotransmitter precursors may pass through the blood-brain barrier (Ailts, Ailts, & Bull, 2007).

Catecholaminergic neurotransmitters – dopamine, epinephrine and norepinephrine

The major catecholamines in the nervous system are biogenic amines and include dopamine, norepinephrine, and epinephrine (Smeets & González, 2000).  Catecholamines are involved in many behaviors including mood regulation, reward-seeking behavior, and modulation of cardiovascular function, as well as self-regulatory behaviors, cognitive functions, and memory consolidation.  These catecholamines and their relationship with normal and psychopathological behaviors are discussed below.

Dopamine

Dopamine, which has both excitatory and inhibitory effects (Carlson, 2007), is involved in mood regulation and plays a central role in reward-seeking behavior, such as approach, consumption, and addiction; behavioral activation; and goal-directed behavior (Başar & Güntekin, 2008; Pessiglione et al., 2006; Wise, 2004). In particular, dopamine transmission from the sustantia nigra and ventral tegmentum to the forebrain structures such as the nucleus accumbens and neostriatum plays an important role in mediating the reward value of food, drink, sex, social reinforcement, drugs of abuse, and brain stimulation (Berridge & Robinson, 1998). Furthermore, as a principal catecholamine in the mammalian brain, dopamine also aids in the modulation of cardiovascular function, catecholamine release, hormone secretion, vascular tone, renal function, and gastrointestinal motility (Missale, Nash, Robinson, Jaber, & Caron, 1998).

Dopamine is involved also in cognitive functions, in working memory, and intentional and attentional processes (Herschkowitz, 2000). Disturbances in the development of the dopaminergic system may lead to several disorders or abnormalities, including dyskinesia, dystonia, tics, obsessive-compulsive disorders, and abnormal eye movements (Herlenius & Lagererantz, 2001). Dopamine, along with serotonin, GABA, glutamate, opioids, and oxytocin, has also been linked to autism (Penn, 2006). Beard and Conner (2003) suggested that iron deficiency in early life relates to alterations in dopamine metabolism, which may cause problems with perception and motivation; and therefore, problems with cognitive and behavioral development as well. Georgieff (2007) noted that fetal and neonatal iron deficiency can result in low levels of dopamine. Low levels of dopamine have also been correlated with attention problems and ADHD (Volkow et al., 2009; Konrad, Gauggel, & Scurek, 2003). Elevated levels have been linked to cognitive, attention problems (Herschkowitz, 2000), and post-traumatic stress disorder symptoms in adult females (Glover et al., 2003).

Moreover, De Bellis et al. (1999a) found higher levels of urinary dopamine in prepubertal maltreated children with posttraumatic stress disorder (PTSD). Specifically, this study compared 18 maltreated children with PTSD with 24 non-abused children in a control group. Significantly higher levels of catecholamines (including dopamine) were found in the PTSD group than were found in the non-abused control group. In addition, the levels of urinary catecolamines and cortisol correlated positively with intrusive thoughts, avoidance, and hyperarousal.  In another study, De Bellis et al. (1999b) found that 44 maltreated children and adolescents with PTSD who were assessed with anatomical magnetic resonance imaging brain scans had 7% and 8% smaller intracranial and cerebral volume than the control group (61 matched controls on age, gender, handedness, Tanner Stage, race, height, and weight). In addition, the maltreated, PTSD group showed increased rates of internalizing and externalizing disorders consistent with results found in studies of abused children. Overall, these results may be explained, according to the authors of that study, as an effect of chronic maltreatment in children with PTSD that altered major biological stress systems (including catecholaminergic neurotransmitters – dopamine, epinephrine, and norepinephrine), and had adverse effects on brain development.

Furthermore, Yehuda, Southwick, Giller, Ma, and Mason (1992) also found higher levels of dopamine in Vietnam combat veterans with posttraumatic stress disorder (PTSD). In this study, authors explained high levels of dopamine as being a result of increased sympathetic nervous system activation in people with PTSD, and linking severity of PTSD symptom clusters with the level of sympathetic nervous system arousal.

