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Possible Role of Caffeine in Autism Spectrum Disorders, a New Testable Hypothesis
Journal of Food Science
... Persico and collaborators [15] showed that ADA plays a relevant role in purine metabolism, which may be altered in some autistic patients. In relation to the modulation of adenosine and autism, various reports suggested the therapeutic potential of the adenosine signaling due to several benefits [28][29][30][31]. Adenosine is known to be an important neuroprotective molecule [32], showing an essential relationship between metabolism and neuronal activity [33]. ...
... Based on behavioral and physiological characteristics of ASD, insufficient adenosine levels may be related to some symptoms (e.g., poor eye contact, repetitive movements) [28,56]. Several studies suggest the therapeutic potential of adenosine in relation to autism [28,30,31,55,57]. Masino and collaborators [28] report that interventions that generate an increase in adenosine levels are an important strategy to alleviate symptoms related to autism. ...
... Multiple adenosine receptor agonists are in clinical trials for various conditions, including cardiac arrhythmias, neuropathic pain, myocardial perfusion imaging, cardiac ischemia, inflammatory diseases, and cancer [58]. Ghanizadeh [31] proposed that caffeine, an adenosine receptor antagonist with differential effects depending on acute or chronic administration, could have beneficial effects in ASD. Furthermore, Tanimura and collaborators [57] showed that adenosine A 2A receptor (A 2A R) activation has been associated with reduced perseverative behaviors. ...
Autism is a neurodevelopmental disorder characterized by symptoms related to stereotyped movements, deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Evidence indicates an important role of extracellular ATP and adenosine as signaling molecules in autism. ATP hydrolysis by ectonucleotidases is an important source of adenosine, and adenosine deaminase (ADA) contributes to the control of the nucleoside concentrations. Considering zebrafish is an animal model that may contribute towards to understanding the mechanisms that underlie social behavior, we investigated the purinergic signaling in a model of embryological exposure to valproic acid (VPA) that induces social interaction deficit in adult zebrafish. We demonstrated embryological exposure to VPA did not change ATP and ADP hydrolysis in zebrafish at 120 dpf, and the cytosolic (soluble) ADA activity was not altered. However, we observed an increase of AMP hydrolysis (12.5 %) whereas the ecto-ADA activity was decreased (19.2 %) in adult zebrafish submitted to embryological exposure to VPA. Quantitative reverse transcription PCR (RT-PCR) analysis showed changes on ntpd8, ADA 2.1, and A2a1 mRNA transcript levels. Brain ATP metabolism showed a rapid catabolism of ATP and ADP, whereas the extracellular metabolism of AMP and adenosine (ADO) occurred slowly. We demonstrated that embryological exposure to VPA altered biochemical and molecular parameters related to purinergic system in adult zebrafish. These findings indicate that the enzyme activities involved in the control of ATP and adenosine levels may be involved in the pathophysiological mechanisms of diseases related to the impairment of social interaction, such as autism.
... Since locomotor activity and social contacts are behavioural patterns normally controlled by eN activity, main adenosine-producing enzyme in the CNS [105,134,164] it is not surprising that the changes in these behavioural patterns contribute to endophenotypes of ASD [165], while eN may be a tool for pharmaceutical intervention in behavioural disorders. Furthermore, several studies suggest the therapeutic potential of adenosine in relation to autism while the interventions generating an increase in adenosine levels are an important strategy to alleviate symptoms related to autism [162,[166][167][168][169]. Synaptically eNmediated formation of extracellular adenosine is responsible for the local activation of A2A receptors [32,134], which are involved in the locomotion, anxiety, inhibition of excitatory neuronal activity, sleep regulation [169] and thus in perseverative behaviors. ...
