Neurotransmitters and Behavior

http://www.crossroadsinstitute.org/neurotransmit.html Highly depressed moody people are extremely low in serotonin and norepinephrine, but will probably have high urinary levels because they are losing so much at any given point in time. If they have insomnia, it is likely that their dopamine and/or PEA levels is high. Highly agitated anxious irritated people will probably have high epinephrine, norepinephrine and dopamine, and relatively low serotonin levels. They may also have markedly elevated PEA levels. In addition, the sex hormones influence multiple neurotransmitters. Estrogen has an anti-dopamine effect, in addition to inducing the formation of new synapses. Progesterone increases the effect of GABA and reduces neurotransmitter activity. Estradiol decreases the level of the enzyme which inactivates the serotonin and dopamine (monoamine oxidase, MAO), thus effectively increases the effects of serotonin and dopamine, where progesterone decreases their effects. DHEA enhances the effect of serotonin and norepinephrine, thus it enhances cognitive function and reduces depression. Cortisol inhibits the release of catecholamines, and increases the effect of GABA, thus reducing anxiety. Currently we can measure 5 major neurotransmitters. * Epinephrine, the major stress neurotransmitter, related to blood pressure, heart rate. * Norepinephrine, a second stress neurotransmitter. High levels of this hormone are seen in states of anxiety and insomnia. It is released in response to perceived threat. Both epinephrine and norepinephrine are manufactured from phenylalanine. * Dopamine, modulates the effect of the excitatory hormones, and is necessary for states of relaxation and mental alertness; such as we get with a predominantly alpha brain wave pattern. * Serotonin, the master neurotransmitter, is manufactured from tryptophan. It is found all over the body and is necessary to modulate the levels of the stress hormones. Serotonin is a precursor of melanin, the hormone that is release at night, when the body is asleep. Falling levels of norepinephrine are required for the conversion of serotonine to melanin to take place. If there are persistently high levels of norepinephrine, as in states of chronic anxiety, this conversion will not take place and the patient will have severe insomnia. * GABA is the foremost inhibitory neurotransmitter in the body. GABA is involved with insomnia, anxiety, and depression. * PEA, phenyl-ethylamine, enables us to pay attention. It is derived from l-phenylalanine, and is frequently low in people with attention deficit disorder and depression, and very high is people with insomnia or severe anxiety. Severely autistic children often have very high levels of PEA. PEA blocks the reuptake of dopamine and norepinephrine. Elevated levels may also be seen in patients with schizophrenia, psychosis, phenylketonuria (PKU) and ADD/ADHD. Low levels may be seen with depression, fatigue, and chocolate cravings. * Histamine is responsible for the effects of an allergic reaction. Epinephrine quickly reduces histamine levels. Long-term elevations of histamines can deplete the body’s supply of epinephrine. High levels may be seen in patients with allergic or inflammatory reactions, those who are restless, those who smoke. Low levels are seen in patients on antihistamines and those who are taking l-dopa (treatment for Parkinson’s disease). *Neuroendocrine Functions in Post-institutionalized Children Researcher: Dana Johnson, M.D., Ph.D. (Department of Pediatrics, Division of Neonatology) Co-Investigators: Megan Gunnar, Ph.D. (Institute of Child Development), Maria Kroupina, Ph.D. (Department of Pediatrics), Anna Petryk, M.D., (Department of Pediatrics), Sandra Lee Iverson, R.N., C.P.N.P., M.S. (Department of Pediatrics), Bradley Miller, M.D., Ph.D. (Pediatric Endocrinology) Collaborator: Patricia Bauer, Ph.D. (Duke University) Funding Source: NIH Abstract: The main goal of this research program is to determine whether early neglect and deprivation can influence the development and interactions between the stress-sensitive system, the hypothalamic-pituitary-adrenocortical (HPA) axis and the growth hormone (GH) system in children that affect physical growth in post-institutionalized children. International Adoption Clinic Department of Pediatrics University of Minnesota MMC 211 420 Delaware St. SE Minneapolis, MN 55455 (612) 624-1164 Telephone (612) 624-8176 Fax LM 2/7; Sandy Iverson will call back. *Neurobehavioral Correlates of Early Deprivation Researcher: Megan Gunnar, Ph.D. (Institute of Child Development) Co-Investigators: Charles A. Nelson, Ph.D. (Harvard Medical School), Dana Johnson, M.D., Ph.D. (Department of Pediatrics, Division of Neonatology), Seth Pollack (University of Wisconsin, Madison) Funding Source: NIMH Abstract: This work explores