Norepinephrine

Norepinephrine has both excitatory and inhibitory effects, however, the behavioral effects of norepinephrine are excitatory (Carlson, 2007). The norepinephrine system is dedicated to self-regulatory functions such as mediation of the orienting response, selective attention, and possibly vigilance (Solanto, 1998). Norepinephrine (noradrenaline) is also involved in sleeping, dreaming, and learning; and because it is released in the blood vessels, it causes blood vessels to contract and the heart rate to increase (Başar & Güntekin, 2008). Beane and Marrocco (2004) proposed that insufficient norepinephrine release may explain problems in reflexive and voluntary attention. Viggiano (2008) noted that a decrease in norepinephrine synthesis usually results in hypoactive behavior; however, a chronic increase may result in hypoactivity as well. Norepinephrine is also associated with mood disorders such as manic depression, also known as bipolar disorder (Başar & Güntekin, 2008); arousal modulation; and an organism’s display of sensitivity toward the environment, which may result in aggressive responses to novel or threatening environmental stimuli (Berman & Coccaro, 1998).  Rogeness (1991) found that children with a history of neglect displayed low levels of urinary norepinephrine.

Furthermore, Yehuda, Southwick, Giller, Ma, and Mason (1992) showed higher levels of norepinephrine in Vietnam combat veterans with PTSD than in outpatients and a normal control group. As in the case of significantly higher dopamine levels, high levels of norepinephrine were correlated with increased sympathetic nervous system activation in people with PTSD.

Animal models show that traumatic stress activates the locus coeruleus (the nucleus in the brain that contains catecholamines – specifically norepinephrine) as well as the sympathetic nervous system leading to the “fight-or-flight” response.  Consequently, this influences the increase of catecholamines within the brain, sympathetic nervous system, and adrenal medulla that affect the increase in heart rate, blood pressure, alertness and circulation of epinephrine, norepinephrine, and dopamine. However, during severe stress the locus coeruleus stimulates the hypothalamic-pituitary-adrenal axis (HPA) and corticotropin-releasing hormone (CRH) is released stimulating adrenocorticotropin (ACTH) and cortisol release. This cascade of chemical changes stimulates behavioral activation and intense arousal expressed in anxiety and hypervigilance (De Bellis, 2002)

The norepinephrine balance is affected not just by traumatic stress but also by high levels of chronic physiological stress as shown by Babisch, Fromme, Beyer, and Ising (2001) on noise exposed subjects.  Specifically, they found that traffic volume as an indicator of noise exposure was associated with a higher concentration of noradrenaline in urine.

Epinephrine

Epinephrine (adrenaline) is an excitatory neurotransmitter (Feldman, Meyer, & Quenzer, 1997) and is considered to have an effect on human memory consolidation (Cahill, Gorski, & Le, 2003) and stress (Charmandari, Kino, Souvatzoglou, & Chrousos, 2003). Delahanty, Nugent, Christopher, and Walsh (2005) reported that elevated levels of urinary epinephrine were positively correlated to levels of post-traumatic stress disorder in children six weeks after a traumatic event. Krantz, Forsman, and Lundberg (2004) also found that stress increases epinephrine levels. They linked epinephrine to cardiovascular activity and muscle tension. Garde, Hansen, Persson, Ohlsson, and Ørbæk (2003) found that arousal, both positive and negative, was associated with increased concentrations of urinary adrenaline; thus, both positive and negative emotions are associated with increased concentrations of epinephrine. Epinephrine, like dopamine and norepinephrine, has been linked to ADHD as well (Konrad, Gauggel, & Schurek, 2003). Furthermore, Yehuda, Southwick, Giller, Ma, and Mason (1992) showed higher levels of epinephrine in Vietnam combat veterans with PTSD than outpatients and a normal control group.