... Furthermore, several studies suggest the therapeutic potential of adenosine in relation to autism while the interventions generating an increase in adenosine levels are an important strategy to alleviate symptoms related to autism [162,[166][167][168][169]. Synaptically eNmediated formation of extracellular adenosine is responsible for the local activation of A2A receptors [32,134], which are involved in the locomotion, anxiety, inhibition of excitatory neuronal activity, sleep regulation [169] and thus in perseverative behaviors. Thus, A2A receptor is a promising candidate for genetic association studies in ASD [162,166] as well as new target for the treatment of repetitive behaviors in autism [167,169]. Naviaux and coworkers hypothesized that ″antipurinergic therapy″ with suramin corrected numerous multisystem abnormalities that defined the ASD-like phenotype in mice models. This includes correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, hypothermia, P2Y2 and P2X7 receptor expression, and signal transduction abnormalities [170]. ...
Background:
Extracellular adenine nucleotides and nucleosides, such as ATP and adenosine, are among the most recently identified and least investigated diffusible signaling factors that contribute to the structural and functional remodeling of the brain, both during embryonic and postnatal development. Their levels in the extracellular milieu are tightly controlled by various ectonucleotidases: ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPP), alkaline phosphatases (AP), ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'- nucleotidase (eN).
Methods:
Studies related to the expression patterns of ectonucleotidases and their known features during brain development are reviewed, highlighting involvement of these enzymes in synapse formation and maturation in physiological as well as in pathological states.
Results:
During brain development and in adulthood all ectonucleotidases have diverse expression pattern, cell specific localization and function. NPPs are expressed at early embryonic days, but the expression of NPP3 is reduced and restricted to ependymal area in adult brain. NTPDase2 is dominant ectonucleotidase existing in the progenitor cells as well as main astrocytic NTPDase in the adult brain, while NTPDase3 is fully expressed after third postnatal week, almost exclusively on varicose fibers. Specific brain AP is functionally associated with synapse formation and this enzyme is sufficient for adenosine production during neurite growth and peak of synaptogenesis. eN is transiently associated with synapses during synaptogenesis, however in adult brain it is more glial than neuronal enzyme.
Conclusion:
Control of extracellular adenine nucleotide levels by ectonucleotidases are important for understanding the role of purinergic signaling in developing tissues and potential targets in developmental disorders such as autism.
... Interestingly, a partial agonist of the GlyR is caffeine. It is noteworthy that autistic children receiving a low dose of daily caffeine over weeks or months have been reported [62] to sometimes experience improvement of autism symptoms as a result of the caffeine. ...
The causes of autism spectrum disorder (ASD) are not well understood. Only a minority of cases are explainable by specific abnormalities in DNA sequence, whereas the majority are widely assumed to be linked to epigenetic effects, and/or likely impacted by environmental factors. Here, we postulate autism causation via environmental and/or dietary sourced toxin acting intermittently in utero on human fetuses to disrupt neurodevelopment in a non-dose dependent manner. Our theory is informed by a mini-review and correlation of selected studies from the research literature related to autism, including radiologic, anatomic, metabolic, neurodevelopmental, pharmacologic and MRI studies. In reviewing and analyzing evidence, we focus on data supporting interaction of the theorized harmful glycine mimetic at one or more of the following calcium inflow regulatory factors for neurons: the N-methyl D-aspartate (NMDA) receptor, the glycine receptor (GlyR) and/or the glycine transporter protein 1 (GlyT1). We postulate this harmful glycine mimetic to act by exerting a direct molecular disruption to calcium regulatory factors for neurons. This disruption appears to occur in a time sensitive, rather than a strictly dose-dependent manner, leading to haphazard disorganizations of the normally carefully choreographed steps of early neuronal migration. Within this analysis, we find support for the contention that a strong candidate for the putative harmful glycine mimetic is glyphosate, the active ingredient in the pervasive herbicide Roundup®. In addition to glyphosate's molecular similarity to glycine, glyphosate is known to have a propensity to avidly bind minerals such as manganese and magnesium, which minerals are implicated in the normal functioning of several neuronal calcium inflow regulatory factors. Our theory highlights areas deserving of further study.
... Regarding adenosine modulation and autism, several reports have suggested therapeutic potential with diverse postulated benefits (Freitag et al., 2010;Ghanizadeh, 2010;Masino et al., , 2011aTanimura et al., 2010). However, at this time the direction of the relationship, the relevance for particular symptoms, and the receptor subtypes and brain regions involved remain speculative. ...
