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When does reward occur? When dopamine is released or when it is binded?

When does reward occur? When dopamine is released or when it is binded?


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I know this is a silly question, but I'm curious as to what is the exact phase when we experience of the thrill of doing an exciting activity.

I believe this briefly describes the whole process. So, what is the exact point where we feel like "rewarded", when dopamine is released or when it is binded to one of its intended receptors?


My understanding of feed forward systems is that the uptake of transmitter would induce the effect. Though, the simultaneous release of more dopamine is part of its effect. The synaptic gap has no mechanism of inducing a response to a transmitter besides the reuptake on the other side. I am no sort of professional so take what I say with a grain.


Abstract

The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.


THE ROLE OF VENTRAL TEGMENTAL AREA

One of the most important parts of the entire reward system, the ventral tegmental area (VTA) is situated in the midbrain, close to the substantia nigra.

The source of many different sorts of neurons, the VTA is most important for its role in the production of dopaminergic neurons. These transmitters are sent from the VTA to different parts of the brain.

Due to the character of the chemicals it produces and sends around the brain, the VTA has an important function in establishing a particular type of behavior.

The reason why this part is usually mentioned with the substantia nigra is the fact that these two elements are two key dopaminergic parts of the brain.

And while the substantia nigra is closely related to the putamen and the caudate – the two parts of the striatum – the VTA is the source of the mesocortical and mesolimbic pathways. The former ends in the cortical parts, while the latter finished in limbic regions of the brain.

The aforementioned increase of dopamine in the NAc when the brain is stimulated either by affirmative or aversive stimuli has its roots in the VTA.

Namely, the release of dopamine and its projection through the mesolimbic pathway are both triggered by the neurons placed in the VTA.

All this leads to the conclusion that the VTA is an integral part of the entire rewarding system. Because of that, some experts consider this part of the brain an important element in the addiction-developing process.

Apart from addiction, the VTA is often cited as an important factor in understanding and treading other cognitive disorders, among which schizophrenia is the most prominent one.

This is mainly so due to the fact that this disorder is connected with high dopamine levels.

Since dopamine production is activated by dopaminergic neurons in the VTA, there’s a correlation between schizophrenia and this part.

On the other hand, low dopamine levels can lead to ADHD (attention-deficit hyperactivity disorder).

Since the VTA has a huge role in dopaminergic projections, which affect numerous cognitive processes in our brain, the VTA is included in both regular and abnormal mental processes.

To cut a long story short, when the VTA doesn’t function properly, the entire brain will have difficulties in maintaining all the functions necessary for normal life.


How Dopamine Works Inside the Brain’s Reward System

Dopamine plays a role in the brain’s reward system, helping to reinforce certain behaviors that result in reward. A surge of dopamine, for instance, is what prompts a laboratory rat to repeatedly press a lever to get a pellet of food, or a human to take a second slice of pizza. (2)

Recently, scientists have shown that dopamine can help with unlearning fearful associations. In a study published in June 2018 in the journal Nature Communications, researchers uncovered the role of dopamine in lessening fearful reactions over time, an important component of therapy for people with anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). (3)


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Dopamine Pathways

Dopamine is a diverse and important neurotransmitter in the human body. Although it is typically thought of as our “reward and salience” neurotransmitter, it has different functions within its four major pathways. Dopamine pathways are neuronal connections in which dopamine travels to areas of the brain and body to convey important information such as executive thinking, cognition, feelings of reward and pleasure, and voluntary motor movements.

Mesolimbic Dopamine Pathways

The first major dopamine pathway is the mesolimbic pathway. This pathway is highly involved in dopamine’s most commonly thought of function: pleasure and reward. This pathway begins at the ventral tegmental area (VTA). The VTA is a dopamine-rich nucleus that covers part of the midbrain and projects dopaminergic action potentials to another area of the brain called the nucleus accumbens (NAc) 1 . It is here in the NAc, where dopamine primarily mediates feelings of pleasure and reward. Thus, whenever a person encounters rewarding or pleasurable stimuli (such as food, sex, drugs, etc.), dopamine is released and sends signals from the VTA to the NAc, which creates positive feelings that reinforce the behavior.