the neurobiological bases of problems in attention/executive functions, sensory integration and emotion/stress regulation that are often exhibited by children who have experienced neglect/privation early in life. Studies of institutionally-reared children yield consistent evidence that early deprivation can have long-term consequences for cognitive and social functioning. Our goal is to more directly examine brain-behavior processes in children from institutionally deprived environments. We argue that this research will (a) inform our understanding of the brain-behavior impact of early deprivation/neglect, (b) enhance our ability to assess the bases of deprived children's cognitive and social-emotional difficulties, and (c) inform research on prevention/intervention for children who experienced early neglect/deprivation. http://www.nih.gov/news/pr/may2001/fmriCOMT.jpg&imgrefurl=http://www.nih.gov/news/pr/may2001/nimh-29.htm&amp;h=313&w=411&sz=89&hl=en&start=18&tbnid=1qAp0oliwMi12M:&amp;tbnh=95&tbnw=125&prev=/images%3Fq%3DCOMT%2Bdopamine%26svnum%3D10%26hl%3Den%26sa%3DG Gene Slows Frontal Lobes, Boosts Schizophrenia Risk National Institute of Mental Health scientists have linked a gene variant that reduces dopamine activity in the prefrontal cortex to poorer performance and inefficient functioning of that brain region during working memory tasks, and to slightly increased risk for schizophrenia. The finding, which must still be confirmed by independent teams of investigators, emerged from an ongoing study of people with schizophrenia and their siblings. The study is among the first to suggest a mechanism by which a gene might confer susceptibility to a mental illness, say the researchers. Daniel Weinberger, M.D., Michael Egan, M.D., NIMH Clinical Brain Disorders Branch, and colleagues, report on their results in the May 29, 2001 Proceedings of the National Academy of Sciences. The most disabling form of mental illness, schizophrenia affects one percent of the adult population, typically in young adulthood, with hallucinations, delusions, social withdrawal, flattened emotions and loss of social and personal care skills. Although its cause remains a mystery, evidence suggests that it is at least 80% heritable, stemming from complex interactions among several genes and non-genetic influences. Several chromosomal regions have been implicated, but none have been definitely confirmed and no genes have yet been linked to the disorder. Given the syndrome's daunting complexity, Weinberger and colleagues have been studying many traits to identify those that patients share with their well siblings, hoping to turn up clues to susceptibility genes. Their brain imaging studies had revealed that both well siblings and patients falter on tasks of working memory and show abnormal activation of the prefrontal cortex, which is required for such "executive" functions. Studies have shown that the chemical messenger dopamine plays a pivotal role in tuning the activity of the prefrontal cortex during such tasks. A gene called COMT (catecho-o-methytransferase) had long been suspected of being involved because it codes for an enzyme that breaks down dopamine after it is secreted into the synapse. People inherit two copies of COMT (one from each parent), each in either of two forms. The most common variant, val, reduces prefrontal dopamine activity, while a somewhat less common form, met, increases it. Weinberger and colleagues administered a working memory task known to activate the pre-frontal cortex, the Wisconsin Card Sorting Test (WCST), to 181 schizophrenia patients, 219 of their well siblings and 75 normal controls. They found that those who had inherited 2 copies of val, on average, performed worse than those with only one copy. Those with two copies of met performed best. COMT accounted for 4.1% of the variance in test performance among patients and controls, suggesting that it influences prefrontal functioning When healthy siblings were asked to perform another working memory task (N-back) while undergoing functional magnetic resonance imaging (fMRI), the prefrontal brain activity of those with two copies of val was least efficient; there was excessive activity for a given level of performance. "It's as if they get poorer gas mileage out of their prefrontal cortex if they have this genetic background," said Weinberger, who led the research team. Brain activity of those with one copy of each variant was more efficient, while activity of siblings who inherited two copies of met showed the highest brain efficiency, on average. Among 104 pairs of parents studied, the investigators discovered that the val form of COMT was transmitted to offspring who eventually developed schizophrenia more often than would be expected by chance: 75 times for val, compared to 51 times for met. Inheriting two copies of the val