In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli postulated to increase adenosine can ameliorate these comorbidities. Because adenosine is a broad homeostatic regulator of cell function and nervous system activity, increasing adenosine's influence might be a new therapeutic target for autism with multiple beneficial effects. This article is part of a Special Issue entitled 'Neurodevelopment Disorder'.
... Because the dose of caffeine was not controlled, and because the effect of caffeine on the nervous system is determined by both the dose and the frequency, it is not possible to make strong interpretations based on this finding. However, akin to the trend for more beneficial effects on persons with Asperger's, the relationship between caffeine and autism deserves further exploration; along these lines, recently others have also posited a relationship between caffeine and autism (Ghanizadeh, 2010). Because of its well-established safety profile and limited side effects, vast epidemiological database, and known actions in the nervous system, caffeine is being considered as a low-cost adjuvant or for its own therapeutic potential in multiple neurological disorders (Arendash & Cao, 2010;Cunha & Agostino, 2010;Prediger, 2010;Chen & Chern, 2011). ...
Autism Spectrum Disorders (ASD) are associated with atypical social, behavioral and physiological characteristics. Here we outline an emerging connection among the increased incidence of epilepsy, disrupted sleep and perseverative behaviors exhibited and sought by persons with autism. Specifically, we propose that persons with autism can benefit from increased levels of adenosine, a powerful inhibitory neuromodulator and the core molecule of adenosine triphosphate (ATP). We review the literature and present recent data obtained via a customized questionnaire administered to parents of children with a confirmed autism diagnosis. This customized questionnaire demonstrates that symptoms of autism are reduced subsequent to stimuli predicted to increase adenosine. In addition, we present evidence from the literature and pilot data from a retrospective study of children with epilepsy or epilepsy and autistic behavior who were treated with a ketogenic diet, a long established anticonvulsant therapy that recently has been shown to suppress seizures via the adenosine A1 receptor (A1R) subtype. Our discussion focuses on the actions of adenosine in the central nervous system, with multiple implications for ASD, and the potential for developing new evidence-based therapies. Taken together, published peer-reviewed research and recent preliminary research suggest that adenosine could help resolve multiple physiological and behavioral symptoms of ASD.
... Thus, strategies for behavioral or metabolic upregulation of adenosine may provide a less disruptive approach [4,33]. A recent hypothesis proposed that caffeine, an adenosine receptor antagonist with differential effects depending on acute or chronic administration, could have beneficial effects in ASD [20]. Interestingly, we revealed a significant interaction between reported caffeine use and behaviors associated with autism, supporting a link between adenosine and autism. ...
Adenosine A2A receptor (A2AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the A2AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of A2ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of A2AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and A2AR antagonists in others (Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety). Moreover, we will try to analyze which are the main obstacles to the conduction of clinical trials with A2AR ligands for the treatment of neuropsychiatric disease.
Autism is characterized by impairments in social interactions, deficits in communication, and repetitive behaviors or stereotyped interests. People with autism also have an increased incidence of seizures, gastrointestinal disorders, sleep disruption, and psychological disorders such as anxiety and depression. Purine abnormalities have been associated with autism, but evidence has not typically linked purines to either the neurochemistry or behavioral hallmarks of the disorder. Here we review emerging and converging lines of evidence suggesting that a metabolic increase in the influence of the purine nucleoside adenosine has the potential to play a key role in reducing multiple behavioral and physiological symptoms of autism. First, results from a questionnaire study of parents of children with autism indicated that stimuli and activities predicted to increase adenosine are observed to reduce symptoms of autism. Second, a ketogenic diet—a high-fat, low-carbohydrate regimen used to treat epilepsy—can reduce electrographic seizures in mice via actions at adenosine A1 receptors, and other research has shown that a ketogenic diet can improve symptoms of autism in children with autism and improve sleep in children with epilepsy. In animal studies, this established metabolic therapy has been shown to increase ATP levels and reduce levels of the intracellular adenosine-metabolizing enzyme adenosine kinase, suggesting possible mechanisms for increased extracellular adenosine. While the number of studies investigating each of these areas is limited to date, accumulating evidence suggests that metabolic strategies to increase adenosine could address some of the core and comorbid symptoms of autism. Further research is needed.
Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.
Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.
An increase in the extracellular concentration of dopamine in the nucleus accumbens (NAc) is believed to be one of the main mechanisms involved in the rewarding and motor-activating properties of psychostimulants such as amphetamines and cocaine. Using in vivo microdialysis in freely moving rats, we demonstrate that systemic administration of behaviorally relevant doses of caffeine can preferentially increase extracellular levels of dopamine and glutamate in the shell of the NAc. These effects could be reproduced by the administration of a selective adenosine A1 receptor antagonist but not by a selective adenosine A2A receptor antagonist. This suggests that caffeine, because of its ability to block adenosine A1 receptors, shares neurochemical properties with other psychostimulants, which could contribute to the widespread consumption of caffeine-containing beverages.
The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain. Adenosine A(1) and A(2A) receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control. Caffeine acts as an antagonist to both types of receptors. Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia. These cells express high levels of adenosine A(2A) receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32. The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.
We have previously shown that the peripheral administration of an A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) protected the hippocampus against kainate-induced excitotoxicity. The present study utilises the intrahippocampal route to further investigate CGS 21680-mediated protection as well as examining the role of adenosine and both A1 and A2A receptors in kainate-induced excitotoxicity. Injections were made directly into the hippocampus of anaesthetised male Wistar rats. Following surgery and the administration of 0.25 nmol kainate in 1 μl of solution, the animals were left to recover for seven days before perfusion and brain slicing. Haematoxylin and eosin staining revealed substantial damage to the CA3 region. Co-administration of the A2A receptor agonist CGS 21680 over a range of doses did not protect the region to any degree. Similarly neither the A1 receptor agonist R-phenylisopropyladenosine (R-PIA), nor adenosine itself reduced kainate-induced damage. The intrahippocampal injection of the selective A2A receptor antagonist, 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385) however, significantly decreased kainate damage to the CA3 region. These results show that adenosine A2A receptor-induced protection is most likely to be mediated peripherally and is probably not due to activation of A2A receptors within the hippocampus. The lack of protection observed with either R-PIA or adenosine may be due to an inhibitory action of the A2A receptor on the neuroprotective A1 receptor. Importantly, this study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage.
Caffeine ranks as one of the top most commonly consumed dietary ingredients throughout the world. It is naturally found in coffee beans, cacao beans, kola nuts, guarana berries, and tea leaves including yerba mate. The total daily intake, as well as the major source of caffeine varies globally; however, coffee and tea are the 2 most prominent sources. Soft drinks are also a common source of caffeine as well as energy drinks, a category of functional beverages. Moderate caffeine consumption is considered safe and its use as a food ingredient has been approved, within certain limits, by numerous regulatory agencies around the world. Performance benefits attributed to caffeine include physical endurance, reduction of fatigue, and enhancing mental alertness and concentration. Caffeine has also been recently linked to weight loss and consequent reduction of the overall risks for developing the metabolic syndrome. However, the caloric contribution of caffeine-sweetened beverages needs to be considered in the overall energy balance. Despite all these benefits the potential negative effects of excessive caffeine intake should also be considered, particularly in children and pregnant women.
Repetitive behaviors are diagnostic for autism and common in related neurodevelopmental disorders. Despite their clinical importance, underlying mechanisms associated with the expression of these behaviors remain poorly understood. Our lab has previously shown that the rates of spontaneous stereotypy in deer mice (Peromyscus maniculatus) were negatively correlated with enkephalin content, a marker of striatopallidal but not striatonigral neurons. To investigate further the role of the indirect basal ganglia pathway, we examined neuronal activation of the subthalamic nucleus (STN) using cytochrome oxidase (CO) histochemistry in high- and low-stereotypy mice. CO activity in STN was significantly lower in high-stereotypy mice and negatively correlated with the frequency of stereotypy. In addition, exposure to environmental enrichment, which attenuated stereotypy, normalized the activity of STN. Co-administration of the adenosine A(2A) receptor agonist CGS21680 and the A(1) receptor agonist CPA attenuated stereotypy dose-dependently. The significant reduction associated with the lowest dose of the drug combination tested was due to its effects on mice with lower baseline levels of stereotypy. Higher doses of the drug combination were required to show robust behavioral effects, and presumably requisite activation of the indirect pathway, in high-stereotypy mice. These findings support that decreased indirect pathway activity is linked to the expression of high levels of stereotypy in deer mice and that striatal A(1) and A(2A) receptors may provide promising therapeutic targets for the treatment of repetitive behaviors in neurodevelopmental disorders.