Catecholamines – Conclusion

Higher levels of epinephrine, norepinephrine, and cortisol in urine may indicate the presence of a state of acute and chronic stress (Babisch, Fromme, Beyer, & Ising, 2001). In addition, animal studies showed altered norepinephrine and epinephrine in plasma as the result of a chronic intermittent stressor (Marby, Gold, & McCarty, 1994).

Norepinephrine and dopamine release in the prefrontal cortex is correlated with a state of arousal (Arnsten & Pliszka, 2011). Under stress conditions, high levels of catecholamines (dopamine and norepinephrine) are released in the prefrontal cortex (Finlay, Zigmond, & Abercrombie, 1995). In addition, low levels of arousal are correlated with low levels of norepinephrine (Foote, Aston-Jones, & Bloom, 1980). The effects of norepinephrine and dopamine on mood, arousal, and behavior are mediated by receptors located within the prefrontal cortex that are sensitive to the neurochemical environment (Arnsten & Pliszka, 2011). Consequently, release of catecholamines that is either insufficient or excessive will lead to impairment of prefrontal cortex function. Specifically, both norepinephrine and dopamine are present in low levels during fatigue and boredom and at moderate levels when an alert state is caused by relevant stimuli or during non-stressed walking. Insufficient levels of dopamine are correlated with unguided attention/responses, distraction, and poor impulse control (untreated ADHD). Moderate norepinephrine levels are correlated with guided attention and responses, and focused, organized and flexible behaviors (optimally treated ADHD). Norepinephrine in high levels is correlated with misguided attention or responses, mental inflexibility or stimulus bond (excessive dose of stimulants) and, impairment of prefrontal cortex functioning (Arnsten & Pliszka, 2011). While the specific cause of ADHD is unidentified, there is evidence that this disorder involves dysfunctional modulation of the cortico-limbic-striatal circuitry by the catecholamines (in particular dopamine, and noradrenaline), as well as serotonin (Dalley, Mar, Economidou, & Robbins, 2008).

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) has both excitatory and inhibitory effects (Carlson, 2007) and may be involved in a wide variety of behaviors such as appetite; emotion; motor and cognitive functions; modulation of neuroendocrine function; and circadian rhythm (Hensler, 2006). Serotonergic abnormalities have been reported in both autism and epilepsy (Chugani, 2004); depression and anxiety disorders (Ressler & Nemeroff, 2000), and ADHD (Hawi et al., 2002). Other researchers have linked reduced serotonin activity to aggressive behavior toward others, other people’s property, and towards oneself (Meyer et al., 2008; Berman & Coccaro, 1998; Meyer et al., 2008; Mitsis et al., 2000; Oades et al., 2008; Tuinier, Verhoeven, & Van Praag, 1996).  Levels below the optimal range indicate a possibility of depression (Booij, Van der Does, & Riedel, 2003) and poor impulse regulation (Kent et al., 2002). Kaufman et al. (1998) found that childhood abuse can lead to a serotonin system that operates inefficiently, leading to cognitive and behavioral problems. One reason for this may be due to Monoamine oxidase A (MAO-A), an enzyme that catalyzes the degradation of dopamine, serotonin, and norepinephrine. Studies have shown that MAO-A expression is impacted by environmental factors, such as childhood maltreatment (Caspi et al., 2002; Foley et al., 2004; Nilsson, 2006; Nilsson, Sjoberg, Wargelius, & Leppert, 2006). When MAO-A activity is activated by maltreatment, levels of dopamine, serotonin, and norephinephrine are also affected (Oreland, Nilsson, Damberg, & Hallman 2007; Shih & Thompson, 1999).