Stimulation of the NAc is important for maintaining our day-to-day activity. However, over-stimulation can lead to cravings for the item that stimulated the NAc. These substances directly increase dopaminergic activity within the mesolimbic pathway, creating intense feelings of euphoria. Overcoming intense cravings that underlines dysfunction in the mesolimbic pathway can be difficult. However, therapy, certain medications, and even some dopamine-increasing supplements may help the struggling individual gain control over cravings 3 .

Mesocortical Dopamine Pathways

The second pathway is called the mesocortical pathway. Like in the mesolimbic pathway, dopaminergic projections within the mesocortical pathway originate in the VTA. From the VTA, action potentials travel to areas in the prefrontal cortex (PFC). The PFC is highly involved in cognition, working memory, and decision making 2 . Thus, when dysfunction within this pathway occurs, individuals may experience poor concentration and the inability to make decisions.

Taking certain medications, such as amphetamines, can upregulate the release of dopamine in the mesocortical pathway, which in turn increases cognition and activity in the PFC. Although this increase in dopamine within the mesocortical pathway may aid in cognition, it may have unintended side effects in the mesolimbic pathway. Thus, one might consider other dopamine-increasing ingredients to potentially aid in cognition, while avoiding addiction 3 .

Nigrostriatal Dopamine Pathways

The next dopamine pathway is the nigrostriatal pathway, which is involved in motor planning. As the name implies, the dopamine projections start in the substantia nigra and go to the caudate and putamen, parts of the basal ganglia. This pathway contains around 80% of dopamine in the brain.

Dopaminergic neurons in the nigrostriatal pathway stimulate purposeful movement. Reduced numbers of dopamine neurons in this pathway is a major aspect of motor control impairment. Additionally, D2 antagonists, such as first-generation antipsychotics, interfere with the nigrostriatal pathway and can cause extrapyramidal symptoms. These movement disorders may include spasms, contractions, tremors, motor restlessness, parkinsonism, and tardive dyskinesia (irregular/jerky movements). 2

Tuberoinfundibular Dopamine Pathways

The final dopamine pathway is the tuberoinfundibular pathway. The dopamine neurons in this pathway begin in the arcuate and periventricular nuclei of the hypothalamus, and project to the infundibular region of the hypothalamus, specifically the median eminence. In this pathway, dopamine is released into the portal circulation that connects this region to the pituitary gland. Here, dopamine functions to inhibit prolactin release.

Prolactin is a protein secreted by the pituitary gland that enables milk production and has important functions in metabolism, sexual satisfaction (countering the arousal effect of dopamine), and the immune system. Blockage of the D2 receptors, common with antipsychotic medications, prevent dopamine’s inhibitory function, thus increasing prolactin levels in the blood. 2 Increases in prolactin can affect menstrual cycles, libido, fertility, bone health, or galactorrhea. 4

As we have seen, dopamine is far more than just a pleasure/reward neurotransmitter. Although it plays this role within the mesolimbic pathway, dopamine also plays important roles in hormone release, cognition, and movement. Since dopamine is such a diverse and important neurotransmitter, it may be beneficial to assess your overall level of dopamine.

Talk to your healthcare provider today about Sanesco’s neurotransmitter assessment, to check the status of your dopamine level or find a Sanesco provider near you. Clinicians can become a Sanesco provider and offer dopamine assessment as well as gain access to more neurotransmitter information.


Dopamine

By the time a person is sitting in front of a neurologist and being told that they have Parkinson’s disease, they will have lost half the dopamine producing cells in an area of the brain called the midbrain.

On this page we will explain what dopamine is and how it relates to Parkinson’s disease.

Dopamine being released by one cell and binding to another. Source: Truelibido

Dopamine is a chemical is the brain that plays a role in many basic functions of the brain, such as motor co-ordination, reward, and memory. It works as a signalling molecule – a way for brain cells to communicate with each other. Dopamine is released from brain cells that produce this chemical (not all brain cells do this), and it binds to target cells, initiating biological process within those cells.

It does this via five different receptors – that is to say, dopamine is released from one cell and can bind to one of five different receptors on the target cell (depending on which receptor is present). The receptor is analogous to a lock and dopamine is the key. When dopamine binds to a particular receptor it will allow something to happen in that cell. And this is how information from a dopamine neuron is passed or transmitted on to another cell. Hence the reason, dopamine is referred to as a neurotransmitter.

