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Neurotransmitters and Learning, Memory and Developmental Disorders

By Margaret Lahey and Shari Rosen
BAMFORD-LAHEY CHILDREN'S FOUNDATION

NEUROTRANSMITTERS AND LEARNING, MEMORY AND DEVELOPMETNAL DISORDERS

Neurotransmitters are important for memory, learning, and behavior among other things. There are many types of chemicals that act as neurotransmitters in the human body and the way that foods may affect these chemicals is important to understanding the possible role of diet in developmental disorders. Neurotransmitters travel across a synapse to bind to a postsynaptic receptor protein; each neurotransmitter binds only to specific receptors on the postsynaptic membrane. There are a number of types of receptors for different neurotransmitters. This binding eventually brings about a change in the electrical state of the postsynaptic cell either exciting or inhibiting it. The action can be decreased or neutralized in a number of ways including: glial cells, which remove neurotransmitters from the synaptic cleft; reuptake, where the chemical is taken back to the axon that released it; blocking, whereby the flow by substances that attach to specific receptors is blocked; and by prolonged exposure to the neurotransmitter.

INTRODUCTION

In this section we discuss only a few of many neurotransmitters focusing on those that may have possible relevance to developmental disorders. Such neurotransmitters include: acetycholine, which is involved in muscle contractions and in diseases such as myasthenia gravis; serotonin (5-HT), which is found in greatest concentration in the gastrointestinal tract and is involved in sensory perception, mood control, depression, impulsivity, aggression, and other behavior problems; dopamine, which is involved in reward or reinforcement, in problems in cognition, and in diseases such as Parkinson's disease, mood disorders, and schizophrenia; norepinephrine, which helps regulate arousal and moods, excites gastrointestinal activity, and modulates endocrine function (e.g., insulin secretion); epinephrine or adrenalin, which is involved in vasoconstriction and dilation, relaxation of smooth muscles of the intestine (thus inhibiting intestinal motility), and endocrine function. The amino acids GABA and glutamate also act as neurotransmitters. GABA is the main inhibitory neurotransmitter reducing anxiety; glutamate is the main excitatory neurotransmitter and is involved in memory formation and in ALS or Lou Gehrig's Disease.

In addition to the above neurotransmitters, there are many peptides found in neural tissue that act as neurotransmitters. A number of these are involved in regulating digestion and absorption and are also considered hormones. Some examples of these include: gastrin, which stimulates hydrochloric acid and intestinal motility; CCK, which stimulates pancreatic excretions as well as gallbladder excretion of bile; and secretin, which stimulates release of pancreatic juice and inhibits motility of the intestines. Secretin, as discussed in the section on digestion below, has been considered as a treatment for autism. The digestive tract has receptors for these and other neuropeptides involved in digestion. The brain also has a number of receptors for peptides such as the opioid peptides, so called because they can produce opium like effects of pain relief and euphoria. Opioid peptides produced by the body include the endorphins and the enkephalins. Beta-endorphin is the most potent endorphin and is localized in brain regions such as the hypothalamus, brain stem and the pituitary gland. Endorphins can further decompose to small fragments that pass the blood-brain barrier more readily. Opioids formed from external substances (i.e., exorphins) will attach to these same opioid receptors if they reach the blood and pass the blood-brain barrier. Exorphins include heroin, peptides from digestion of food protein, and the drug Naltrexone, which is used to block the opioid receptors. Other neuroactive peptides include oxytocin and vasopressin, which are synthesized in the hypothalamus with receptors located primarily in the brain. These neuropeptides have been associated with the modulation of memory and with the formation of social attachments (Insel, 1997).

DIETARY INFLUENCES

Most neurotransmitters are synthesized within the brain; however, dietary precursors can influence both rate and function of some neurotransmitters even when no deficiency exists (Anderson & Johnston, 1983; Young, 1996). The manufacture and release of these neurotransmitters depends in large part on the concentration of the particular precursor in the blood (Lamb, 1983). Although factors within the brain also control synthesis and function of neurotransmitters, ingestion of particular foods can give rise to changes in the neural activity in the brain with resultant changes in physiological functioning and behavior; changes may be subtle in the healthy individual but for those with particular diseases or problems (e.g., depression) they could be significant (Maher, 2000; Young, 1996). To have any effect on behavior, the neurotransmitter must be released from the neurons and act on the receptors of postsynaptic neurons and this may be influenced by factors other than the level of the neurotransmitter (Young, 1996).