form accounts for a 1.5-fold increased risk for schizophrenia in the general population. The researchers suspect that COMT's effect, while modest, may be amplified through interaction with other susceptibility genes and environmental factors. For example, they are studying a gene in the brain's hippocampus that, together with COMT, could boost schizophrenia risk three-fold. Although it's not yet known exactly how the COMT val variant impairs prefrontal efficiency, evidence suggests that by reducing dopamine it reduces signal-to-noise ratios of communications between neurons, much like static drowns out weak radio stations. "The COMT val allele is certainly not a necessary or sufficient causative factor for schizophrenia, nor is it likely to increase risk only for schizophrenia," caution the researchers. "However, its biological effect on prefrontal function and the relevance of prefrontal function for schizophrenia implicate a mechanism by which it increases liability for the disorder." The researchers are planning to study a COMT inhibitor medication as a possible adjunct treatment to enhance cognitive performance in patients with the val variant. There is evidence that current anti-psychotic drugs work by blocking D2 dopamine receptors in lower dopamine circuits. The NIMH researchers propose that the COMT inhibitor will specifically enhance dopamine circuits specific to the prefrontal cortex. Psychoneuroendocrinology. 1994;19(1):85-117. Role of oxytocin in the neuroadaptation to drugs of abuse. Sarnyai Z, Kovacs GL. Chronic OXT (Oxytocin) treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum. In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine. This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction. Biochem Biophys Res Commun. 2007 Jan 19;352(3):823-9. Hyperactivity and alteration of the midbrain dopaminergic system in maternally stressed male mice offspring. * Son GH, * Chung S, * Geum D, * Kang SS, * Choi WS, * Kim K, * Choi S. Department of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea. We recently demonstrated that prolonged maternal stress produces profound and long-lasting deficits in brain functions by programming a subset of target genes. We have now examined the possible effects of prenatal stress on the motility of adult offspring and dopamine (DA)-related gene expression in their midbrains, one of the target brain regions of stress hormones. Maternally stressed adult male mice showed impaired response habituation to novelty, and increased wheel-running activity associated with altered responses to DA receptor and DA transporter (DAT) blockers. Along with the behavioral changes, the expression profiles of several genes of the midbrain DAergic system appeared to be altered. Expression of DAT was reduced and expression of DA receptors and striatal DA-regulated neuropeptide genes was also affected. Taken together, the present findings indicate that maternal stress can cause hyperactivity in adult offspring associated with alterations in the midbrain DAergic system suggestive of a functional hyperdopaminergic state. J Pediatr. 2003 Jul;143(1): Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. * Kahn RS, * Khoury J, * Nichols WC, * Lanphear BP. Division of General and Community Pediatrics, and Children's Environmental Health Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. robert.kahn@cchmc.org OBJECTIVE: To examine the joint effects of a dopamine transporter (DAT) polymorphism and maternal prenatal smoking on childhood hyperactivity-impulsivity and inattentiveness. STUDY DESIGN: A cohort of 161 children was followed prospectively from age 6 months to 60 months. Primary outcomes were the DSM-IV hyperactive-impulsive and inattentive scales of the Conners' Parent Rating Scale Revised-Long Version (CPRS R:L). A secondary outcome was the oppositional scale. Predictors included DAT genotype and maternal report of prenatal smoking. Children homozygous for the 480-bp DAT allele (DAT +/+) were compared with all other children (DAT +/- or -/-). RESULTS: In multivariate analyses, children with both prenatal smoke exposure and the DAT +/+ genotype had significantly elevated hyperactive-impulsive scores (beta, 7.5; SE, 2.9; P<.01) compared with children with no smoke exposure and DAT +/- or -/-. Inattentive scores were not significantly elevated in this group, but oppositional scores were a full standard deviation higher. Neither prenatal smoke exposure alone nor DAT +/+ genotype alone was significantly associated with increased scores. CONCLUSIONS: Child hyperactivity-impulsivity and oppositional behaviors were associated with a DAT polymorphism but only when the child also had exposure to maternal prenatal smoking. This study emphasizes the importance of incorporating environmental cofactors in genetic studies of attention deficit hyperactivity disorder.