(L) Is the Pleasure Molecule Dopamine? (2008)

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COMMENTS: One controversy surrounding dopamine is whether it is behind feelings of pleasure. It's well established that dopamine produces desire and cravings or "wanting", but is it involved in "liking". Researchers have separated the liking from wanting in food experiments, and determined dopamine is not involved in the hedonic aspects of food. But does this also apply to sex, friendly interactions and love? Studies clearly demosntrate that self reports of pleasure equate with dopamine levels.

Original Blog Post on Brain Stimulant

Is the brain neurotransmitter dopamine involved in sensory pleasure? The blog Neuroscientifically Challenged has an excellent discussion about dissension in the ranks among scientist who believe that dopamine does not mediate sensory pleasure but something else, desire.

"When a link between dopamine transmission and rewarding experiences (e.g. eating, sex, drugs) was established, it caused many to understandably hypothesize that dopamine was responsible for our subjective experience of pleasure."

"But science eventually caught up with the hype when researchers began to notice that dopamine didn’t correlate exactly with pleasure."

The researcher Kent Berridge has done extensive research in this area. He has discovered that dopamine does not alter the experience of taste hedonics. Basically this means that dopamine doesn't alter how good food tastes. So how does this translate into the real world? Well alcohol for instance can make food taste much better. That is often why people drink beer and pizza together.

Alcohol interacts with a person's opioid system and this is most likely the cause of the enhanced taste hedonics. Activation of the mu-opioid receptor in specific areas of the brain can make sensory taste experience that much more pleasurable. So a pizza that would normally be fodder might taste amazing after taking alcohol or an opiate like heroin. Increasing dopamine on the other hand doesn't make things taste any better (taking cocaine for instance). Berridge has done a lot of testing on animals and has found what he calls several "hedonic hotspots" in the brain.

In hotspots the hedonic gloss that amplifies natural pleasure is painted by brain chemicals such as mu opioids and endocannabinoids, which are natural brain versions of heroin and marijuana. If we activate those neurochemical receptors (via painless microinjection of tiny droplets of drug directly into a hedonic hotspot) we increase the 'liking' reactions elicited by sweetness."

So increasing activation of opioid receptors and endocannabinoid receptors can make food taste subjectively better (at least for rats and mice). How the hell do you tell if a rat or a mouse enjoys food more? Well apparently the researchers can actually look at a mouse (or rats) face to tell how much it likes eating a particular food. Their facial expression gives away their emotions in the same manner a human's face would. However is how good something taste the right descriptive term for pleasure? Pleasure has to be defined in some way and I am not confident that taste hedonics is pleasure per se. I can imagine a person who would subjectively find food to taste good, but still claim to feel anhedonic overall. The rating of subjective anhedonia encompasses multiple rating scale items that can be found at this site "Negative Symptom Initiative". The items on the scale include; frequency of the experience of pleasure during social interactions, frequency of the experience of pleasure during physical sensations, intensity of the experience of pleasure during recreational/vocational activities. So for this pleasure rating scale, there is no mention of taste hedonics (however some other scales do include that measure on their rating items). So taste hedonics might be separable from other sensory pleasures such as pleasure from sexual activity or social activity indicating separate neurotransmitters being involved for separate rating items.

Some clues to dopamine's role in pleasure have come from studies on rats (see Kent Berridge's website). In one study performed, researchers decreased dopamine in the nucleus accumbens of rats by 99%. The researchers found that the rats would no longer eat food on their own. Dopamine has an overall stimulating effect on behavior and suppressing its activity generally decreases the incentive an animal or person has to do things and leaves them demotivated. The researchers actually force fed the rats food and checked their facial expressions to tell how much they actually enjoyed eating it. Under these conditions, the rats found the food just as tasty as when having normal dopamine levels indicating that decreasing this neurotransmitter does not decrease consummatory "pleasure". In another study performed, researchers found that mutant mice with increased dopamine levels show higher "wanting" but not "liking" of sweet sugar food. Meaning they were more likely to eat food, but showed no increased taste hedonics.

I personally think the evidence for dopamine's involvement for specific aspects of sensory pleasure is fairly good and I disagree with the researchers who casts its role aside completely. For one thing it has been known for some times that anti-psychotics which block dopamine receptors tend to reduce motivation as well as cause anhedonia. So it may be premature to separate incentive salience (desire) from reward. Dopamine may actually be involved in both of those emotions. There is also the problem that receptors for dopamine do different things in different areas. So activation of receptors in the mesolimbic system (the nucleus accumbens) may be associated with pleasure while in other brain areas dopamine receptor activation may be associated with different responses like desire.

