Reward Deficiency Syndrome (RDS): Is there a Solution?

Abstract

In the early sixties we knew relatively very little about the workings of the brain especially the interrelatedness of the brain reward circuitry and the Pre-frontal cortices. Understanding the importance of the main neurotransmitters such as serotonin, GABA, dopamine and acetylcholine were unknown for the most part and endorphins was not even a part of our scientific acumen. The 1956 doctrine of Jellinek and the disease concept of alcoholism was new and not generally accepted [1]. At that time most scientists working in the field of addiction agreed that alcoholism is the result -at least in part -of deficiencies or imbalances in brain chemistry-perhaps genetic in origin. However so little was known that nothing specific was espoused by the then newly called neuroscientists. For thousands of years, human beings have had a love/hate relationship with alcohol. No one knows when the first beer was brewed, but it was earlier than 5,000 B.C. In fact, wine dates back to 3,000 B.C.; brandy appeared late in the twelfth or early thirteenth century, but grain-based ‘hard’ liquors such as whiskey and gin had very little impact until the seventieth century. It was Claudia Black [2] who promoted the concepts of the term Children of Alcoholics (COAS) as well as Adult Children of Alcoholics (ACOAS) that now constitutes over 30 million in the United Sates alone. The major hazard for this group is that they may carry risk alleles that could drive them to drink or carry behaviors of a dry drunk. This is important since the understanding that children of alcoholics could carry certain genes in variant forms (unknown at that time) similar to their parents and or siblings, and that these genetic polymorphisms could induce aberrant behaviors including drug seeking was at best just a plausible thought. In the early days of treatment it was difficult to overcome patient denial and the acceptance of alcoholism as areal disorder of the brain was dismissed by most of the populace up until 1990. Although the conviction that alcoholism was a disease rather than a symptom of moral weakness was growing in the late ninetieth and early twentieth centuries, there was no knowledge of how the disease might be acquired or treated and such was largely guesswork. In fact, one theory suggested that alcoholism was the result of an infection, and as such a few patients were treated with germicidal agents without any positive effect. The first somewhat effective treatment of alcoholism on record is from the 1930’s whereby “aversion therapy” was first employed by Charles Shadel which later became the Schick- Shadel hospital [3]. It is noteworthy, that many of the treatment goals employed today began with the advent of utilization of counselors. In the early 1950’s it was Daniel J. Anderson, a psychologist at Willmar State Hospital in Minneapolis, that first used a recovering person from AA, to serve as recovery coach which resulted in the development of the field designated as a “Counselor of Alcoholism”. The Search for the Solution At the beginning of the 1940’s most research into alcoholism could be classified under three headings: observation and analysis of psychological behaviors; observation and analysis of cultural and social variables: laboratory investigation into the physiological effects of alcohol on the body. Early clues came from laboratory experiments such as the work of Jorge Mardones who pioneered the concept of nutrigenentics. He showed that one important factor (coined the N1 factor); having reduced vitamin B complex caused increased alcohol consumption in rats. This effect was significantly attenuated by the administration of yeast rich in vitamin B complex. Then in later experiments in which he tested voluntary consumption of alcohol under dietary deficiency, he employed rats that had been inbred for seven generations. Mardones found that young rats preferred alcohol if their parents had also preferred alcohol before them [4]. Roger Williams from the University of Texas at Austin furthered developed the concept of “metabolic individuality” and drawing from the work of Mardones advanced the concept of “genotropic theory of alcoholism”. The theory held that some people carried a deficiency of glutamine due to a genetic deficiency of an enzyme. In conjunction with Bill Shive they found that by isolating an amino acid from human liver called L-Glutamine, followed by experiments in rats showing that there was a 35% reduction of alcohol consumption in the group that was administered L-glutamine compared to placebo. However, the response diminished over time, but indicated an important nutritional component tied to genetics [5]. In 1952, it was Leonora Mirone who first found that the inbred mouse strain C57 when given a choice of water or 5% ethanol in water more often chose ethanol over water supporting Williams concept on “genotropic