In this chapter, we will review the activity of the brain's reward system. We will also outline the software (brain chemistry) and hardware (brain anatomy) involved in regulating an individuals response to activities necessary for survival including sex, eating and social interaction. Software includes the dopamine neurotransmitter as well as key proteins and molecules. We will show how scientists and researchers use brain imaging techniques to identify the regions of the brain involved in addiction as well as tolerance, sensitization and dependence.

Brain Reward System

By using functional magnetic resonance imaging (fMRI) and positron emission topography (PET), researchers mapped the regions of the brain that mediate addictive behaviors and identified the core software and hardware components of the brain's reward circuit. These techniques measure changes in blood flow associated with neouronal activity. Researchers have been able to establish that these same regions are at play across various potentially addictive behaviors whether substance abuse or an activity such as gambling.

The pleasure circuit of the brain as it relates to anatomy, consists of the Ventral Tegmental Area (VTA) [DEFINE], the nucleus accumbens, hippocampus, the prefontral cortex and he amygdala. The key brain chemistry components are the neurotransmitter dopamine, the protein Delta FoSB and the molecule CREB. Brain chemistry and anatomy evolved to construct a highly intricate and powerful method of identifying and recordng which behaviors are rewarded with pleasure and euphoria.

Neurons in the VTA release the dopamine neurotransmitter to the brain's nucleus accumbens. Dopamine travels from the VTA to the nucleus accumbens via the dopamine pathway. After an activity (e.g. substance use) has stimulated the release of dopamine in the VTA, the extra dopamine is reabsorbed in a process called reuptake. Some drugs such as cocaine prevent this process from occurring and thus the pleasure center is stimulated more intensely and for longer periods of time. After a drug user has consistently used a drug to increase the dopamine levels, the VTA will adapt by producing less dopamine causing the user to need more stimulation of the area to feel the same level of pleasure. This is what is referred to as tolerance. The brain reward system is critical in the experience of addiction; animals with lesions in these brain regions no longer show an interest in addictive substances or behaviors. (note)

The amygdala is instrumental in assessing whether an experience is valuable or detrimental thereby dictating whether it should be repeated helping to forge the connection between an experience and other cues. (note) The hippocampus particpates in recording temporal and environmental information about the experience and the prefrontal cortex coordinate and process all this information to determine the ultimate behavior of the individual.  (note) Essentially, the VTA acts as an electrical current resistor, reinforcing to the individual how rewarding an activity is. The more valuable the activity, the more likely it is to be remembered and repeated. The VTA sends an electrical signal causing dopamine to attach to the corresponding D2 receptors [define] on the accumbens neuron [define]. To later shut down the signal, the VTA neuron removes the dopamine and repackages it to be used again as needed. Potentially addictive behaviors temporarily tamper with brain anatomy and chemistry to create an excess of dopamine in the nucleus accumbens producing a jolt that induces euphoria. All potentially addictive behaviors cause the nucleus accumbens to be flooded with dopamine and sometimes even faux dopamine signals.

Regions involved in the brain's reward circuitry communicate via the VTA pathway by releasing the neurotransmitter glutamate. Potentially addictive behaviors alter the responsiveness of the VTA and nucleus accumbens to glutamate for days. Changes in sensitivity to glutatamate in the reward pathway enhance both the release of dopamine from the VTA and responsiveness to dopamine in the nucleus accumbens, thereby promoting CREB and Delta FoSB activity. This altered glutamate sensitivity strengthens the neuronal pathways that link memories of drug-taking experiences with high reward, thereby feeding the desire to seek the drug.

The interesting thing about D2 receptors is that their prevalence may be partially responsible for why some people become addicted and others do not. In a study conducted (note), participants had to take the over the counter drug Ritalin, commonly used for ADHD. The participants who liked the drug had fewer D2 receptors than those that disliked it. This may seem counterintuitive at first, but the explanation could be simple. People relying more on healthy environmental sources for their stimulation are less inclined to use the drugs, while those that are not getting enough dopamine liked the sensation, because the drug increases their levels.

Tolerance

After an individual has consistently engaged in a potentially addictive behavior to increase dopamine levels, the VTA adapts and the brain reward system is suppressed resulting in less dopamine. This causes the user to need more stimulation of the area to feel the same level of pleasure. This is is referred to as tolerance. A molecule referred to as CREB is pivotal in the experience of tolerance. (note) Tolerance occurs because dopamine responsive cells are induced to increase production of a signalling molecule known as AMP (cAMP), a precursor to the activation of CREB. Persistent drug use for example, causes sustained activation of CREB which controls the production of dynorphin, a natural molecule with opium like efects (note). The end result is the dampening or suppression of the brain's reward circuitry. An increase in dynorphin also contributes to dependence, as its inhibition of the the reward pathway leaves the individual, in the drugs absence, depressed and unable to take pleasure in previously enjoyable activities.

Sensitization


Chronic engagement in potentially addictive behaviors, whether an activity or use of a substance, induces changes in brain chemistry and anatomy that can last for weeksor even years after the last induction. These adaptions which increase CREB activity and glutamate signaling, dampen sought after pleasure and euphoria (tolerance) while also increasing cravings. If the subject abstains, CREB declines lessening the tolerance and sensitization sets in, activating the intense craving that compels the subject to engage. Environmental or perceptive cues elicit powerful memories of pleasure attained serving to exacerbate the situation. This agonizing compulsion persists despite long

periods of abstention. CREB activity does not last long enough to explain sensitization; the protein delta FoSB is responsible for these longeer lasting molecular changes.As the unstable Delta FosB concentrations rises gradually and progressively in participating brain regions, it remains active in nerve cells for weeks to months after drug administration thereby causing hypersensitivy to the drugs.

The drug induced changes to the brain's reward system we have reviewed are responsible for the complex experience of addiction which includes tolerance, dependence, craving, relapse and sensitization. Using fMRI and PET techniques, neuroscientists continue to unravel brain neurotransmitters, proteins, molecules and anatomy that illuminate material nature of addiction. This discovery will continue to imnform the diagnosis and ultimately the treatment of potentially addictive behaviors.


NOTES

Dopamine

Dopamine is the chemical messenger transmitted from the VTA to the Nucleus Accumbens. It is a neurotransmitter responsible for many aspects of human functioning including

regulating movement and controlling attention.

Ventral Tegmental Area (VTA)

This is a cluster of nerve cells at the midbrain that basically initiates the pleasure reward process.

Nucleus Accumbens

The Nucleus Accumbens is a structure in the brain well beneath the frontal cortex.

Neuron

????

Hippocampus

The hippocampus is a brain region that exists in both hemispheres critical for the consolidation of memories. The hippocampus plays an important role in the formation of

addiction, because it records both the pleasure felt and the instigator. The hippocampus lets the user know later on that the drug felt really good.

Prefrontal Cortex

The Prefrontal Cortex is an area of the brain located at the front of the frontal lobe. The prefrontal cortex is beyond the primitive areas of the brain and is what gives us

the ability to plan ahead and make sophisticated judgements about a stimulus in order to make thoughtful decisions. It also allows us to restrict ourselves from performing

undesirable actions.