Pramipexole a dopamine agonist drug which stimulates the D2/D3 type dopamine receptors and has been shown to have anti-anhedonic properties. This is a critical detail indicating that dopamine is directly involved with sensory pleasure as it shows that increasing dopamine receptor activation can directly enhance a person's pleasure. I previously talked about D2 dopamine gene therapy which increased this receptor in the reward region of the brain to reduce drug craving. It is fairly well known that cocaine can cause intense euphoria (i.e. pleasure) and also anhedonia as a result of drug withdrawal because of receptor downregulation. Kent Berridge seems to basically discount dopamine's role and he believes that it mediates "incentive salience" (i.e. wanting or desire) and not pleasure. He is not alone among his views either.

We’ve suggested that pleasure ‘wanting’, rather than ‘liking’, best captures what dopamine does. Usually ‘liking’ and ‘wanting’ go together for pleasant incentives, as two sides of the same psychological coin. But our findings indicate ‘wanting’ may be separable in the brain from ‘liking’, and that mesolimbic dopamine systems mediate only ‘wanting’."

One also has to be very careful about categorizing sensory pleasure and one must take care to distinguish taste hedonics from pleasure derived from sex or socializing. Dopaminergic drugs are known to be both pro-sexual and pro-social. They seemingly can enhance the pleasure a person obtains from having sex or being social.

Can we really correlate a specific neurotransmitter with sensory pleasure? To me it is erroneous to think that one neurotransmitter system mediates sensory pleasure. At least three different drugs with different mechanism of action are rewarding. Increasing dopamine, decreasing NMDA receptor activation and increasing mu-opioid activation are all independently rewarding mechanisms of drug action (meaning they induce pleasure). The main rewarding effect of altering these specific neurotransmitters concentrations may be due to decreasing the excitability of the medium spiny neurons in the nucleus accumbens. So instead of a specific neurotransmitter, it may be their net effect on overall neuron activity and it seems likely that neurotransmitters overlap and interact on levels that may currently be unclear or too complex to understand completely. There are many other neurotransmiters and intracellular cascades that may also be involved with reward, so assigning absolute value to a single neurotransmitter may be premature. Researchers tend to move toward reductionism and get over attached to a specific neurotransmitter when correlating a specific behavioral state.

Not only that, while drug manipulation of the brain is instructive for telling us which neurotransmitter is associated with a specific mental state it is not an absolute measure. An example is that transcranial magnetic stimulation is currently used as a noninvasive mapping technique that can activate or knock out specific brain regions to determine their function. If an activity in a specific brain region region is suppressed (as in 'knocked out') by TMS stimulation and a subject then performs worse on a certain task, this gives researchers the idea that that area is involved in that task. However it only tells scientists that the region is associated with that task not necessarily an absolute positive involvement. Using drugs to test theories is in effect the same as doing a knock out of a brain region. A drug has multiple non-selective effects on the brain which are in general "unnatural". When a dopamine agonist can decrease feelings of anhedonia, that still doesn't necessarily tell us that dopamine is absolutely involved with pleasure. Like "knocking out" brain regions with TMS it may merely tell us that dopamine is associated with pleasure under certain circumstances. A dopamine D2/D3 agonist while informative, it is still creating a novel functioning of brain activity. For instance, a D2/D3 agonist can actually abnormally decrease activation of the D1 receptor subtype (due to reduced dopamine brain levels from stimulation of D2/D3 autoreceptors). So drugs can have many unintended effects that are difficult to measure and quantify.

I think neuroscientist researchers get too caught up in thinking that they can understand the brain and explain it by correlating behavior specific neurotransmitter concentrations or receptors. The problem is that the brain is a complex organ and any manipulation actually alters the functionality in unpredictable ways. Some researchers expect to find the final common molecular pathway of pleasure in the future. However, that pathway is continually shifting in response to outside manipulation and scientists may never in reality find that elusive molecular signature of reward. That molecular signatures of reward are not necessarily static and unchangeable. The brain consists of 100 billion neurons and trillions of synapses with a large array of various protein receptors and neurotransmitters. Each individual brain contains a unique pattern of matter and a different subjective experience for the person. Scientists can correlate changing specific neurotransmitter concentrations, receptor proteins, or brain activation/deactivation with subjective experience. However each time a manipulation is made there is a subtle alteration in the brain's original functioning. I would call this Heisenberg's "Uncertainty Principle" for the brain. When decoding brain activity, you can't measure a specific aspect of the brain without altering subjective experience in a potentially unknowable way. The act of measuring the brain (like using drugs) changes the functionality of the brain in a completely new way making absolute measurement of brain functioning impossible. Not to mention an absolute definition of many sensory emotions can be extraordinarily complex. The word pleasure may have different meanings to different people, thus its use may be somewhat limited. What does this mean for dopamine? I think its safe to say that it is associated or involved with pleasure, but the full story is obviously extremely complex.