Amino acids, which are the building blocks of proteins and present in food proteins, are precursors for a number of neurotransmitters. In fact, some amino acids, such as tryptophan, are available only from dietary sources (Groff & Gropper, 1999). The effect of food is most obvious for the amino acids tryptophan, tyrosine, phenylalanine and these amino acids serve as the biosynthetic precursors for the neurotransmitters serotonin, dopamine, and norepinephrine. Single meals can influence the brain's uptake of these amino acids and modify their conversion to neurotransmitters (e.g., Fernstrom, 1994; Groff & Gropper, 1999; Wurtman, 1988). The transport of amino acids into the brain and thus their conversion into neurotransmitters is determined by the ratio of plasma levels of large molecule neutral amino acids to one another; for example, the plasma tryptophan ratio to other plasma amino acids affects brain levels of tryptophan (e.g., Liberman, Caballero, & Finer, 1986; Maher, 2000; Yokogoshi & Wurtman, 1986). Large neutral amino acids such as tryptophan and tyrosine compete with one another for transport into the brain and there is less tryptophan in most proteins than other amino acids like tyrosine. Plasma and brain levels of tryptophan and the synthesis of serotonin are increased in animals and humans following a carbohydrate meal but are blocked if protein is eaten first or is included with the carbohydrates (e.g., Fernstrom, 1988; Fernstrom & Fernstrom, 1995; Spring, 1984). Although carbohydrates lack the amino acid tryptophan, the carbohydrate meal affects tryptophan plasma levels by increasing the levels of insulin, which in turn stimulates the uptake of competing amino acids (but not tryptophan) into muscle tissue (e.g., Groff & Gropper, 1999; Spring, 1984). By contrast, ingestion of protein increases the levels of competing amino acids thus decreasing the likelihood that tryptophan will be transported across the blood-brain barrier (e.g., Spring, 1984). Most of the research on dietary precursors to neurotransmitters has been done on tryptophan.

The amino acids tyrosine and phenylalanine are precursors to dopamine; norephrine is synthesized from dopamine and epinephrine is synthesized from norephrine. As noted above, the level of these precursors in the blood influences the amount of tryptophan that crosses the blood brain barrier (Fernstrom, 1994). However, increased levels of tyrosine in the brain do not directly correlate with an increase in the neurotransmitter dopamine and the behavioral effects of loading with tyrosine are controversial (Groff & Gropper, 1999). The effect of increased dietary sources of tyrosine on levels of tyrosine in the brain appears to vary with region of the brain and the effect of increased levels in the brain on neural activity is influenced by the firing rate of the neuron (McTavish, Cowen, & Sharp, 1999: Groff & Gropper, 1999). When firing rate is markedly increased as in Parkinson's disease or dopamine-depleting lesions, tyrosine can increase levels of dopamine (Groff & Gropper, 1999). The amino acids glutamate and aspartate are neurotransmitters but their level in the brain seems not to be influenced by diet.

Choline is the precursor for the neurotransmitter acetylcholine and is found in the form of phosphatidylcholine, or lecithin, in many foods (e.g., eggs, liver, soybeans, peanuts) but the richest source used by the brain is endogenous. However, taken in large quantities, dietary lecithin does increase plasma and brain levels of choline. The effect of dietary precursors on acetycholine release in animals is influenced by a number of factors including environmental conditions such as novel surroundings (Kopf, Buchholzer, Hilgert, et al., 2001). Dietary deficiency of choline impairs the release of acetylcholine in the hippocampus and impairs memory in animals (Nakamura, Suzuki, Umegaki, et al., 2001). As with tyrosine, it appears that synthesis of acetycholine in response to dietary choline restriction may vary with the region of the brain (Nakamura et al., 2001). Cholergenic antagonists can produce memory deficits, and choline supplementation has been found to produce memory improvement in animals, human adults with choline deficiency, and in young normal humans (Gozes, Bardea, Reshef, et al., 1996; Groff & Gropper, 1999; Ladd, Sommer, LaBerge, & Toscano, 1993; Holmes, Yang, Liu, et al., 2002; Buchman, Sobel, Brown, et al., 2001). The availability of a dietary source of choline is particularly important for brain development related to memory and attention in the fetus and infant of animals and humans (Meck, & Williams, 1999; Yang, Liu, Cermak, et al., 2000; Yen, Mar, Meeker, et al., 2001; Zeisel, 2000).

The effect of diet on the function and levels of the neurotransmitters that are important for learning and behavior is another way that diet can affect learning and behavior as noted in Hypothesis A above. Given this possible effect, it is important to consider whether there is any dysfunction of neurotransmitters in developmental disorders and whether diet is associated with such dysfunction.

DEVELOPMENTAL DISORDERS

Because neurotransmitters are vitally important for control of cognition and behavior many have pursued the study of their relation to developmental disorders. The two neurotransmitters receiving the most attention are serotonin and dopamine.

