The human reward system is made up of neural structures responsible for incentive salience (desire), associative learning (primarily positive reinforcement and classical conditioning), and positive/pleasure emotions (e.g. euphoria). 

• Dopamine is the primary neurotransmitter of the brain’s reward mechanisms
• Most important reward pathway is the mesolimbic dopamine pathway.
• Thisconnects the ventral tegmental area (VTA) of the midbrain, to the nucleus accumbens (NAc) and olfactory tubercle, which are located in the ventral striatum 
• Theprojections from the VTA are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors.
• The NA itself consists mainly of GABAergic medium spiny neurons. 

When a rewarding stimulus, such as eating food, or direct stimulation by a drug occurs, dopaminergic neurons in the VTA are activated. These neurons project to the NAc, and their activation causes dopamine levels in the NAc to rise,activating dopamine receptors and generating a reward response, thus encouraging repetition and learning. –> any activity that resulted in a reward from your brain will therefore be one you want to repeat. This is essentially how your brain keeps you alive and reproducing.

 Another major dopamine pathway, the mesocortical pathway, also originates in the VTA but travels to the prefrontal cortex, and is thought to integrate information which determines whether a behavior will be elicited.Thebasolateral amygdala projects into the NAc and is thought to also be important for motivation, while the hippocampus plays a role in learning and memory. 

Even though increased dopamine in the brain reward system is generally thought to be the final common pathway for the reinforcing properties of drugs, other neurotransmitters such as serotoninare involved in the modulation of both drug self-administration and dopamine levels.  Serotonin may be important in modulating motivational factors, or the amount of work and individual is willing to perform to obtain a drug. Serotonergic neurons project both to the NA and VTA and appear to regulate dopamine release at the NA.  

• Excessive intake of addictive drugs  –> repeated release of high amounts of dopamine –>increased dopamine receptor activation. 
• The intrinsic purpose of an endogenous reward center is to reinforce behaviors that promote survival, so when a drug stimulates this center, drug-seeking behavior is also promoted - induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens
• Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation, resulting in a decrease in the sensitivity to natural stimuli. 
• Alongside the positive reinforcement, these withdrawal symptoms can be considered negative reinforcing factors. 
• Discontinued drug use will often induce various negative responses such as chronic irritability, physical pain, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards.

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP), (CREB), (NF-κB). Overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. This means an individuals actual genes are changed by chronic drug use to make them even more addicted  - not just a case of being able to stop when they chose. 

How serotonin curbs cocaine addiction

Contrary to common thinking, cocaine triggers an addiction only in 20% of the consumers. But what happens in their brains when they lose control of their consumption? Thanks to a recent experimental method, neuroscientists at the University of Geneva (UNIGE), Switzerland, have revealed a brain mechanism specific to cocaine, which has the particularity of triggering a massive increase in serotonin in addition to the increase in dopamine common to all drugs. Indeed, serotonin acts as an intrinsic brake on the overexcitement of the reward system elicited by dopamine, the neurotransmitter that causes addiction. These results are published in the journal Science.

Addiction is defined as the compulsive search for a substance despite the negative consequences, whereas dependence is characterised as the occurrence of a withdrawal symptom — the physical effects of which vary greatly from one substance to another — when consumption is stopped abruptly. It thus affects everyone, whereas addiction affects only a minority of users, even after prolonged exposure. For example, it is estimated that 20% of cocaine users and 30% of opiate users are addicted. “The same principle applies to all potentially addictive products”, says Christian Lüscher, a professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine, who led the research. “Here in Switzerland, for instance, almost all adults consume alcohol from time to time, which is a strong stimulator of the reward system. However, only a small proportion of us will become alcoholics.”

Addiction triples without serotonin

To assess how cocaine addiction arises in the brain, the research team developed a series of experiments. “Most of the time, scientific experiments aim to reproduce a systematic mechanism. Here, the difficulty lies in observing a random phenomenon, which is triggered only once in five times”, explains Yue Li, a researcher in Christian Lüscher’s laboratory and first author of the study.

The scientists first taught a large group of mice to self-administer cocaine voluntarily, and then added a constraint: each time they self-administered cocaine, the mice received a slightly unpleasant stimulus (electric shock or air jet). Two groups then emerged: 80% of the mice stopped their consumption, while 20% continued, despite the unpleasantness. “This compulsive behaviour is precisely what defines addiction, which affects 20% of individuals, in mice as well as in humans”, emphasises Vincent Pascoli, a scientific collaborator in the Geneva group and co-author of this study.

