Attention-deficit-hyperactivity disorder and reward deficiency syndrome

Abstract

Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD(2) A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.

Keywords: attention deficit hyperactivity disorder (ADHD); genes; neuropsychological deficits; reward deficiency syndrome; reward dependence; treatment.

Figure 1

Interactions in brain reward regions. (1) Serotonin in the hypothalamus indirectly activates opiate receptors and causes a release of enkephalins in the ventral tegmental region A₁₀. The enkephalins inhibit the firing of GABA, which originates in the substantia nigra A₉ region. (2) GABA’s normal role, acting through GABA B receptors, is to inhibit and control the amount of dopamine released at the ventral tegmental regions for action at the nucleus accumbens. When dopamine is released in the nucleus accumbens, it activates dopamine D₂ receptors, a key reward site. This release is also regulated by enkephalins acting through GABA. The supply of enkephalins is controlled by the amount of the neuropeptidases that destroy them. (3) Dopamine also may be released into the amygdala. From the amygdala, dopamine stimulates the hippocampus and the CA and cluster cells stimulate dopamine D₂ receptors. (4) An alternate pathway involves norepinephrine in the locus ceruleus whose fibers project into the hippocampus at a reward area centering around cluster cells that have not been precisely identified, but which have been designated as CAx. When GABA A receptors in the hippocampus are stimulated, they cause the release of norepinephrine.

Figure 2

Diagrammatic representation of the mechanisms of action of stimulants in treating ADHD. Figure 2a (top left) shows the basal unstimulated state with dopamine stored in the vesicles and low levels of dopamine in the synapse. Figure 2b (top right) shows the result of stimulation of the dopamine neuron with the vesicles releasing dopamine into the synapse and re-uptake of dopamine into the presynaptic neuron by the dopamine transporters. Figure 2c (bottom left) shows that in the presence of stimulants, the function of the dopamine transporters is partially blocked and the basal level of dopamine increases in the synapse. This results in the occupation of the presynaptic dopamine D₂ receptors by dopamine. Now, when the nerve is stimulated (Figure 2d, bottom right), because of the occupation of the presynaptic D₂ receptors, the amount of dopamine released from the vesicles is decreased. Adapted from Seeman and Madras (1998).