We had a brief overview of Serotonin last week, but another compound frequently dubbed the happiness molecule is Dopamine. Surely,

Dopamine Must be the Happiness Molecule Right?

Dopamine has perhaps a much more straightforward and direct relationship with both reward and pleasure, and so this statement is somewhat more correct than the one about serotonin. But the reality, is as usual, far more complicated and interesting.

Before we get started, we should first establish some definitions. What is reward and what is pleasure?

Reward vs Pleasure

Reward and Pleasure are two concepts that are intimately linked and are often hard to distinguish, but they do have an important difference.

REWARD

Reward is the form of reinforcement that your brain uses to teach it to repeat desired activity patterns and build up habits, when taken to its logical extreme, reward allow a behavior to become a habit, and then a habit to become an addiction.

Reward on its own, is not inherently pleasurable nor euphoric. It instead presents itself as a learning or craving for a specific substance, behavior, or activity. Reward is usually heavily implicated in pleasure, and in most normal every day events, the two are impossible to be detangled. This leads to a phenomenon where the vast majority of rewarding things are also just plain fun, and our cravings seem to make sense.

However, in specific situations (such as with certain drugs), it is possible to receive reward in the absence of pleasure. Any drug addict who no longer receives the magical effects of the drug but is still hopelessly addicted and cannot stop redosing understands the phenomenon of pleasure-less reward very very well.

Reward is directly mediated by dopamine activity in the Mesolimbic pathway, which we will discuss below.

`Rewarding Stimuli are Often Also Pleasurable`

PLEASURE

Pleasure is instead the subjective experience of happiness, fun, elation, euphoria, mood lift, etc. Pleasure allows for desirable emotions and moods. Pleasure is generally a direct result of reward and is mediated by endocannabinoids and endorphins and is generally a downstream effect of dopamine.

The Four Major Dopamine Pathways

Now that we got some definitions out of the way, let's look at what dopamine actually does in the brain. Unlike serotonin, dopamine has a far more limited set of functions, being involved in just 4 major distinct pathways in the brain. Of these, the first two are most relevant to mood, cognitive, and behavioral regulation, so most of our discussion will focus there.

MESOLIMBIC PATHWAY

The mesolimbic pathway originates in the ventral tegmental area (VTA) region of the midbrain, where dopamine producing neurons project their long axons all the way into a structure known as the Nucleus Accumbens (NAcc). The Nucleus Accumbens is a structure filled with dopamine receptors and has a primary role in regulation of reward (both the anticipation of a reward and in reward seeking behavior). Heightened dopamine is directly linked to higher perceived anticipatory reward (cravings) and reward driven behavior. All manner of rewarding behaviors or substances such as food, drugs, sex are directly regulated here. The mesolimbic pathway makes you down bad.

Neurons in the nucleus accumbens contain a protein called Delta FosB, which causes a series of long lasting changes in the neuron in response to prolonged or excessive activation of the dopamine receptors. These changes eventually lead to habit forming and addiction forming behavioral changes, and due to the long lasting duration of these changes habits and addictions are generally hard to shake once formed.

In addition to reward seeking prior to the acquisition or completion of the rewarding substance or behavior, the nucleus accumbens is also involved in consummatory pleasure, but this is not localized to just the nucleus accumbens. Numerous brain structures all play a role in pleasure, with the most prominent of these being termed the "hedonic hotspots". As mentioned previously, these hedonic hotspots tend to be filled with cannabinoid and opioid receptors, listening to endocannabinoid and endorphin release triggered by upstream dopamine activity.

Extremely heightened dopamine levels here, beyond amounts that would be reasonable even in a heavily addicted individual, is directly linked with the "positive" symptoms of schizophrenia and psychosis (e.g. hallucinations, thought disorders, delusions). It is hypothesized that this is due to the mesolimbic dopamine pathway's role in the assignment of salience. Essentially, with so much stimulation on a constant basis, our brains need a way to filter out useful information from junk. One good way of doing so is by seeing which stimulus presents the highest reward; a juicy steak is far more interesting and worth paying attention to than a moldy stale bread, after all. This generally works out pretty well, but in the presence of excessive dopamine, our brains can start drawing excessive significance on arbitrary happenings. This is potentially what leads to psychotic patients believing that someone on TV is speaking to them directly.

MESOCORTICAL PATHWAY

The VTA region of the midbrain doesn't just shoot its lanky axons into the nucleus accumbens but instead also projects into the frontal cortex of your brain. Of the frontal cortex, of particular interest is the section known as the prefrontal cortex or PFC.

The PFC is the executive center of the brain and is involved in higher order cognition tasks such as: focus, motivation, decision making, emotional control. Dopamine is heavily involved in these extremely important effects and the PFC has the hefty job of joining the numerous signals from the disparate regions of the brain into a single cohesive consciousness. Loss of dopamine activity here is correlated with depressive symptoms, lack of motivation, poor emotional control, and impulsivity. ADHD tends to involve a disregulation in the mesocortical pathway, producing too much dopamine at times (leading to hyperfocus) and too little at others (leading to avolition and executive dysfunction). Schizophrenia is also correlated with a lowered dopamine levels in the mesocortical pathway, leading to the "negative" symptoms such as diminished speech, diminished motivation, diminished sociability, flattened affect.

It is important to note that while dopamine has a direct relationship to both the positive and negative symptoms, this is not a 1:1 relationship and many other neurotransmitter systems and brain regions are heavily implicated. Looking at dopamine alone is not remotely enough to understand the complex phenomenon of schizophrenia, and is only presented here as a way to illustrate dopamine's role in the brain.

NIGRASTRIATAL PATHWAY

There's another series of dopamine producing neurons that are not in the VTA but instead in the substantia nigra. These project into the dorsal (back) striatum, a region of the brain primarily involved in regulation of movement. Parkinsons is a disorder characterized in loss of dopamine neurons in the nigrastriatal pathway and the tell tale signs are movement disorders such as excessive shaking and jerky movements.

A common treatment for schizophrenia and psychosis is the ingestion of antipsychotic medicine which generally work by blocking dopamine receptors. Since these medicine do not do a good job of singling out the mesolimbic dopamine, they also tend to inhibit dopamine activity in the nigrastriatal pathway, leading to parkinsons like side effects in long term patients.

The compound MPTP, which was unfortunately mixed in a bad shipment of the drug MPPP (a synthetic opioid), is a potent neurotoxin that kills dopamine producing neurons. Researchers use this compound to target the nigrastriatal pathway and study the effects of parkinsons.

Parkinsons is usually treated with L-Dopa, the chemical precursor to dopamine. This helps your brain produce more dopamine and reduce some of the effects of parkinsons.

TUBEROINFUNDIBULAR PATHWAY

This pathway runs from the hypothalamus to the pituitary gland and is used in the regulation of the release of prolactin. Dopamine receptors here have a negative relationship with prolactin, and heightened dopamine leads to lowered prolactin release and vice versa. Prolactin has an inhibitory effect on sexual satisfaction, and is typically released after orgasm and can play a role in the refractory period. Higher dopamine in this pathway is linked with heightened sexual pleasure and could be part of the explanation for why dopaminergic psychostimulants have such pro-sexual effects (partially also due to mesolimbic pathway).

Fun fact: Cabergoline, a dopamine agonist used in the treatment of parkinsons has a fascinating side effect of reducing the refractory period in men!

Ok, Dopamine MUST be the Happiness Molecule Then... Right?