Neurochemical correlates of autistic disorder: A review of the literature

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Abstract

Review of neurochemical investigations in autistic disorder revealed that a wide array of transmitter systems have been studied, including serotonin, dopamine, norepinephrine, acetylcholine, oxytocin, endogenous opioids, cortisol, glutamate, and gamma-aminobutyric acid (GABA). These studies have been complicated by the fact that autism is a very heterogeneous disorder which often presents with comorbid behavioral problems. In addition, many of these studies employed very small samples and inappropriate control groups, making it difficult to draw conclusions with confidence. Overall, serotonin appears to have the most empirical evidence for a role in autism, but this requires further investigation and replication. There is little support for the notion that a dysfunction of norepinephrine or the endogenous opioids are related to autism. The role of dopaminergic functioning has not been compelling thus far, though conflicting findings on central dopamine turnover require further study. Promising new areas of study may include possible dysfunction of the cholinergic system, oxytocin, and amino acid neurotransmitters. Implications for pharmacotherapy are briefly discussed for each neurotransmitter system with brief research examples. Review of this work emphasizes the need for future studies to control for subject variables, such as race, sex, pubertal status, and distress associated with blood draws, which can affect measures of neurochemical function. In addition, research in neurochemistry must continue to work in concert with other subspecialties to form a more comprehensive and theory-based approach to the neurobiological correlates of autistic disorder.

Section snippets

Neurochemical correlates of autistic disorder

Autism is a pervasive developmental disorder characterized by impaired social interaction, deficits in verbal and nonverbal communication, and stereotyped interests and behaviors. Although the estimated prevalence in the general population ranges from 0.04 to 0.2% (Sponheim & Skjeldal, 1998; Chakrabarti & Fombonne, 2001), its emergence early in life, its profound impact on families, and its chronic course have resulted in enormous emotional and financial costs (Bristol et al., 1996). It is now

Serotonin

Among all neurochemical investigations in autism, serotonin (5-hydroxytrypamine or 5-HT) has stimulated the most research and investigation. Serotonin is an indolamine that is derived from the essential amino acid tryptophan. Tryptophan is hydroxylated by tryptophan hydroxylase to create 5-hydroxytryptophan (5-HTP); this is the rate-limiting step in the synthesis of serotonin. Under normal physiological conditions, this enzyme is not fully saturated; therefore, increases in dietary tryptophan

Dopamine

Dopamine (DA) is a catecholamine that is synthesized from the dietary amino acid tyrosine. Once ingested, tyrosine is hydroxylated (by tyrosine hydroxylase) into l-dihydroxyphenylalanine (l-DOPA). This is the rate-limiting step of the synthesis of dopamine. l-DOPA is then converted to dopamine via the enzyme DOPA decarboxylase. Most DA-containing neurons lie in the midbrain; in particular, three important DA systems project from the substantia nigra and the ventral tegmental area (Carlson, 2001

Norepinephrine

Norepinephrine (also known as noradrenaline) is a catecholamine that is synthesized from DA through the action of the enzyme DA beta-hydroxylase. Nearly every region of the brain receives input from noradrenergic neurons (Carlson, 2001). The cell bodies of the most important system are located in the locus coeruleus, which is located in the dorsal pons. The projections of this area are distributed widely throughout the brain, and activity of these systems is thought to play a critical role in

Acetylcholine

Acetylcholine (ACh) is the neurotransmitter found at the neuromuscular junction, in autonomic nervous system ganglia, and in multiple sites in the CNS (Kandel, Schwartz, & Jessel, 1995). In the brain, three systems have been of interest to neuroscientists: the dorsolateral pons (involved in REM sleep), the basal forebrain (which activates areas of the cerebral cortex and facilitates learning), and the medial septum (which projects to the hippocampus, an area involved in memory). There are two

Oxytocin

Oxytocin (OT) is a peptide synthesized in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in the brain. Cells in the PVN that synthesize oxytocin project diffusely throughout the brain and the brainstem (Sofroniew & Weindl, 1981). It has also been found that receptors for oxytocin are located throughout the limbic system in the forebrain and in the autonomic centers in the brainstem (Barberis & Tribollet, 1996). These observations strongly suggest that OT acts centrally as a

Endogenous opioids

Endogenous opioids are peptides that exert effects on the central nervous system, acting as neuromodulators. There are three distinct types: beta-endorphins, enkephalins, and dynorphin. Each type of opioid has a different affinity for a certain receptor subtype: beta-endorphins for mu receptors (implicated in analgesia and euphoria), the enkephalins for mu and delta (less understood, perhaps associated in analgesia and reinforcement), and dynorphins for kappa receptors (implicated in spinal

Cortisol

Cortisol is a glucocorticoid that is released by the adrenal cortex in response to stress. Its secretion is controlled by the hormone adrenocorticotropin (ACTH), which is released from the pituitary. ACTH release, in turn, is under the control of corticotropin-releasing factor (CRF) which is produced in the hypothalamus. Normally, cortisol limits its own release via a feedback loop, by suppressing the release of CRF and ACTH. Abnormalities in this feedback mechanism have been studied

Amino acid neurotransmitters: glutamate and GABA

Glutamate and gamma-aminobutyric acid (GABA) are the two transmitter substances that are linked to widespread synaptic communication in the CNS. Glutamate is the principal excitatory transmitter substance in the brain and spinal cord, whereas GABA is responsible for most of the inhibitory communication in the brain (Carlson, 2001, Kandel et al., 1995). Glycine is the principle inhibitory transmitter in the spinal cord and lower brain stem. These substances are widely produced in the central

Discussion

At first glance, the bulk of neurochemical research in autism has been inconclusive, contradictory, and somewhat disappointing. Most of these studies employed few subjects and included comparison groups that were not appropriate, making it difficult to draw clear-cut conclusions. However, there appear to be some areas that may prove fruitful for future researchers. Clearly, serotonin remains the most promising area for future neurochemical research. With the development of sophisticated imaging

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