Kenneth Blum, Ph.D., Edward J. Modestino, Ph.D., and Mark S. Gold, M.D.

The brain regions circuitry tied to pleasure are difficult toaccurately describe, partly, because of many different ways we can trigger enjoyment or “Feel Good.” Pleasure can result from engaging in sex, eating tasty food, watching a movie, accomplishments at school and athletics, consuming drugs, and noble efforts to help the community, the country, and the world. It is noteworthy that research suggests that the later type of satisfaction, supporting the community, may result in the most substantial positive effects on our immune system, but these pathways are not understood. Similarly, one key to happiness involves a network of good friends. However, it is by no means clear how the higher forms of satisfaction and pleasure are related to an ice cream cone, or to your team winning a sporting event that may stem back to the old chariot days. Recent multidisciplinary research, using both humans and detailed invasive brain analysis of animals has discovered some critical ways that the brain processes pleasure.

Remarkably, there are pathways for ordinary liking and pleasure, which are limited in scope. However, there are many brain regions, often termed hot and cold spots, that significantly modulate (increase or decrease) our pleasure or even produce the opposite of pleasure— that is disgust and fear. More specifically, one particular region of the nucleus accumbens is organized like a computer keyboard, with specific stimulus triggers in rows— producing an increase and decrease of pleasure and disgust. Moreover, the cortex has unique roles in the cognitive evaluation of our feelings of pleasure. Importantly, the interplay of these multiple triggers and the higher brain centers in the cortex are very complex and are just being discovered.

Desire and Reward Centers
Surprisingly, many different sources of pleasure activate the same circuits between the mesocorticolimbic regions. Reward and desire are two aspects of pleasure induction and have a very widespread large circuit. Some part of this circuit distinguishes between desire and dread. The so-called pleasure circuitry called ‘REWARD” involves a well-known dopamine pathway in the mesolimbic system that can influence both pleasure and motivation.

In simplest terms, the well-established mesolimbic system is a dopamine circuit for reward. It starts in the ventral tegmental area (VTA) of the midbrain and travels to the nucleus accumbens.

It is the cornerstone target to all addictions. The VTA is encompassed with neurons using glutamate, GABA, and dopamine. The nucleus accumbens (NAc) is located within the ventral striatum and is divided into two sub-regions—the motor and limbic regions associated with core and shell respectively. The NAc has spiny neurons that receive dopamine from the VTA and glutamate (a dopamine driver) from the hippocampus, amygdala and medial prefrontal cortex. Subsequently, the NAc projects GABA signals to an area termed the ventral pallidum (VP). The region is a relay station in the limbic loop of the basal ganglia, critical for motivation, behavior, emotions and the “Feel Good” response. This defined system of the brain is involved in all addictions – substance and non –substance that our laboratory in 1995 coined “Reward Deficiency Syndrome” (RDS).

Furthermore, ordinary “liking” of something, or pure pleasure, is represented by small regions mainly in the limbic system (old reptilian part of the brain). These may be part of larger neural circuits. In Latin, hedus is the term for “sweet”; and in Greek, hodone is the term for “pleasure.” Thus, the word Hedonic is now referring to various subcomponents of pleasure: some associated with purely sensory and others with more complex emotions involving morals, aesthetics, and social interactions. The capacity to have pleasure is part of being healthy and may even extend life especially if linked to optimism, a dopaminergic response. Psychiatric illness often includes symptoms of an abnormal experience of pleasure referred to as anhedonia. A negative feeling state is called dysphoria, which can consist of many emotions such as pain, depression, anxiety, fear, and disgust. Previously, many scientists used animal research to uncover the complex mechanisms of pleasure, liking, motivation and even emotions like panic and fear. However, as a significant amount of related research about the particular brain regions of pleasure/ reward circuitry has been derived from invasive studies of animals, these cannot be directly compared with subjective states as espoused in humans.

For the advanced reader, in an attempt to resolve the controversy regarding the causal contributions of mesolimbic dopamine systems to reward, we have previously evaluated the three main competing explanatory categories: “liking,” “learning,” and “wanting.” That is, dopamine may mediate (a) liking: the hedonic impact of reward, (b) learning: learned predictions about rewarding effects, or (c) wanting: the pursuit of rewards by attributing incentive salience to reward-related stimuli. We have evaluated these hypotheses, especially as they relate to the RDS, and we find that the incentive salience or “wanting” hypothesis of dopaminergic functioning is supported by a majority of the scientific evidence. Various neuroimaging studies have shown that anticipated behaviors such as sex and gaming, delicious foods and drugs of abuse all affect brain regions associated with reward networks, and may not be unidirectional. Drugs of abuse enhance dopamine signaling which sensitizes mesolimbic brain mechanisms that apparently evolved specifically to attribute incentive salience to various rewards. Addictive substances are voluntarily self-administered, and they enhance (directly or indirectly) dopaminergic synaptic function in the NAc. This activation of the brain reward networks (producing the ecstatic “high” that users seek). Although these circuits were initially thought to encode a set point of hedonic tone, it is now being considered to be far more complicated in function, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms (genetic variations) of various dopaminergic genes and the genes related to other neurotransmitters (and their genetic variants), may have an additive effect on vulnerability to various addictions. This Reward Deficiency Syndrome model of etiology holds very well for a variety of chemical and behavioral addictions.

