**3. Adrenergic CNS changes in autism**

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

manipulation of dopamine has clinical efficacy in ASD [62, 63], for example with risperidone, a drug approved to treat ASD.

Other lines of support come from observations of lower levels of dopamine β-hydroxylase in the plasma of autistic patients [64, 65] and reductions in platelet [66] and urine dopamine [67]. Similarly, inferences have been published that the mesolimbic cortex and striatum may provide a neurologic substrate linked with the motor and behavioral symptoms seen in autism as a result of a dopaminergic imbalance in these structures [68, 69].

Nguyen et al. [70] used in silico methods to clarify the genetics underlying the contribution of dopamine the etiology and pathogenesis of autism and found genes implicated that regulate both Ca++ metabolism and dopaminergic neurotransmission. They found proteins implicated in ASD regulate dopamine signaling in multiple places including reuptake and catabolism, and they defined discrete molecular clusters that act on systems implicit in dopaminergic systems such as androgen receptors that stimulate DOPA decarboxylase. Another finding was the potential role of dopamine mediating the modulation of dendritic spines which determine synaptic strength and may be important in the developmental delays associated with ASD [71].

In an interesting cybernetic model, Kriete and Noelle [72] developed a sophisticated methodology to investigate the role of dopamine and the changes in executive function associated with autism. They showed that the intensely focused cognition associated with autism, as well as the pathognomonic lack of cognitive plasticity and inability to react with appropriate conscious focus to changes in the stimulus milieu could be modeled as changes in dopaminergic systems in the prefrontal cortex. By differentiating cognitive control from plasticity, and further by showing how developmental changes in younger brains can account for the timing of the manifestation of autistic symptoms, these authors findings support a causal adrenergic mechanism underling at least some of the symptoms associated with autism.

Taken together, a good case can be made for dopamine as a key mediator of the motor, speech, social behavior, behavioral perseveration, and reward aberrations that are typical symptoms of autism. The precise regulation of dopaminergic function of autonomic function appears to involve the projection of Purkinje cells to the medial prefrontal cortex (mPFC) and the ventral tegmental area (VTA) of the striatum. Atrophied Purkinje cells is one of the most consistent neuropathologies associated with autism [73–76], and MRI data indicates persons with autisticism have smaller than normal cerebellar vermal volume [77]. Mice with diminished Purkinje cell mass evidence numerous autistic symptoms such as repetitive behaviors and impaired executive function [78]. Cerebellar Purkinje cells project to the mPFC where it appears they modulate dopaminergic transmission in this region directly, and via a remodeling of the VMA and thalamic interactions with the mPFC, and it has been suggested that cerebellar deficits observed in autism result in cortical, thalamic, and striatal integration via dopamine mediated pathways [79].

An immunologic linkage of dopaminergic function in autism was reported by Kirsten et al. [80] when they prenatally exposed rat pups to lipopolysaccharide, a stimulator of innate and adaptive immunity. Autistic symptoms of impaired communication, deficits in learning and memory, and repetitive/restricted behavior were observed in the presence of impaired tyrosine hydroxylase (TH) function which was taken as a marker of reduced striatal dopaminergic function. Support for this concept was also found when rat pups were given poly I:C, an immunogenic stimulator, and upregulation of various genes associated with dopamine neural development were observed [81].

The phosphatase and tensin homolog on chromosome ten (PTEN) is tumor inhibitory gene that inhibits PI3K and MAPK pathways, and a germline mutation of

**103**

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

for therapeutic intervention in autism [85].

**4. GI abnormalities in ASD**

amine responses (reviewed in [98]).

diets are terminated (cited in [100]).

tion tested.

this gene has been associated with autism [82]. Mouse mutations of this gene have resulted in symptoms similar to autism [83], and PTEN deletions have been found to enhance the survival and the function of dopaminergic neurons [84]. Work in this area has shown that mice with PTEN mutations have elevated TH and DA2 receptors in the striatum and prefrontal cortex, that PTEN reduces TH phosphorylation via MAPK suppression, downregulates dopamine synthesis in PC12 (pheochromocytoma) cell cultures, and that a PTEN-TH pathway may function as a "core regulator of dopamine signaling". Moreover, this mechanism appears to be operative in autistic patients, as 3 PTEN mutants identified in autistic patients cannot suppress TH, which supports the concept of TH suppression as a potential mechanism

Consistent with the finding that TH over activity might underlie the symptoms of autism is the finding by D'Souza et al. [86] that the commonly used model for autism in which symptoms in animals are induced by administering valproic acid is related to the ability of this agent to induce TH transcription at every concentra-

Autism is associated with gastrointestinal pathology from the esophagus to the colon [87–91]. The literature suggests that GI pathophysiology is an intrinsic component of autism in many patients and may be a central component to the etiology of the disease. GI problems have been reported in 42% of children with ASD and 12% of controls, with chronic diarrhea and constipation being the most prevalent problems. The severity of these problems correlates with the severity of ASD [92]. It is noteworthy that in both GI dysfunction and ASD imaging reveals abnormalities in brain regions associated with emotional and sensory functions [93, 94], and GI problems contribute to behavioral problems, attentional deficits, and self injury [95]. Gut bacteria influence intestinal permeability, mucosal immunity, the enteric nervous system, pituitary functions, and the modulation of pain (cited [96]). There is increasing reason to believe that the interaction between gastric microbiota and the brain are contributory to the symptoms seen in ASD. This is mediated via the autonomic innervation of the intestine and the hypothalamic– pituitary axis which is innervated by catecholamines and which generates GI signaling molecules affecting enteroendocrine and mucosal immune cells. The "Gut Brain Axis" is comprised of central and peripheral nervous systems as well as the neuroendocrine and immune systems, and communication is bidirectional, with vagal inputs to the brain as well as endocrine and neuroendocrine signaling [97]. Catecholamines are associated with stress reactions and, interestingly, GI microbiota respond to stress with changes in their efferent and afferent catechol-

