L1-79 and the Role of Catecholamines in Autism

*John Rothman*

### **Abstract**

A growing body of evidence supports a role for catecholaminergic dysfunction in the core symptoms of autism spectrum disorder (ASD). This paper reviews the direct and indirect role of catecholamines on the central and peripheral nervous systems in ASD. Catecholamines innervate every tissue in the body and almost all tracts of the brain, providing a common neurologic regulatory mechanism for all ASD symptoms. Because the morphology of the catecholaminergic synapse is regulated by growth factors that are released contemporaneously with neurotransmitters, an event that results in abnormally large catecholamine release, will also release high levels of growth factors, which can result in the budding and arborization of nerve terminals. Here, we hypothesize that a hypertrophic synaptic morphology can occur in catecholaminergic systems and increase catecholaminergic tone throughout the body, resulting in an imbalance between catecholaminergic neurologic mechanisms and those that oppose them, and consequently pathology. By exerting a presynaptic effect to inhibit tyrosine hydroxylase and thus the synthesis, storage and release of all catecholamines, L1–79 (a tyrosine hydroxylase inhibitor) may diminish neurotransmitter release and its associated growth factors exerting a therapeutic effect on ASD by reducing the hypertrophic morphology of the synapse and bringing catecholamines back into a homeostatic balance with oppositional neurologic and metabolic influences.

**Keywords:** autism, autism spectrum disorder, catecholamines, D, L-α-methyl-para-tyrosine, L1–79

### **1. Introduction**

Childhood autism is more prevalent than childhood cancer, juvenile diabetes and pediatric AIDS combined, with an estimated prevalence of 3 M children in Europe, 1.5 M in the US, and tens of millions throughout the rest of the world. More disturbing is that for no explicable reason childhood autism appears to be increasing at a rate of 10–17% per year [1]. Typically displayed in early childhood, autism may be associated with many co-morbidities that include epilepsy, attention deficit/ hyperactivity disorder (ADHD), abnormal sensory or motor responses, disturbed sleep, reduced cognitive functionality, anxiety and aggression [2–4], or none at all.

In 2019 the CDC reported the rate of autism in the US to be 1 in 59 children, with boys being 4 times more susceptible than girls [5]. This means that 1 in 42 boys are diagnosed with autism. There was an increase of about 30% since the assessment of autism prevalence conducted previously (**Table 1**), and more almost 3x the rate that was reported only 20 years ago. In New Jersey the observed rate of autism was


#### **Table 1.**

*CDC: Prevalence of autism in the US [5].*

1 in 46 children, which means that 1 in 29 boys born in New Jersey are likely to be autistic [6, 7].

The lifetime cost of raising an autistic child was estimated in 2014 to be \$3.2 M more than the cost of raising a non-autistic child [8], and this does not take into account the societal costs of maintaining these this population as adults once their families are no longer able to do so. The societal costs of autism are broad and deep, and many have never been explored. For example, it was only in mid-2017 that information was developed on the rate of healthcare utilization by autistics and it was found that their need for psychiatric care as well as care for the high incidence of autism associated comorbidities was far beyond that of the general population or other elements of the psychiatric patient population [9]. Similarly, it was not until September of 2017 that the rate of school suspension and expulsion was dramatically higher in the autistic population, and growing as the autistic population grew in numbers [10].

Recently, attention has been brought to bear on autism associated mortality rates. Although autism is not typically considered to be a fatal disease, several investigators have reported a significantly increased mortality in the autistic population with the major cause of death being suicide. A matched case cohort study based upon the Swedish National Patient Registry and the Cause of Death Registry looked at deaths between 1987 and 2009 and found a 256% greater death rate in autistic patients compared to the general population. The mean age at the time of death was 70.2 years for the general population and 58.39 for patients with autism, with suicide associated with better performing patients [11]. A review of 1706 children and adolescents reported an 18% increased risk of suicidal ideation or attempts in autism [12]. 35% of patients with Asperger's syndrome were reported in a Canadian study t have attempted suicide [13]. Similarly, in Japan [14], Australia [15], England [16], and Belgium [17]. In a French review of the PubMed literature it was found that overall 21.3% of autism patients reported suicidal ideation or had attempted suicide, with the noteworthy observation that "… the methods used are often violent" [18].

Autism is quite heterogenous and has a broad pallet of potential symptoms. These symptoms transcend established investigative disciplines including behavioral studies, developmental studies, neurology, pharmacology and so forth. No truly workable definition of autism has yet emerged to define this heterogenous constellation of symptoms. Theories regarding the causes of autism include impairments within the autonomic nervous system [19], cerebellar dysfunction [20], mitochondrial impairment [21], exposure to toxins [22], and many others.

**101**

*L1-79 and the Role of Catecholamines in Autism DOI: http://dx.doi.org/10.5772/intechopen.95052*

**2. Autonomic function and autism**

siveness and emotional responsiveness overlap.

