Attention Deficit Hyperactivity Disorder

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A role for altered dopamine neurotransmission as the underlying cause of ADHD has been suggested by several observations. First, drugs used to treat ADHD, such as methylphenidate (Ritalin) and amphetamine (Adderal), increase synaptic levels of dopamine in experimental animals and in human subjects. In patients with ADHD, the maximal therapeutic effects of these drugs occur during the absorption phase of the kinetic curve, which parallels the acute release of dopamine into the synaptic cleft. These drugs are said to have "paradoxical" effects in ADHD children because they cause hyperactivity in normal children but have a "calming" or cognitive-focusing effect on ADHD children. Second, molecular genetic studies have identified genes that encode proteins involved in dopamine neurotransmission as candidate genes for ADHD. Third, neuroimaging studies have shown reduced activation in the striatum and frontal cortex of ADHD patients that is reversed by the administration of methylphenidate at least in a subset of children. Recently, functional magnetic resonance imaging studies have demonstrated differences between children with ADHD and normal controls in the degree of corticostriatal activation during a stimulus-controlled go/no-go task and its modulation by methylphenidate. Off drug, ADHD children showed impaired inhibitory control on this task and reduced striatal activation relative to the control subjects. Administration of methylphenidate significantly increased inhibitory control and frontostriatal activation in ADHD patients. These observations indicate that an optimal level of corticostriatal activation is necessary for subjects to display normal inhibitory control. Since methylphenidate increased both corticostriatal activation and inhibitory control, it follows that decreased corticostriatal activation and the poor inhibitory control may be due to reduced dopamine tone in the brain, perhaps in the striatum. However, it is equally likely that the mesolimbic dopamine system may mediate these effects by virtue of its afferent projections to the prefrontal cortex.

dopamine transporter and amphetamine primarily reverses it. Studies indicate these drugs are also primary reinforcers in animals because they will self-administer these drugs, and their propensity to do so is an excellent predictor of abuse liability in humans.

Many animal studies using a variety of different paradigms to study the role of dopamine in the rewarding properties of the psychostimulant drugs have suggested that dopamine is critically involved in this process in experimental animals. In the case of cocaine, studies carried out in human subjects have also supported the idea that enhanced dopamine transmission is responsible for the euphoric effects of this drug in humans. Dopamine appears to be a critical mediator of reward in the brain.

Dopamine also appears to play a role in craving, which often leads to relapse in abstinent human substance abusers. Brain imaging studies have identified the amygdala and the dopamine-rich nucleus accumbens as putative neuroanatomical substrates for cue-induced craving. Nucleus accumbens dopamine levels increased withdrawn from cocaine when they were exposed to cues that were previously associated with cocaine intake. Studies in humans examining the level of the dopamine metabolite HVA have reported that craving during abstinence is associated with increased HVA.

It also appears that the dopamine D3 receptor may be involved in cocaine craving. Animal models of cocaine craving have shown that the D3 selective partial agonist, BP 897, attenuates craving while lacking any intrinsic, primary rewarding effects.

A very interesting aspect of repeated amphetamine or cocaine administration is behavioral sensitization. Behavioral sensitization or reverse tolerance refers to the progressive augmentation of drug affects that are elicited by repeated administration of the drug. Sensitization to psychostimulants was characterized in experimental animals as early as 1932 and in humans in the 1950s. Behavioral sensitization develops when psychostimulant administration is intermittent. Tolerance develops during continuous administration.

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