Histamine

Histamine has both excitatory and inhibitory effects (Feldman, Meyer, & Quenzer, 1997) and is involved in various central nervous system functions such as arousal, anxiety, activation of the sympathetic nervous system, regulation of sleep-wake cycle, water retention, and suppression of eating (Brown et al., 2001). Some researchers consider histamine to play an important role in regulating energy and endocrine homeostasis, and synaptic plasticity and learning as well (Haas & Panula, 2003). Histamine has also been described as having a modulator role in immune responses (Hough & Leurs, 2006; Tanaka & Ichikawa, 2006).

A high concentration of histamine is found in many foods especially in products of microbiological fermentation such as aged cheese, sauerkraut, wine, processed meat, and citrus foods (Bodmer, Imark & Kneubühl, 1999; Mainz & Novak, 2007; Ruiz-Capillas, & Jiménez-Colmenero, 2004). The amount of histamine found in certain foods may be a contributing factor for high levels of histamine in children. European legislation permits histamine levels twice as high as what the U. S. Food and Drug Administration allows. Some researchers warn against “histamine toxicity” from foods and beverages; thus, there is a need for health authorities to set safe, legal limits on biogenic amines such as histamine (Ruiz-Capillas & Jiménez-Colmenero, 2004).

Allergies, mastocytosis, bacterias, or gastrointestinal bleeding may also cause an excess of histamine (Mainz & Novak, 2007). Mainz and Novak (2007) reported that histamine causes smooth muscle cell contraction, vasodilatation, increased vascular permeability, mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias. The histamine system, proposed as a danger response system, releases more histamine during extreme conditions such as dehydration, hypoglycemia, or stress (Brown, Stevens, & Haas, 2001). In animal studies, histamine has been linked to inducing experimental anxiety, which suggests that histamine may play an important role in the regulation of anxiety (Ikarashi & Yuzurihara, 2002).

Histamine has also been linked to Alzheimer’s disease and schizophrenia (Fernández-Novoa & Cacabelos, 2001) as well as Down’s syndrome and Parkinson’s disease (Haas & Panula, 2003). According to some researchers, histamine also has an effect on memory processes (Blandina, Efoudebe, Cenni, Manaioni, & Passani, 2004; Philippu & Prast, 2001). Histamine has also been associated with anxiety and sleep problems (Brown et al., 2001; Hough & Leurs, 2006; Tanaka & Ichikawa, 2006). Adverse psychological stimulation, such as immobilization stress or social isolation, results in release of Substance P in the brain (Ebner, Rupniak, Saria, & Singewald, 2004). Substance P, a neuropeptide, induces histamine release resulting in inflammation as well as negative moods, fear, and anxiety (Rosenkranz, 2007).

PEA

Beta-phenylethylamine (PEA) is an excitatory neurotransmitter that functions like an amphetamine (Kahane, 2009). Decreased PEA levels have been associated with depression (Nakagawara, 1992;) and ADHD (Kusaga et al., 2002). Increased levels have been observed in individuals with anxiety and schizophrenia (see Burchett & Hicks, 2006). There is a very strong association between Monoamine oxidase B (MAO-B), an enzyme that catalyzes the degradation of PEA, and adverse psycho-social environments (e.g., maltreatment) and criminal behavior (Oreland, 2007). In addition, MAO-B is associated with susceptibility to many psychiatric disorders (for a review, see Volavka, 1999), and plays a role in mood regulation (Bortolato, Godar, Davarian, Chen, & Shih, 2009); emotional responses, including exploratory activity, arousal, and behavioral reinforcement (Sabelli & Javaid, 1995); violent criminality (Asberg, 1997; Belfrage, Lindberg, & Oreland, 1992; Longato-Stadler, af Klinteberg, Garpenstrand, Oreland, & Hallman, 2002); and suicide (Verkes et al., 1998). In sum, studies have shown that an individual’s psycho-social environment influences both MAO activity (which has a direct effect on PEA levels) and behavioral expression in individuals.