Over many years, the controversy of dopamine involvement especially in “pleasure” has led to confusion in terms of trying to separate motivation from actual pleasure. We take the position that animal studies cannot provide real clinical information as described by self-reports in humans. On November 23rd, our concerns may have been highlighted. A brain system involved in everything from addiction to autism appears to have evolved differently in people than in great apes, a large team reported in the journal Science. In essence, although non-human primate brains are similar to our own, the disparity between other primates and those of human cognitive abilities tells us that surface similarity is not the whole story. Sousa et al. found various differentially expressed genes, to associate with pleasure related systems. Furthermore, the dopaminergic interneurons located in the human neocortex were absent from the neocortex of nonhuman African apes. Such differences in neuronal transcriptional programs may underlie a variety of neurodevelopmental disorders.

In simpler terms, the system controls the production of dopamine, a chemical messenger that plays a significant role in pleasure and rewards. The senior author, Dr. Nenad Sestan from Yale, stated: “Humans have evolved a dopamine system that is different than the one in chimpanzees.” This may explain why the behavior of humans is so unique from that of non-human primates, despite the fact that our brains are so surprisingly similar, Sestan said. It might also shed light on why people are vulnerable to mental disorders such as autism. Remarkably, this research finding emerged from an extensive, multicenter collaboration to compare the brains across several species. These researchers examined 247 specimens of neural tissue from six humans, five chimpanzees, and five macaque monkeys. These researchers analyzed which genes were turned on or off in 16 regions of the brain. It was observed, while the differences among species were subtle, there was a remarkable contrast in the neocortices, specifically in an area of the brain that is much more developed in humans than in chimpanzees. In fact, these researchers found that a gene called Tyrosine Hydroxylase (TH), an enzyme, which is involved in the production of dopamine, was expressed= in the neocortex of humans, but not chimpanzees. The neurotransmitter dopamine is best known for its essential role within the brain’s reward system; the very system that responds to everything from sex, to gambling, to food, to addictive drugs. However, dopamine also assists in regulating emotional responses, memory, and movement. Notably, abnormal dopamine levels have been linked to disorders including Parkinson’s, schizophrenia, and spectrum disorders such as autism and addiction or Reward Deficiency Syndrome.

Nora Volkow, the director of NIDA, pointed out that one alluring possibility is that the neurotransmitter dopamine plays a substantial role in humans’ ability to pursue various rewards that are perhaps months or even years away in the future. This same idea has been suggested by Dr. Robert Sapolsky, a Professor of Biology and Neurology at Stanford University. Dr. Sapolsky cited evidence that dopamine levels rise dramatically in humans when we anticipate potential rewards that are uncertain and even far off in our futures, such as retirement or even the possible afterlife. This may explain what often motivates people to work for things that have no apparent short-term benefit, he says.

Moreover, the neocortex wasn’t the only area of the brain to show differences in gene expression among species. Sousa et al. also found differences in much older areas, including an ancient structure called the cerebellum. Accordingly, an ancient part of the human brain seems to have a very recent change. It will take years to understand more fully what all the changes mean, but this finding could eventually help divulge what makes the human brain unique, and even what goes wrong in a range of brain disease states. The role of dopamine in brain function has been well established throughout many decades of research and has merited the Nobel Prize in 2000, and continued work by one of us (KB) and Ernest P. Noble showing the role of dopamine genetics in severe alcoholism, and also by MSG and Charles Dackis with regard to the “dopamine depletion hypothesis” and cocaine. The new findings by Sousa et al., also calls for the importance of dopamine homeostasis through genetic addiction risk (GARS) testing and Pro dopamine regulation (KB220PAM).

Kenneth Blum, B.Sc. (Pharmacy), M.Sc., Ph.D. & DHL; received
his Ph.D. in Neuropharmacology from New York Medical College
and graduated from Columbia University and New Jersey College
of Medicine. He also received a doctor of humane letters from
Saint Martin’s University Lacey, WA. Dr. Blum has authored over
600 medical articles, chapters, abstracts, journals, and sixteen
professional books on a wide variety of psychiatric research
subjects, including psychiatric comorbidity, detox, and addiction
treatment and psychiatric genetics.

Edward Justin Modestino, Ph.D., is a neuroscientist who
focuses his research on various pathologies (i.e., ADHD,
narcolepsy, PD and Reward Deficiency Syndrome) using both
psychophysiological and neuroimaging techniques. He received
his undergraduate education at Harvard in psychobiology; and his
master’s degree in psychobiology and a post-master’s degree in
cognitive neuroscience both from the University of Pennsylvania.
He completed a Ph.D. in complex systems and brain sciences
at Florida Atlantic University. After this, he completed two
postdoctoral fellowships in neuroimaging, the first in Psychiatry
and Neurobehavioral Sciences at the University of Virginia Health
System, and the second in Neurology at Boston University School
of Medicine. Currently, he is an Associate Lecturer in Psychology
at Curry College in Milton, MA.

Mark S. Gold, MD, Chairman of the RiverMend Health Scientific
Advisory Boards, is an award-winning expert on the effects of
opiates, cocaine, food, and addiction on the brain. His work over
the past 40 years has led to new treatments for addiction and
obesity which are still in widespread use today. He has authored
over 1000 medical articles, chapters, abstracts, journals, and
twelve professional books on a wide variety of psychiatric
research subjects, including psychiatric comorbidity, detox, and
addiction treatment practice guidelines.