The five different dopamine receptors can be grouped into two populations, based on the action initiated by the binding of dopamine. Dopamine receptors 1 and 5 are considered D1-like receptors, while Dopamine receptors 2,3 and 4 are considered D2-like receptors. Through these various receptors, dopamine is influential in many different activities of the brain, especially motor co-ordination.

Dopamine in motor co-ordination

When you are planning to move your arm or leg, the process required for actually initiating that action begins in an area of the brain called the motor cortex. It runs across the very top of your brain – from just above your temple to the top of your skull. And the motor cortex is divided into regions that control specific body parts (for example the legs are controlled by the very top of the motor cortex, while mouth and tongue are controlled by regions closer to you temples.

While the idea of initiating a movement starts in the motor cortex, your ability to actually move is largely controlled by the activity in a specific group of brain regions, collectively known as the ‘Basal ganglia‘.

The location of the basal ganglia structures (blue) in the human brain. Source: iKnowledge

The basal ganglia receives signals from the overlying motor cortex, processes that information before sending the signal on down the spinal cord to the muscles that are going to perform the movement.

Think of the motor cortex as excited kids wanting to do something and the basal ganglia as the parental figures deciding if this action is a good idea.

And the most important participant in that basal ganglia ‘regulation’ of movement is a structure called the thalamus.

A brainscan illustrating the location of the thalamus in the human brain. Source: Wikipedia

The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement.

The direct/indirect pathways

The processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In simple terms, the direct pathway encourages movement, while the indirect pathway does the opposite (inhibits it). The two pathways work together like a carefully choreographed symphony.

The motor features of Parkinson’s disease (slowness of movement and resting tremor) are associated with a breakdown in the processing of those two pathways, which results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement.

Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition

Both the direct and indirect pathways finish in the thalamus, but their effects on the thalamus are very different. The direct pathway leaves the thalamus excited and active, while the indirect pathway causes the thalamus to be inhibited.

The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the cortex, telling it what to do (‘get excited and move’ or ‘don’t get excited and do not move’, respectively).

Where does dopamine come into the picture?

In Parkinson’s disease, we often talk about the loss of the dopamine neurons in the midbrain as a cardinal feature of the disease. When people are diagnosed with Parkinson’s disease, they have usually lost approximately 50-60% of the dopamine neurons in an area of the brain called the substantia nigra.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

The midbrain is – as the label suggests – in the middle of the brain, just above the brainstem (see image below). The substantia nigra dopamine neurons reside there.

Location of the substantia nigra in the midbrain. Source: Memorylossonline

The dopamine neurons of the substantia nigra generate dopamine and release that chemical in different areas of the brain. The primary regions of that release are areas of the brain called the putamen and the Caudate nucleus. The dopamine neurons of the substantia nigra have long projections (or axons) that extend a long way across the brain to the putamen and caudate nucleus, so that dopamine can be released there.

The projections of the substantia nigra dopamine neurons. Source: MyBrainNotes

In Parkinson’s disease, these ‘axon’ extensions that project to the putamen and caudate nucleus gradually disappear as the dopamine neurons of the substantia nigra are lost. When one looks at brain sections of the putamen after the axons have been labelled with a dark staining technique, this reduction in axons is very apparent over time, especially when compared to a healthy control brain.

The putamen in Parkinson’s disease (across time). Source: Brain

EDITOR’S NOTE: I WOULD JUST LIKE TO ADD THAT THE IMAGE ABOVE IS NOT REPRESENTATIVE OF EVERYONE WITH PARKINSON’S. THE IMAGE IS BEING USED HERE TO PROVIDE AN EXAMPLE OF THE DOPAMINE FIBRE LOSS OBSERVED IN THE PUTAMEN. THIS PROCESS CAN TAKE LONGER IN SOME INDIVIDUALS THAN THE PERIOD OF TIME INDICATED.

Under normal circumstances the dopamine neurons release dopamine in the basal ganglia that excites the direct pathway and inhibits the indirect pathway. This acts as a kind of lubricant for movement.

With the loss of dopamine neurons in Parkinson’s disease, however, there is an increased amount of activity in the indirect pathway. As a result, the thalamus is kept inhibited. With the thalamus subdued, the overlying motor cortex has trouble getting excited, and thus the motor system is unable to work properly. And this is the reason why people with Parkinson’s disease have trouble initiating movement.