theory of alcoholism” [6]. With this previous research it was Gerald McClearn of the Institute of Behavioral Genetics at the University of Colorado, Boulder that refined the mouse model by selective breeding and today stands as the father of “animal models of alcoholism” [7]. In the 1960’s many laboratories turned to the concept that stress was a factor in increasing alcohol consumption. This work was led by notables such as Masserman and Yum who showed that neurotic cats following a stressful event when given a choice of milk or an alcoholic beverage chose the ethanol beverage of milk [8]. This was further supported by others Casey [9] and Nobles group [10] suggesting the importance of stress in alcoholism. Finally, it was Robert D. Myers of Purdue University that showed that the more you drink alcohol the more you want. He accomplished this by injecting different concentrations of alcohol into the brains of rats up to 1,000 infusions and following a time period the rats infused more consumed higher amounts of alcohol when deprived of food and water [11]. Then in subsequent experiments Myers and Veale in 1968 devised an experiment whereby they found that administration of a substance para-chloraphenyalalnine (pCpA) that reduced the amount of the neurotransmitter serotonin in the brain induced a long-term aversion to alcohol suggesting the significant role of serotonin in alcohol intake. This work also was extended to another substance known to reduce both dopamine and norepinephrine call alpha-methyl- para – tyrosine) alpha-mPT) also shown to induce aversion to ethanol. These experiments were the beginning of understanding neurotransmitter imbalances and subsequent alcohol intake in humans [12]; including the dopamine antagonistic therapy for alcohol and opiate addiction favored by FDA approved drugs. Understanding these earlier concepts including other work involving common mechanisms of action between opiates and alcohol and aldehyde-dopamine adducts [13,14] the rest of the paper further presents newer solutions along with the prospects of better genetic diagnosis and nutrigenomic intervention favoring dopamine agonistic not antagonistic therapies. Embracing New Solutions and Genetic Risk Assessment Prior to 1990 there was only one study directed at psychiatric genetics [15]. Egeland et al. [15] analyzed the segregation of Restriction Fragment Length Polymorphisms (RFLP) in an Old Order Amish population (pedigree) and localized a dominant gene, possibly tyrosine hydroxylase in chromosome 11, linked to a strong predisposition to manic depressive disease. This finding was retracted in 1989 by Kelsoe et al. [16]. Following these very early studies Blum and Noble and their respective groups reported on the first ever confirmed association of the dopamine D2 receptor gene (DRD2) and severe alcoholism [17]. While the findings were controversial at the time, [18] it is confirmed [19] and remains the most widely studied gene in psychiatric genetics. The discovery lead to the development of an entire field of medicine– known as Psychiatric Genetics and it has 14,937 publications as of 10/26/14 on PubMed. Despite harmful negative consequences, drug and alcohol dependence is considered a relapsing chronic condition with compulsive seeking behaviors (including non-substance addictive behaviors). All psychoactive drugs including cannabis, ethanol, opioids, stimulants, nicotine as well as disruptive behaviors such as internet gaming, dysfunction sex, overeating amongst others lead to neuronal release of dopamine [20]. Le Foll et al. [19] carried out a meta-analysis and found a significant association between DRD2 and alcohol dependence. Further studies have shown significant linkage between carriers of the DRD2 Taq A1 allele and familiar alcoholism [21]. Overall, this indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans. Support for Reward Deficiency Syndrome (RDS) as the “True Phenotype” In 1995, Blum questioned the validity of the theorized neurochemical mechanisms of a number of psychoactive drugs such as alcohol and opiates. This concern was highlighted by the original work of Virginia Davis [22], Gerald Cohen [23], Michael Collins [24] and others [25] related to common mechanisms between alcohol and opiates [26]. As such in 1996 Blum and his group coined the term Reward Deficiency Syndrome (RDS) publishing the concept in the Royal Society of Medicine [27]. Mark Gold’s theory, the “Dopamine Depletion Hypothesis”, proposed an important role for dopamine in the effects of cocaine [28,29]. Euphoric properties of cocaine lead to the development of chronic abuse, and appear to involve the acute activation of central DA neuronal systems. Dopamine depletion is hypothesized to result from overstimulation of these neurons and excessive synaptic metabolism of the neurotransmitter. DA depletion may underlie dysphoric aspects of cocaine abstinence, and cocaine urges. Neurochemi