Caffeine is a widely used psychoactive substance in both adults and children that is legal, easy to obtain, and socially acceptable to consume. Although once relatively restricted to use among adults, caffeine-containing drinks are now consumed regularly by children. In addition, some caffeine-containing beverages are specifically marketed to children as young as 4 years of age. Unfortunately, our knowledge of the effects of caffeine use on behavior and physiology of children remains understudied and poorly understood. The purpose of this article is to review what is known about caffeine use in children and adolescents, to discuss why children and adolescents may be particularly vulnerable to the negative effects of caffeine, and to propose how caffeine consumption within this population may potentiate the rewarding properties of other substances. The following topics are reviewed: (1) tolerance and addiction to caffeine, (2) sensitization and cross-sensitization to the effects of caffeine, (3) caffeine self-administration and reinforcing value, and (4) conditioning of preferences for caffeine-containing beverages in both adults and children.
The present study investigated the effect of adenosine on glial glutamate efflux. Adenosine (from 1 nM to 100 microM) enhanced the release from cultured rat glial cells in a bell-shaped dose-responsive manner for the hippocampus and in a dose-dependent manner for the superior colliculus, and a similar increase was obtained with the A2a adenosine receptor agonist, 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS21680), but not with the A1 adenosine receptor agonist, N6-cyclohexyladenosine (CHA). Adenosine and CGS21680 also enhanced glutamate efflux from Xenopus oocytes injected with the poly (A)+ mRNAs derived from cultured glial cells for the hippocampus and the superior colliculus together with and without the A2a adenosine receptor mRNA, but instead such increase was not found in oocytes expressing A2a adenosine receptors alone. The results of the present study thus suggest that adenosine enhances glutamate efflux from glial cells via A2a adenosine receptors, and this may represent a mechanism underlying the facilitatory action of adenosine on hippocampal and superior colliculus neurotransmissions.
The aim of the present work was to determine whether systemic administration of the adenosine A(2A) receptor antagonist, SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4,triazolo[1,5-c]pyrimidine), could modulate striatal glutamate outflow in the rat. Microdialysis experiments were performed in male Wistar rats implanted with microdialysis probes in the striatum. Pretreatment (15 min before) with SCH 58261 (0.01 and 0.1, but not 1 mg/kg intraperitoneally) significantly prevented K(+)-stimulated glutamate release. These results suggest that SCH 58261 could possess neuroprotective effects in the low dose range, while, at higher doses, the occurrence of additional mechanisms may limit the neuroprotective potential of this drug.
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.
2010 Caffeine and Adenosine
- Ja Ribeiro
- Sebastiao
Ribeiro JA, Sebastiao AM. 2010 Caffeine and Adenosine. J Alzheimers Dis 20(S1):3–15
Neurochemical correlates of autistic disorder: a review of the literature
- Ks Lam
- Mg Aman
- Le Arnold
Lam KS, Aman MG, Arnold LE. 2006. Neurochemical correlates of autistic disorder: a review
of the literature. Res Dev Disabi 27(3):254–89.
Neurochemical correlates of autistic disorder: a review of the literature
- K S Lam
- M G Aman
- L E Arnold
Lam KS, Aman MG, Arnold LE. 2006. Neurochemical correlates of autistic disorder: a review
of the literature. Res Dev Disabi 27(3):254-89.
Neurochemical correlates of autistic disorder: a review of the literature
- Lam