People with Parkinson’s disease will often be tested with a brain scan called a DAT-scan when they are diagnosed. This imaging technique results assesses the amount of dopamine being released in the putamen. It results in a horizontal image of the brain being presented on a computer screen with red (hot) regions that overlap with the location of the putamen in healthy individuals, indicating the normal release of dopamine. In people with Parkinson’s disease, however, there is a significant reduction in the release of dopamine (due to less dopamine neurons being present to generate dopamine), resulting in less red colouring on the computer screen image of the brain. In people with later stage Parkinson’s disease, there is even less colouring on the computer image (see image below).

Dopamine transporter (DAT) in normal (A), early Parkinson’s (B) and late stage Parkinsons’ (C) brains. Source: Lancet


Dopamine Is _________

In a brain that people love to describe as “awash with chemicals,” one chemical always seems to stand out. Dopamine: the molecule behind all our most sinful behaviors and secret cravings. Dopamine is love. Dopamine is lust. Dopamine is adultery. Dopamine is motivation. Dopamine is attention. Dopamine is feminism. Dopamine is addiction.

Dopamine is the one neurotransmitter that everyone seems to know about. Vaughn Bell once called it the Kim Kardashian of molecules, but I don’t think that’s fair to dopamine. Suffice it to say, dopamine’s big. And every week or so, you’ll see a new article come out all about dopamine.

So is dopamine your cupcake addiction? Your gambling? Your alcoholism? Your sex life? The reality is dopamine has something to do with all of these. But it is none of them. Dopamine is a chemical in your body. That’s all. But that doesn’t make it simple.

What is dopamine? Dopamine is one of the chemical signals that pass information from one neuron to the next in the tiny spaces between them. When it is released from the first neuron, it floats into the space (the synapse) between the two neurons, and it bumps against receptors for it on the other side that then send a signal down the receiving neuron. That sounds very simple, but when you scale it up from a single pair of neurons to the vast networks in your brain, it quickly becomes complex. The effects of dopamine release depend on where it’s coming from, where the receiving neurons are going and what type of neurons they are, what receptors are binding the dopamine (there are five known types), and what role both the releasing and receiving neurons are playing.

And dopamine is busy! It’s involved in many different important pathways. But when most people talk about dopamine, particularly when they talk about motivation, addiction, attention, or lust, they are talking about the dopamine pathway known as the mesolimbic pathway, which starts with cells in the ventral tegmental area, buried deep in the middle of the brain, which send their projections out to places like the nucleus accumbens and the cortex. Increases in dopamine release in the nucleus accumbens occur in response to sex, drugs, and rock and roll. And dopamine signaling in this area is changed during the course of drug addiction. All abused drugs, from alcohol to cocaine to heroin, increase dopamine in this area in one way or another, and many people like to describe a spike in dopamine as “motivation” or “pleasure.” But that’s not quite it. Really, dopamine is signaling feedback for predicted rewards. If you, say, have learned to associate a cue (like a crack pipe) with a hit of crack, you will start getting increases in dopamine in the nucleus accumbens in response to the sight of the pipe, as your brain predicts the reward. But if you then don’t get your hit, well, then dopamine can decrease, and that’s not a good feeling. So you’d think that maybe dopamine predicts reward. But again, it gets more complex. For example, dopamine can increase in the nucleus accumbens in people with post-traumatic stress disorder when they are experiencing heightened vigilance and paranoia. So you might say, in this brain area at least, dopamine isn’t addiction or reward or fear. Instead, it’s what we call salience. Salience is more than attention: It’s a sign of something that needs to be paid attention to, something that stands out. This may be part of the mesolimbic role in attention deficit hyperactivity disorder and also a part of its role in addiction.

But dopamine itself? It’s not salience. It has far more roles in the brain to play. For example, dopamine plays a big role in starting movement, and the destruction of dopamine neurons in an area of the brain called the substantia nigra is what produces the symptoms of Parkinson’s disease. Dopamine also plays an important role as a hormone, inhibiting prolactin to stop the release of breast milk. Back in the mesolimbic pathway, dopamine can play a role in psychosis, and many antipsychotics for treatment of schizophrenia target dopamine. Dopamine is involved in the frontal cortex in executive functions like attention. In the rest of the body, dopamine is involved in nausea, in kidney function, and in heart function.

