Attention dopamine

Somoza EC, Winhusen TM, Bridge TP, et al An open-label pilot study of methylpheni-date in the treatment of cocaine-dependent patients with adult attention deficit/ hyperactivity disorder. J Addict Dis 23 77—92, 2004 Sora 1, Wichems C, Takahashi N, et al Cocaine reward models conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95 7699-7704, 1998 Soral, Hall FS, Andrews AM, etal Molecular mechanisms of cocaine reward combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Nad Acad Sci U S A 98 5300-5305, 2001 Spear J, Alderton D Psychosis associated with prescribed dexamphetamine use 0etter). 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

The exact cause of attention-deficit hyperactivity disorder is unknown, but dysfunction in neurotransmitters norepinephrine and dopamine has been implicated as a key component. 

Dresel, S., Krause, J., Krause, K. H. et al. Attention deficit hyperactivity disorder binding of 99mTc TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur. J. Nucl. Med. 27 1518-1524,2000. 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

Responses in the dopamine system are more complex (see chapter by Balfour, this volume). Repeated nicotine injections resulted in enhanced extracellular DA levels in the NAc (Benwell and Balfour 1992, 1997), but not in the striatum (Benwell and Balfour 1997). Analysis of the precise placement of dialysis probes has revealed differential responses to drugs of abuse, including nicotine, between the NAc core (ventral striatum) and shell (Di Chiara 2002 Balfour 2004 Wonnacott et al. 2005 see chapter by Balfour, this volume). Moreover, the sensitised neurotransmitter responses observed in the hippocampus and NAc were markedly attenuated if rats received a constant infusion of a low level of nicotine (Benwell and Balfour 1997). Thus, transient peaks of nicotine appear capable of sensitising some brain pathways with respect to catecholamine release, but the responses may be mitigated by lower sustained plasma concentrations, possibly due to desensitisation. The extent that presynaptic nAChRs contribute to this process in vivo is unclear presynaptic a7 nAChRs on glutamatergic afferents to the VTA merit attention as potential mediators of sensitisation (see Sect. 2.2.2). 

With respect to the dopamine Dj-hke receptors, including the dopamine receptor, which is ten times more sensitive to dopamine and has a much more narrow tissue expression than the dopamine Dj receptor, few studies have found evidence of coding variants associated with a disease state (41,42). Untranslated promoter SNPs, however, have been associated with various disease states (60). These studies, while equivocal, suggest association with bipolar disorder, alcohohsm, and attention-deficit disorder to name a few (60-65). 

Vandenbergh, D. J., Thompson, M. D., Cook, E. H., et al. (2000) Human dopamine transporter gene coding region conservation among normal, Tourette s disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol. Psychiatry. 5, 283-292. 

Gornick, M. C., Addington, A., Shaw, P., et al. (2007) Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD) an update. Am. J. Med. Genet. 144, 379-382. 

Chlorpromazine (Thorazine) was among the first drugs employed to treat schizophrenia it is a dopamine antagonist. This finding focused attention on... 

Dopamine-Stimulating Medications. A variety of drugs that increase the availability of dopamine have been studied in cocaine addicts including L-DOPA, bupropion, amantadine, and methylphenidate. In small uncontrolled trials, these have shown some benefit, but definitive studies have yet to be performed. In addition, some dopamine-stimulating medications (in particular, the stimulants like methylphenidate or the amphetamines) are themselves subject to abuse, though, of note, this is typically not a problem when they are prescribed to patients who do not have a history of substance abuse such as, for example, in the treatment of attention deficit-hyperactivity disorder. 

The most successful treatments for ADHD have been those that increase the activity of the neurotransmitters dopamine and norepinephrine. It has been known for some time that our brains nse these two substances to focns attention during response to challenging or stressfnl situations. The theory that medications that increase the activity of either dopamine and/or norepinephrine would be good treatments for ADHD has largely proved true, and we now have medications that can help children and adults with ADHD tremendously. 

Despite these alternatives, there are a few patients who cannot tolerate stimulants or who may be susceptible to abusing them. In such cases, the alternatives are limited. The best treatments for poor attention (in lieu of the stimulants) are antidepressants that boost norepinephrine and/or dopamine activity in the brain. Currently, this includes the TCAs, MAOls, and possibly venlafaxine or duloxetine. 

Much attention has been paid to the catecholamines noradrenaline and dopamine following the discovery that their depletion in the brain leads to profound mood changes and locomotor deficits. Thus noradrenaline has been implicated in the mood changes associated with mania and depression, while an excess of dopamine has been implicated in schizophrenia and a deficit in Parkinson s disease. 

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