The experiment was repeated with mice in which cocaine was no longer linked to the serotonin transporter, so that only dopamine increased when the substance was taken. 60% of the animals then developed an addiction. The same was found in other animals with a reward system stimulation protocol that did not affect serotonin. “If serotonin is administered to the latter group, the rate of addiction falls to 20%”, says Christian Lüscher. “Cocaine therefore has a kind of natural brake that is effective four times out of five.”

A delicate synaptic balance

When cocaine is consumed, two forces are at work in the brain: dopamine on the one hand, whose sudden increase leads to compulsion, and serotonin on the other, which acts as a brake on compulsion. Addiction therefore occurs when an imbalance is created between these two neuroregulators and dopamine overtakes serotonin.

“Actually, dopamine triggers a phenomenon of synaptic plasticity, through the strengthening of connections between synapses in the cortex and those in the dorsal striatum. This intense stimulation of the reward system then triggers compulsion. Serotonin has the opposite effect by inhibiting the reinforcement induced by dopamine to keep the reward system under control”, explains Christian Lüscher.

What about other drugs?

Apart from the increase in dopamine, each substance has its own specificity and effect on the brain. If the addictive effect of cocaine is naturally reduced by serotonin, what about other drugs? The Geneva neuroscientists will now look at opiates — which are more addictive than cocaine — and ketamine, which is much less so. The aim is to understand in detail how the brain reacts to these drugs and why some people are much more vulnerable to their harmful effects than others.

Beyond dopamine: New reward circuitry discovered

The key to overcoming addictions and psychiatric disorders lives deep inside the netherworld of our brains and the circuitry that causes us to feel good. Just like space, this region of the brain needs more exploration.

The oldest and most known reward pathway is the mesolimbic dopamine system, which is composed of neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens – a key structure in mediating emotional and motivation processing,

Dopamine is a neurotransmitter that is released when the brain is expecting reward.A spike in dopamine could come be from eating pizza, dancing, shopping and sex. But it can also come from drugs, and lead to substance abuse.

In the search for new therapies to treat addiction and psychiatric illness, researchers are examining pathways beyond dopamine that could play a role in reward and reinforcement.

In a paper published in Nature Neuroscience, researchers from the Bruchas Lab at UW Medicine pushed the science forward on our reward pathways and found another such pathway.

“This study opens new avenues to understanding reward circuitry that might be altered in abuse of nicotine, opiates or other drugs as well as neuropsychiatric diseases that affect reward processing including depression,” said corresponding author Dr. Michael Bruchas, professor of anesthesiology and pain medicine at the University of Washington School of Medicine.

The researchers found that approximately 30% of cells in the VTA – the midbrain – are GABA neurons. Neurons are the fundamental units of the brain and nervous system, the cells responsible for receiving sensory input from the external world, for sending motor commands to our muscles, and for transforming and relaying the electrical signals at every step in between.

VTA GABA neurons have increasingly been recognized as involved in reward and aversion, as well as potential targets for the treatment of addiction, depression and other stress-linked disorders.

“What we found are unique GABAergic cells that project broadly to the nucleus accumbens, but projections only to a specific portion contribute to reward reinforcement,” said co-lead author Raajaram Gowrishankar, a postdoctoral scholar in the Bruchas Lab and the Center for the Neurobiology of Addiction, Pain and Emotion.

In male and female mice, researchers showed that long-range GABA neurons from the VTA to the ventral, but not the dorsal, nucleus accumben shell are engaged in reward and reinforcement behavior. They showed that this GABAergic projection inhibit cholinergic interneurons – key players in reward-related learning.

These findings “further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction,“ the researchers wrote.

Gowrishankar said the findings are allowing scientists to understand subregions of the brain and to visualize how specific neuromodulators are released during reward processing. In science terms, the researchers were able to highlight heterogeneity, or differences, in the brain.

"It’s really important that we don’t think of structures in the brain as monolithic," said Gowrishankar. "There’s lots of little nuance in brain – how plastic it is, how it’s wired. This finding is showing one way how differences can play out.”