Evidence suggests that some individuals with autism have problems with tryptophan-serotonin metabolism in the brain and that this is related to clinical symptoms (e.g., Chugani, Muzik, Behan, et al., 1999; Cook, Courchesne, Lord, et al., 1997; Cook & Leventhat, 1996; Croonenberghs, Delmeire, Verkerk, et al., 2000; D'Eufemia, Finocchiaro, Celli, et al., 1995; Herault, Petit, Martineau, ete al., 1996; Hoshino, Yamanoto, Kaneko, et al., 1986; Leboyee, Philippe, Bouvard, et al., 1999). In adults with autism, depletion of tryptophan (via low tryptophan diet and ingestion of tryptophan-free drink of amino acids) resulted in an increase in symptoms such as whirling, flapping, rocking, and self-injurious behavior among many of the subjects (McDougle, Naylor, Cohen, et al., 1996). In 60% of autistic children tested, researchers found a tripeptide that stimulates serotonin uptake thus decreasing the amount of serotonin available to the children (Pedersen, Liu, Reichelt, 1999). In another study, anxiety and mood symptoms improved in approximately half of the children who received a serotonin reuptake inhibitor (e.g., Namerow, Thomas, Bostic, et al., 2003). All these data support the hypothesis that a serotonin dysfunction is related to symptoms of autism in some individuals. One study links the problems of serotonin with the immunological abnormalities associated with autism suggesting that the problems with serotonin metabolism in some subjects may be secondary to ongoing genetically based autoimmune processes (Warren & Singh, 1996).

Dopamine is an important neurotransmitter for cognitive function and some have hypothesized that individuals with ADHD may have problems related to this neurotransmitter (e.g., Decker & Rye, 2002; Gill, Daly, Heron, et al., 1997; Nieoullon, 2002; Solanto, 2002). A number of studies have found a link between the dopamine transporter and dopamine receptor genes in some individuals with ADHD (DiMaio, Grizenko, & Joober, 2003; Faraone, Doyle, Mick, & Biederman, 2002; Gill, et al., 1997; Roman, Schmitz, Polanczyk, et al., 2001). One study found decreased dopamine release in the brains of adult ADHD subjects as compared with those of controls (Schuster, 2003). Changing the transmission of dopamine is hypothesized as a means of improving cognitive impairment (Nieoullon, 2002). Stimulants that are often prescribed for improving symptoms of ADHD are considered as a way of compensating for dopamine (and norepinephrine) deficiency in ADHD as they act to block the reuptake of catecholamines, such as dopamine, and/or facilitate their release (Solanto, 2002). A study using a dopamine agonist with children exhibiting symptoms of both ADHD and restless leg syndrome in sleep reported improvement in sleep as well as visual memory, behavioral symptoms and in some children variable attention (Walters, Mandelbaum, Lewin, et al., 2000). These findings could also be interpreted to support the hypothesis of a dopaminergic deficit in at least some children with ADHD. Dysfunction of the dopaminergic system in both mother (during pregnancy) and child has also been related to autism (e.g., Ernst, Zametkin, Matochik, et al., 1997; Garreau, Barthelemy, Bruneau, et al., 1988; Launay, Bursztejn, Ferrari, et al., 1987; Martineau, Herault, Petit, et al., 1994; Robinson, Schutz, Macciardi, et al., 2001; Takahashi, Tortenson, Danfors, et al., 2001).

Dysfunctions of the neurotransmitters epinephrine and norepinephrine as well as the amino acid glutamate have been associated with developmental disorders (Launay et al., 1987; Moreno-Fuenmayor, Borjas, Arrieta, et al., 1996). Moreover, problems with the endogenous endorphins have received considerable attention in relation to both autism and mental retardation (e.g., Leboyer et al., 1999; Nagamitsu, Matsuishi, Kisa, et al., 1997; Sandman, 1988; Tordjman, Anderson, McBride, et al., 1997; Willemsen-Swinkels, Buitelaar, Weijnen, et al., 1995, 1996). Finally, GABA levels have been studied less frequently than serotonin, but have also been reported to be elevated in the plasma of children with autism (Dhossche, Applegate, Abraham, et al., 2002).

Controlling the synthesis and levels of neurotransmitters is the function of many of the pharmaceutical approaches to psychiatric disorders. As noted above, diet is also a source of many of the precursors of the neurotransmitters and can influence the levels of precursors as well as the synthesis of the neurotransmitters. Other than the study of opioids and their relation to endorphins, which is discussed below under proteins, it appears that little research has been done on whether dietary changes can influence levels or synthesis of neurotransmitters in children with developmental disorders.

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