Neurotransmitters in pediatric disorders of learning, behavior and development

Posted on September 22, 2010 by Dr. Jonathan

Neurotransmitters, the signaling molecules of brain function, are one of the factors that must be included when evaluating and treating pediatric disorders of learning, behavior and development. A paper published in the journal Biological Psychiatry offers an overview in the context of ADHD:

“The etiology of ADHD has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging studies suggest that dysfunction in the fronto-subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic systems, contribute to the pathophysiology of ADHD.”

Moreover, from the remedial perspective:

“Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.”

Another paper in the same issue discusses the neuropsychopharmacology of ADHD:

“Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD…Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms…Imaging studies suggest stimulants increases DA levels in the brain…”

The author sums up his findings by stating:

“…ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.”

The authors of another paper in the same issue of Biological Psychiatry address the role of the catecholamine neurotransmitters dopamine and norepinephrine in prefrontal executive functions:

“The prefrontal cortex guides behaviors, thoughts, and feelings using representational knowledge, i.e., working memory. These fundamental cognitive abilities subserve the so-called executive functions: the ability to inhibit inappropriate behaviors and thoughts, regulate our attention, monitor our actions, and plan and organize for the future. Neuropsychological and imaging studies indicate that these prefrontal cortex functions are weaker in patients with attention-deficit/hyperactivity disorder and contribute substantially to attention-deficit/hyperactivity disorder symptomology.”

They describe further evidence for the importance of the catecholamine neurotransmitters in ADHD:

“Optimal levels of norepinephrine acting at postsynaptic α-2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine α-2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of attention-deficit/hyperactivity disorder, including impulsivity and locomotor hyperactivity.”

The authors conclude by stating:

“Most effective treatments for attention-deficit/hyperactivity disorder facilitate catecholamine transmission and likely have their therapeutic actions by optimizing catecholamine actions in prefrontal cortex.”

Interesting research published in the journal Sleep reveals a link between intermittent hypoxic insults (short periods of suboptimal oxygen levels) and dopamine dysregulation. The authors tested…

“…the hypothesis that intermittent hypoxic insults, occurring during this period of critical brain development, lead to persistent reductions in extracellular levels of dopamine within the striatum. We also tested the hypothesis that post-hypoxic rats exhibit increased novelty-induced behavioral activation and increased basal levels of locomotor activity, two indexes of impaired dopaminergic functioning.”

Behavior of their postnatal animals was recorded and correlated with dopamine measurements after intermittent bursts of hypoxic (oxygen-reduced) gas. They demonstrated heightened response to novelty, locomotor hyperactivity and reduced extracellular dopamine. This brings to mind an earlier post on oxygen and disorders of learning and behavior. What did the authors conclude from their data?

“These data, in conjunction with our previous observations, support our hypothesis that intermittent hypoxic insults occurring during a period of critical brain development lead to sequestration of dopamine presynaptically within nigrostriatal axons. We postulate that neonatally occurring hypoxic insults are one potential pathogenic mechanism underlying disorders of minimal brain dysfunction, such as attention-deficit/hyperactivity disorder, characterized by executive dysfunction and hyper responsiveness to novel stimuli, which is responsive to agents promoting enhanced extracellular levels of synaptic dopamine.”

More nuanced evidence for the importance of neurotransmitters in ADHD is presented in a paper published in the journal Progress in Brain Research that highlights dopamine-serotonin interactions.

“Poor control of attention-related and motor processes, often associated with behavioural or cognitive impulsivity, are typical features of children and adults with attention-deficit hyperactivity disorder (ADHD). Until recently clinicians have observed little need to improve on or add to the catecholaminergic model for explaining the features of ADHD. Recent genetic and neuroimaging studies however provide evidence for separate contributions of altered dopamine (DA) and serotonin (5-HT) function in this disorder.”

Their findings are an excellent example of the importance of considering each child as an individual and avoiding the regrettable tendency to ‘rubber-stamp’ a diagnosis and associated treatment—in this case stimulants or re-uptake inhibitors:

“While the monoamine metabolite levels excreted in ADHD are often correlated, this may well flow from a starting point where 5-HT activity is anomalously higher or lower than the generally lower than normal levels for DA. It appears that perhaps both situations may arise reflecting different diagnostic subgroups of ADHD, and where impulsive characteristics of the subjects reflect externalizing behaviour or cognitive impulsivity…Interactions mediated by macroglia are also likely. However, it remains difficult to ascribe specific mechanisms to their effects (in potentially different subgroups of patients)…”

Moreover, there are individual differences in the receptors for dopamine that come into play with ADHD. In a study published in Archives of General Psychiatry the authors examine polymorphisms in dopamine receptors.

“Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis.”

They investigated polymorphisms (gene variants) for both the dopamine D1 receptor (DRD1) gene and the dopamine transporter (DAT1) gene in 105 children with ADHD in comparison with 103 healthy controls, and used cerebral cortical thickness and the presence of DSM-IV–defined ADHD as metrics. The data painted an interesting picture:

“Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls…By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development.”

