It is noteworthy that our laboratory has proposed that Attention Deficit Disorder (ADHD) is a subtype of RDS, having dopaminergic allelic associations among other deficit genes. In fact, being carriers of specific polymorphisms of the dopaminergic system places these individuals, both children and adults, at high risk for RDS behaviors (i.e. Substance Use Disorder [SUD] etc.) [59
]. The linking of ADHD and obesity via a dopaminergic mechanism has also been proposed by others [61
]. There is strong evidence indicating that dopamine dysregulation is very important in the pathophysiology of ADHD, as well as in the mechanism of the therapeutic action of stimulant drugs. With regard to therapeutic implications, recent studies indicate that methylphenidate (MPH), a drug widely used for ADHD, reduced overall energy intake with a selective reduction in dietary fat [61
]. The findings are consistent with a reward deficiency model [34
] of obesity whereby low brain dopamine predicts overeating and obesity, and administering agents that increase dopamine results in reduced feeding behavior. The obesity epidemic has focused attention on obesity's health consequences beyond cardio-vascular disease and diabetes. Current findings link both obesity and ADHD to the dopamine system and implicate dopamine genes in body weight, eating, and ADHD, among others. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals with the ADHD subtype Attention Deficit Disorder (ADD) may increase their risk for obesity. Thus, individuals and populations with a high prevalence of hypodopaminergic genes may experience higher rates of obesity in the presence of abundant food [62
]. From an evolutionary perspective, Campbell and Eisenberg [62
] suggest that alterations in the dopamine system appear to affect a wide range of behavioral phenotypes. They suggest that recent evolutionary changes in the dopamine receptor genes selected to increase cognitive and behavioral flexibility may now be associated with attention problems and increased food consumption in an obesity gene environment.
With this said we must consider these results with caution, especially in terms of in vivo studies by Chen et al [63
] showing a down-regulation of D2 receptor density following a 6 day infusion of the D2 agonist quinpirole [64
]. Interestingly, continuous infusion of quinpirole caused a significant down-regulation of striatal D2 dopamine receptors without significantly changing the density of D1 receptors. This was accompanied by a decrease in the level of D2 receptor messenger RNA in the striatum as measured by northern blotting. The down-regulation of dopamine receptors was selective for D2 dopamine receptors. Moreover, continuous treatment with quinpirole resulted in a significant increase in striatal mu opioid receptor levels without significant change in the delta opioid receptors. This treatment also induced a significant decrease in proenkephalin messenger RNA in the striatum. Taken together, these results suggest that the down-regulation of D2 dopamine receptor and D2 receptor messenger RNA is the result of the persistent stimulation of D2 receptors and that the up-regulation of mu opioid receptors may be a compensatory response to a decreased biosynthesis of enkephalin. While this appears at first sight to contradict our suggestion, we theorize that the difference in continuous stimulation by a slow (more physiological and natural) release of DA, as proposed herein, will result in a proliferation in D2 receptors as seen in the in vitro studies [28
] and documented by the consistent anti-craving effects observed in clinical trials [18
It is noteworthy that diminished DA receptors are not inevitably associated with depression or addictive behaviors. In fact, while the lower incidence of Parkinson's disease (PD) among smokers may be explained by a protective effect of cigarette smoke, or by a tendency to avoid addictive behaviors among future PD cases, this does not hold true for alcoholism. Hernan et al [64
] conducted an indirect test of the latter hypothesis by comparing the incidence of PD between alcoholics and nonalcoholics in the General Practice Research Database of the United Kingdom. Their case-control study included 1,019 cases and 10,123 matched controls. Overall, they did not find a lower incidence of PD among alcoholics compared with nonalcoholics (odds ratio: 1.09; 95 % CI: 0.67, 1.78). However, the contrary made be true. In Parkinson's disease, dopamine dysregulation syndrome (DDS) is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings or Reward Deficiency Syndrome, as reported by Linazaroso et al [65
]. In this regard, Witjas et al [66
] describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus (STN) deep brain stimulation greatly reduced the behavioral disorders as well as completely abolishing the addiction to dopaminergic treatment. According to the authors [66
], dopaminergic addiction in patients with Parkinson's disease therefore does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction. These findings related to Parkinson's disease partly support our proposal herein.
There is an abundance of studies showing that acute blockade of DA receptors will result in an attenuation of substance seeking as in the case observed for the Cannabinoid CB1 receptor antagonist, Rimonabant, which neuronal blocks DA-release [67
]. This and other work has prompted Berridge [68
] to rethink the role of DA as a so called "well-being substance". According to Berridge there are three competing explanatory categories: 'liking,' learning, and 'wanting.' Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead meadiate learned predictions of future reward, and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? In this regard, recent evidence indicates that dopamine is not needed for new learning, and is not sufficient to mediate learning directly by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short-circuit and sensitize the dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards. Interestingly, Alcaro et al [69
] agree with Berridge's view by suggesting that the rewarding properties of drugs of abuse are, in part, caused by the activation of the "SEEKING" disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect. The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors. In our view this predisposition is genetic and involves among other candidate genes the DRD2 gene. One important example of hedonic "wanting" and or "SEEKING" predisposition involves polymorphisms of the DRD 2 gene [70
]. Statistical analysis revealed a significant association between the DRD2 TaqI A genotypes and "Eros" (a loving style characterized by a tendency to develop intense emotional experiences based on physical attraction to the partner), thus supporting hedonism as a "wanting" or "SEEKING" phenomena. Exploiting this view one might argue that the "reward center" be simplified and termed "the well-being system".