Glutamate

Glutamate is an excitatory neurotransmitter (Carlson, 2007) and is considered to be the principal mediator of sensory information, motor coordination, emotions, and cognition, including memory formation and memory retrieval (Hassel & Dingledine, 2006). Glutamate also plays a role in alleviating the neuronal effects of stress, anxiety, and modulates neuronal activity throughout the central nervous system (Johnson et al., 2005; Niswender, Jones, & Conn, 2005). It has been implicated in initiation and propagation of seizures (Holmes, 1995) as well as in the pathophysiology of mood disorders (Sanacora, Zarate, Krystal, & Manji, 2008). Glutamate has also been implicated in depersonalization disorder, which has been associated with childhood emotional maltreatment and trauma (Simeon, 2004). Furthermore, an excess of glutamate has been associated with obsessive-compulsive disorder (Carlsson, 2000), while a shortage has been associated with ADHD (Moore et al., 2006) and depressive symptoms (Tordera et al., 2011). Glutamate dysfunction has also been associated with autism (Page et al., 2006; Shinohe et al., 2006) and schizophrenia (Coyle, 2006). Acute stress alters the release of glutamate in the brain (Musazzi et al., 2010) and rearing environments marked by neglect and isolation are associated with reduced expression of glutamate in the brain, leading to cognitive deficits and psychiatric disorders. Glutamate dysfunction caused by stress is also suspected to play a role in schizophrenia and addiction (Melendez, Gregory, Bardo, & Kalivas, 2004). Extremely high glutamate levels, which lead to cell damage/death, have been found in children with traumatic brain injury who have also been victims of child abuse (Ruppel, 2001).

GABA

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS, plays a trophic role during early brain development, including neuronal wiring, plasticity of neuronal network, and neural organization (Herlenius & Lagercrantz, 2001). GABA synthesis reaches peak activity during the second year of life; thus, at age two, children should show improvement in integrating information (Herschkowitz, 2000). Olsen and Betz (2006) reported a link between altered GABAergic function and neurological and psychiatric disorders, primarily related to hyperexcitability, including developmental malfunctions; mental retardation and epilepsy, sleep disorders; drug dependence, sensorimotor processing, and motor coordination. Brambila, Perez, Barale, Schettini, and Soares (2003) reported low levels in both depressed and manic patients. Johnston and Singer (2001) reported low levels of GABA in cerebral spinal fluid in individuals with seizures. Moreover, elevated plasma GABA levels have been found in youngsters with Autistic Disorder, and some researchers consider GABA to be a biochemical marker of Autism (Dhossche et al., 2002) as well of ADHD with conduct disorder (Prosser et al., 1997).

Summary

In summary, maltreatment can affect levels of the neurotransmitters discussed above.  Health and childcare practitioners should be aware that children with histories of trauma, neglect, and other forms of maltreatment often exhibit behavior that is driven by irregular levels of neurotransmitters that stem from maltreatment (Purvis, McKenzie, Cross, Kellermann, & Huisman, 2011). Urinary assays to assess specific levels of each neurotransmitter to determine whether they are within optimal ranges may be helpful in planning appropriate therapies and interventions (e.g., behavioral or psychological interventions, supplements, or medication) and also in assessing the efficacy of interventions.

In a recent study, significant reduction in maladaptive behaviors was observed for at-risk children when serotonin and Gaba were increased with natural supplements (Cross, Kellermann, McKenzie, Purvis, Hill, & Huisman, 2011). Furthermore, NT testing has been used to detect child abuse. In one case study, a mother was seeking reinstatement of full custody of her child who had been in foster care for one year. However, the child demonstrated extreme reactions to her mother’s presence during visitation sessions. The child was tested for neurotransmitter activity at baseline and immediately after visitation by the mother. A spike in the levels of several neurotransmitters after visitation indicated a dramatic stress response associated with the visitation. When the mother was presented with these neurotransmitter results as well as her results on the Adult Attachment Interview (AAI), she confessed to using abusive parenting practices with the child (Purvis, McKenzie, Kellermann, & Cross, 2010).

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