A trial of 36 autistic children found pain, chronic diarrhea, bloating, GI irritability, chronic gastritis, esophagitis, chronic duodenitis, diminished carbohydrate digestive enzymes and reduced pancreatic exocrine secretion in response to secretin challenge [88]. Secretin has not been found to be an effective treatment for autism. In a survey of parents of 500 autistic children, half responded that their children had loose stools or chronic diarrhea, and intolerance for wheat and cow's milk [99]. A number of reports mention improvements in autistic symptoms when reduced gluten and casein diets are implemented and the return of symptoms when these

Lucarelli et al. [101] observed an improvement in social skills and the ability to communicate in a trial of 36 autistics who were given diets with diminished

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

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

risperidone, a drug approved to treat ASD.

imbalance in these structures [68, 69].

with ASD [71].

manipulation of dopamine has clinical efficacy in ASD [62, 63], for example with

Other lines of support come from observations of lower levels of dopamine β-hydroxylase in the plasma of autistic patients [64, 65] and reductions in platelet [66] and urine dopamine [67]. Similarly, inferences have been published that the mesolimbic cortex and striatum may provide a neurologic substrate linked with the motor and behavioral symptoms seen in autism as a result of a dopaminergic

Nguyen et al. [70] used in silico methods to clarify the genetics underlying the contribution of dopamine the etiology and pathogenesis of autism and found genes implicated that regulate both Ca++ metabolism and dopaminergic neurotransmission. They found proteins implicated in ASD regulate dopamine signaling in multiple places including reuptake and catabolism, and they defined discrete molecular clusters that act on systems implicit in dopaminergic systems such as androgen receptors that stimulate DOPA decarboxylase. Another finding was the potential role of dopamine mediating the modulation of dendritic spines which determine synaptic strength and may be important in the developmental delays associated

In an interesting cybernetic model, Kriete and Noelle [72] developed a sophisticated methodology to investigate the role of dopamine and the changes in executive function associated with autism. They showed that the intensely focused cognition associated with autism, as well as the pathognomonic lack of cognitive plasticity and inability to react with appropriate conscious focus to changes in the stimulus milieu could be modeled as changes in dopaminergic systems in the prefrontal cortex. By differentiating cognitive control from plasticity, and further by showing how developmental changes in younger brains can account for the timing of the manifestation of autistic symptoms, these authors findings support a causal adrenergic mechanism underling at least some of the symptoms associated with autism. Taken together, a good case can be made for dopamine as a key mediator of the motor, speech, social behavior, behavioral perseveration, and reward aberrations that are typical symptoms of autism. The precise regulation of dopaminergic function of autonomic function appears to involve the projection of Purkinje cells to the medial prefrontal cortex (mPFC) and the ventral tegmental area (VTA) of the striatum. Atrophied Purkinje cells is one of the most consistent neuropathologies associated with autism [73–76], and MRI data indicates persons with autisticism have smaller than normal cerebellar vermal volume [77]. Mice with diminished Purkinje cell mass evidence numerous autistic symptoms such as repetitive behaviors and impaired executive function [78]. Cerebellar Purkinje cells project to the mPFC where it appears they modulate dopaminergic transmission in this region directly, and via a remodeling of the VMA and thalamic interactions with the mPFC, and it has been suggested that cerebellar deficits observed in autism result in cortical, thalamic, and striatal integration via dopamine mediated pathways [79]. An immunologic linkage of dopaminergic function in autism was reported by Kirsten et al. [80] when they prenatally exposed rat pups to lipopolysaccharide, a stimulator of innate and adaptive immunity. Autistic symptoms of impaired communication, deficits in learning and memory, and repetitive/restricted behavior were observed in the presence of impaired tyrosine hydroxylase (TH) function which was taken as a marker of reduced striatal dopaminergic function. Support for this concept was also found when rat pups were given poly I:C, an immunogenic stimulator, and upregulation of various genes associated with dopamine neural

The phosphatase and tensin homolog on chromosome ten (PTEN) is tumor inhibitory gene that inhibits PI3K and MAPK pathways, and a germline mutation of

**102**

development were observed [81].

this gene has been associated with autism [82]. Mouse mutations of this gene have resulted in symptoms similar to autism [83], and PTEN deletions have been found to enhance the survival and the function of dopaminergic neurons [84]. Work in this area has shown that mice with PTEN mutations have elevated TH and DA2 receptors in the striatum and prefrontal cortex, that PTEN reduces TH phosphorylation via MAPK suppression, downregulates dopamine synthesis in PC12 (pheochromocytoma) cell cultures, and that a PTEN-TH pathway may function as a "core regulator of dopamine signaling". Moreover, this mechanism appears to be operative in autistic patients, as 3 PTEN mutants identified in autistic patients cannot suppress TH, which supports the concept of TH suppression as a potential mechanism for therapeutic intervention in autism [85].

Consistent with the finding that TH over activity might underlie the symptoms of autism is the finding by D'Souza et al. [86] that the commonly used model for autism in which symptoms in animals are induced by administering valproic acid is related to the ability of this agent to induce TH transcription at every concentration tested.