With all of these wonderful, interesting things that dopamine does, it gets my goat to see dopamine simplified to things like “attention” or “addiction.” After all, it’s so easy to say “dopamine is X” and call it a day. It’s comforting. You feel like you know the truth at some fundamental biological level, and that’s that. And there are always enough studies out there showing the role of dopamine in X to leave you convinced. But simplifying dopamine, or any chemical in the brain, down to a single action or result gives people a false picture of what it is and what it does. If you think that dopamine is motivation, then more must be better, right? Not necessarily! Because if dopamine is also “pleasure” or “high,” then too much is far too much of a good thing. If you think of dopamine as only being about pleasure or only being about attention, you’ll end up with a false idea of some of the problems involving dopamine, like drug addiction or attention deficit hyperactivity disorder, and you’ll end up with false ideas of how to fix them.

The other reason I don’t like the “dopamine is” craze is because the simplification takes away the wonder of dopamine. If you believe “dopamine is,” then you’d think that we’ve got it all figured out. You begin to wonder why we haven’t solved this addiction problem yet. Complexity means that the diseases associated with dopamine (or with any other chemical or part of the brain, for that matter) are often difficult to understand and even more difficult to treat.

By emphasizing dopamine’s complexity, it might feel like I’m taking away some of the glamour, the sexiness, of dopamine. But I don’t think so. The complexity of how a neurotransmitter behaves is what makes it wonderful. The simplicity of a single molecule and its receptors is what makes dopamine so flexible and what allows the resulting systems to be so complex. And it’s not just dopamine. While dopamine has just five receptor type, another neurotransmitter, serotonin, has 14 currently known and even more that are thought to exist. Other neurotransmitters have receptors with different subtypes, all expressed in different places, and where each combination can produce a different result. There are many types of neurons, and they make billions and billions of connections. And all of this so you can walk, talk, eat, fall in love, get married, get divorced, get addicted to cocaine, and come out on top of your addiction some day. When you think of the sheer number of connections required simply for you to read and understand this sentence—from eyes to brain, to processing, to understanding, to movement as your fingers scroll down the page—you begin to feel a sense of awe. Our brain does all this, even while it makes us think about pepperoni pizza and what that text your crush sent really means. Complexity makes the brain the fascinating and mind-boggling thing that it is.

So dopamine has to do with addiction, whether to cupcakes or cocaine. It has to do with lust and love. It has to do with milk. It has to do with movement, motivation, attention, psychosis. Dopamine plays a role in all of these. But it is none of them, and we shouldn’t want it to be. Its complexity is what makes it great. It shows us what, with a single molecule, the brain can do.


Functions of predictions

Predictions provide advance information about future stimuli, events, or system states. They provide the basic advantage of gaining time for behavioral reactions. Some forms of predictions attribute motivational values to environmental stimuli by association with particular outcomes, thus identifying objects of vital importance and discriminating them from less valuable objects. Other forms code physical parameters of predicted objects, such as spatial position, velocity, and weight. Predictions allow an organism to evaluate future events before they actually occur, permit the selection and preparation of behavioral reactions, and increase the likelihood of approaching or avoiding objects labeled with motivational values. For example, repeated movements of objects in the same sequence allow one to predict forthcoming positions and already prepare the next movement while pursuing the present object. This reduces reaction time between individual targets, speeds up overall performance, and results in an earlier outcome. Predictive eye movements ameliorate behavioral performance through advance focusing (Flowers and Downing 1978).

At a more advanced level, the advance information provided by predictions allows one to make decisions between alternatives to attain particular system states, approach infrequently occurring goal objects, or avoid irreparable adverse effects. Industrial applications use Internal Model Control to predict and react to system states before they actually occur (Garcia et al. 1989). For example, the “fly-by-wire” technique in modern aviation computes predictable forthcoming states of airplanes. Decisions for flying maneuvers take this information into account and help to avoid excessive strain on the mechanical components of the plane, thus reducing weight and increasing the range of operation.

The use of predictive information depends on the nature of the represented future events or system states. Simple representations directly concern the position of upcoming targets and the ensuing behavioral reaction, thus reducing reaction time in a rather automatic fashion. Higher forms of predictions are based on representations permitting logical inference, which can be accessed and treated with varying degrees of intentionality and choice. They often are processed consciously in humans. Before the predicted events or system states occur and behavioral reactions are carried out, such predictions allow one to mentally evaluate various strategies by integrating knowledge from different sources, designing various ways of reaction and comparing the gains and losses from each possible reaction.