**3. Adrenergic CNS changes in autism**

The autonomic nervous system has been implicated in symptoms that resemble

Kushki [19] hypothesized a chronically over activated autonomic system is a correlate of autism based upon the exaggerated levels of anxiety that attend autism [33], physiologic hyperarousal [36–38], and other correlates. Anxiety is perhaps the greatest co-morbidity associated with autism which may drive other features of the disease [39, 40], and has been associated with central nervous system structures that are linked to autonomic function [41, 42]. Phenotypically autism and anxiety both present with stereotyped repetitive and limited interests, avoidance behaviors and speech problems [43–45]. The relationship between anxiety and reported autonomic symptoms of elevated heart rate, perspiration, and other sequelae of the "fight or flight" reaction reveal a role for the peripheral nervous system function in autism [36–38]. However, this may be secondary to central autonomic activation. Central functions may manifest as elevated emotional responsiveness and exaggerated threat perception or diminished inhibition of fear responses [36], which are associated with the central structures mentioned above in which autonomic respon-

There is a considerable body of evidence, which will not be reviewed here, that associates autism with cholinergic function in the central nervous system, specifically with various α-subtype nicotinic receptors, notably in the cerebellum. However, as autonomic function is classically considered to be a balance of cholinergic and catecholaminergic systems, perceived increases or decreases in cholinergic function may be manifestations of change in the dynamic balance of these systems with catecholaminergic tone. It may be possible to effect therapeutic change through manipulation of either acetylcholine-based manipulations or the counterbalancing of dopamine, norepinephrine, or epinephrine mediated mechanisms.

Recent work by Hamilton, et al. [46] who sequenced exomes of families with a history of autism found deficiencies in the human dopamine transporter gene (hDAT), a protein responsible for the presynaptic reuptake of dopamine. CNS dopamine is a crucial element in systems that mediate motor function, motivation, attention and reward [47–50]. As this system is known to be associated with ADHD, and approximately 45% of autistic patients manifest symptoms of ADHD [3, 51–53], there is reasons to suspect a common pathway underlying these two diseases. Moreover, dopamine related genes *DRD1, DRD3* and *DRD4* are associated with an increased risk for ASD [54] as well as repetitive stereotyped behavior [55–57], and defiant and anxiety disorders [56]. Males with multiple tandem repeats in the monoamine oxidase-A (MAOA) promotor gene responsible for degrading dopamine show in increased proclivity for autism [58]. Aside from changes in synaptic dopamine uptake and degradation, changes dopamine receptor function and avidity have been reported [59–61], as have changes in dopamine synthesis and DOPA decarboxylase. Additionally, it has been observed that pharmacologic

those seen in autism. ASD has been associated with abnormal findings in autonomic related structures including the insula [23, 24] and the amygdala [25–27]. Autonomic related changes such as increases in basal heart rate [28–31] and diminished heart rate variability due to psychosocial challenges [32, 33] are seen in autism. The autism-autonomic linkage is exemplified by the consequences of respiratory sinus arrhythmia (RSA) that includes difficulties with socialization [30, 34], language difficulties [34, 35], and delays in cognitive development [35].

*Autism Spectrum Disorder - Profile, Heterogeneity, Neurobiology and Intervention*

**Number of ADDM Sites Reporting**

 1992 6 6.7 (4.5–9.9) 1 in 150 1994 14 6.6 (3.3–10.6) 1 in 150 1996 8 8.0 (4.6–9.8) 1 in 125 1998 11 9.0 (4.2–12.1) 1 in 110 2000 14 11.3 (4.8–21.2) 1 in 88 2002 11 14.7 (5.7–21.9) 1 in 68

**Prevalence per 1,000 Children (Range)**

**This is about 1 in X children…**

**Identified Prevalence of Autism Spectrum Disorder**

**Birth Year**

**ADDM Network 2000-2010 Combining Data from All Sites**

*CDC: Prevalence of autism in the US [5].*

**Surveillance Year**

1 in 46 children, which means that 1 in 29 boys born in New Jersey are likely to be

The lifetime cost of raising an autistic child was estimated in 2014 to be \$3.2 M more than the cost of raising a non-autistic child [8], and this does not take into account the societal costs of maintaining these this population as adults once their families are no longer able to do so. The societal costs of autism are broad and deep, and many have never been explored. For example, it was only in mid-2017 that information was developed on the rate of healthcare utilization by autistics and it was found that their need for psychiatric care as well as care for the high incidence of autism associated comorbidities was far beyond that of the general population or other elements of the psychiatric patient population [9]. Similarly, it was not until September of 2017 that the rate of school suspension and expulsion was dramatically higher in the autistic population, and growing as the autistic population grew

Recently, attention has been brought to bear on autism associated mortality rates. Although autism is not typically considered to be a fatal disease, several investigators have reported a significantly increased mortality in the autistic population with the major cause of death being suicide. A matched case cohort study based upon the Swedish National Patient Registry and the Cause of Death Registry looked at deaths between 1987 and 2009 and found a 256% greater death rate in autistic patients compared to the general population. The mean age at the time of death was 70.2 years for the general population and 58.39 for patients with autism, with suicide associated with better performing patients [11]. A review of 1706 children and adolescents reported an 18% increased risk of suicidal ideation or attempts in autism [12]. 35% of patients with Asperger's syndrome were reported in a Canadian study t have attempted suicide [13]. Similarly, in Japan [14], Australia [15], England [16], and Belgium [17]. In a French review of the PubMed literature it was found that overall 21.3% of autism patients reported suicidal ideation or had attempted suicide, with the noteworthy observation that "… the methods used are often violent" [18]. Autism is quite heterogenous and has a broad pallet of potential symptoms. These symptoms transcend established investigative disciplines including behavioral studies, developmental studies, neurology, pharmacology and so forth. No truly workable definition of autism has yet emerged to define this heterogenous constellation of symptoms. Theories regarding the causes of autism include impairments within the autonomic nervous system [19], cerebellar dysfunction [20], mitochondrial impairment [21], exposure to toxins [22], and many others.

**100**

autistic [6, 7].

**Table 1.**

in numbers [10].