The authors sum up the significance of their findings:

“The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.”

In other words, there are genetic differences in the dopamine receptor and transport systems that can manifest as brain thinning and problems with attention.

The practical message is that children (and adults) with disorders of learning and behavior should be evaluated as individuals for problems with neurotransmitter production, transport and receptor populations. The functional approach prefers physiological interventions to supply depleted or insufficient resources for intrinsic neurotransmitter production and receptor maintenance, strategies to protect receptors and transporters from inflammatory damage due to autoimmune microglial activation, and related physiological treatment methods.

Compulsive eating and dopamine receptor dysfunction

Posted on May 11, 2010 by Dr. Jonathan

As most of you well know, the neurotransmitter dopamine and its receptors are critical to the brain’s reward pathways, and dysfunction of these pathways is associated with addictive behaviors. This paper recently published in the journal Nature Neuroscience elucidates the role of dopamine receptors in compulsive eating with obesity. The authors first noticed that…

“…development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking.”

On investigating the underlying mechanism they found that compulsive feeding was present in obese but not lean rats because…

“Striatal (corpus striatum of the brain) dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs.”

What did they conclude from their data?

“These data demonstrate that overconsumption of palatable food [which produces insulin resistance] triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.”

Journal of Neuorendocrinology A paper published in the Journal of Neuroendocrinology adds further support to the importance of dopamine in appetite regulation. Ghrelin is a peptide produced in the stomach that increases appetite by stimulating a part of the brain (VTA = ventral tegmental area) that is rich in dopamine producing neurons:

“Interestingly, ghrelin infusions into the VTA increase food intake dramatically, and stimulate dopamine release from the VTA…ghrelin increases food intake by modulating the activity of dopaminergic neurones in the VTA.“

The author offers this conclusion:

“On the basis of these data as well as the fact that VTA dopamine cells respond to other metabolic hormones such as insulin and leptin, it is proposed that VTA dopamine cells…are first-order sensory neurones that regulate appetitive behaviour…”

Pharmacology Biochemistry Behavior Blood sugar and insulin have such a powerful effect on the brain and energy (nutrient) seeking behavior it’s no wonder there’s abundant evidence that they are associated with dopamine in the regulation of appetite. This paper published in Pharmacology Biochemistry and Behavior notes that:

“The hormones insulin, leptin, and ghrelin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis…CNS circuitry that subserves reward and is also a direct and indirect target for the action of these endocrine regulators of energy homeostasis.”

Their research demonstrates that insulin and leptin can dampen reward satisfaction through an effect on dopamine signaling:

“Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, the midbrain dopamine (DA) and opioidergic pathways.”

Another study published in Acta Diabetologica also confirms the profound effect of insulin on dopamine signaling:

“Administration of various doses of glucose to rats produced a significant decrease of dopamine turnover…a close connection between 3,4-dihydroxyphenylacetic acid (DOPAC) (metabolite of dopamine) variation and insulin plasma level was demonstrated. However, glucose did not affect dopamine metabolism in starved or streptozotocin-treated rats (rats made to be diabetic). This indicates that the effect of glucose on the central dopaminergic system is mediated by pancreatic insulin, even in the presence of endogenous brain insulin.”

Moreover, dopamine gives the message that the cells are satisfied and shuts down pancreatic production of insulin as described in this paper published in The Journal of Biological Chemistry:

“Both dopamine and insulin actions in the brain modulate appetite and feeding behaviors. In this work we show for the first time that pancreatic beta cells express dopamine receptors mediating inhibition of glucose-stimulated insulin secretion.”

They go on to further describe the close association of dopamine with insulin and problems related to blood sugar regulation and obesity:

“Moreover, antipsychotic (neuroleptic) drugs blocking dopamine receptors may cause hyperinsulinemia, hypoglycemia, increase appetite, and obesity and are associated with diabetes. Therefore, dopamine action on beta cells (of the pancreas that secrete insulin)might have relevant implications for the study of obesity and diabetes, in particular in situations where dopamine transmission is altered.”

As if that wasn’t enough, the effect of insulin on dopamine signaling is so strong that it can even block the effects of amphetamine as described in this study published in PLoS Biology:

“Amphetamines mediate their behavioral effects by stimulating dopaminergic signaling throughout reward circuits of the brain. This property of amphetamine relies on its actions at the dopamine transporter (DAT)…we and others have revealed the novel ability of insulin signaling pathways in the brain to regulate DAT function as well as the…actions of amphetamine…by depleting insulin, or…insulin signaling, we can severely attenuate amphetamine-induced dopamine release and impair DAT function. Our findings demonstrate in vivo the novel ability of insulin signaling to dynamically influence the neuronal effects of amphetamine-like psychostimulants.”

The bottom line: compulsive eating (and other addictive behaviors) occurs when the reward (satisfaction) circuits are not functioning. To feel satisfied, we need adequate dopamine production and healthy insulin regulation. For the former we have natural precursor therapy to replenish exhausted dopamine resources. Healthy insulin and blood sugar regulation is, of course, a fundamental to any health strategy.