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=                             Mesolimbic                             =
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                            Introduction
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The mesolimbic pathway, sometimes referred to as the reward pathway,
is a dopaminergic pathway in the brain. The pathway connects the
ventral tegmental area in the midbrain to the ventral striatum of the
basal ganglia in the forebrain. The ventral striatum includes the
nucleus accumbens and the olfactory
tubercle.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894302/figure/F3/
Figure 3: The ventral striatum and self-administration of amphetamine]

The release of dopamine from the mesolimbic pathway into the nucleus
accumbens regulates incentive salience (e.g. motivation and desire for
rewarding stimuli) and facilitates reinforcement and reward-related
motor function learning; it may also play a role in the subjective
perception of pleasure. The dysregulation of the mesolimbic pathway
and its output neurons in the nucleus accumbens plays a significant
role in the development and maintenance of an addiction.


                              Anatomy
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The mesolimbic pathway is a collection of dopaminergic (i.e.,
dopamine-releasing) neurons that project from the ventral tegmental
area (VTA) to the ventral striatum, which includes the nucleus
accumbens (NAcc) and olfactory tubercle. It is one of the component
pathways of the medial forebrain bundle, which is a set of neural
pathways that mediate brain stimulation reward.

The VTA is located in the midbrain and consists of dopaminergic,
GABAergic, and glutamatergic neurons. The dopaminergic neurons in this
region receive stimuli from both cholinergic neurons in the
pedunculopontine nucleus and the laterodorsal tegmental nucleus as
well as glutamatergic neurons in other regions such as the prefrontal
cortex. The nucleus accumbens and olfactory tubercle are located in
the ventral striatum and are primarily composed of medium spiny
neurons. The nucleus accumbens is subdivided into limbic and motor
subregions known as the NAcc shell and NAcc core. The medium spiny
neurons in the nucleus accumbens receive input from both the
dopaminergic neurons of the VTA and the glutamatergic neurons of the
hippocampus, amygdala, and medial prefrontal cortex. When they are
activated by these inputs, the medium spiny neurons' projections
release GABA onto the ventral pallidum.


                              Function
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The mesolimbic pathway regulates incentive salience, motivation,
reinforcement learning, and fear, among other cognitive processes.

The mesolimbic pathway is involved in motivational cognition.
Depletion of dopamine in this pathway, or lesions at its site of
origin, decrease the extent to which an animal is willing to go to
obtain a reward (e.g. the number of lever presses for intravenous
nicotine delivery in rats or time spent searching for food).
Dopaminergic drugs are also able to increase the extent an animal is
willing to go to obtain a reward. Moreover, the firing rate of neurons
in the mesolimbic pathway increases during anticipation of reward,
which may explain craving. Mesolimbic dopamine release was once
thought to be the primary mediator of pleasure, but is now believed to
have only a minor or secondary role in pleasure perception.


Mechanisms of addiction
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The mesolimbic pathway and a specific set of the pathway's output
neurons (e.g. D1-type medium spiny neurons within the nucleus
accumbens) play a central role in the neurobiology of addiction. Drug
addiction is an illness caused by habitual substance use that induces
chemical changes in the brain's circuitry. An addictive drug is
defined as a substance that affects the mesolimbic system directly or
indirectly by increasing extracellular levels of dopamine.

Common addictive substances such as cocaine, alcohol, and nicotine
have been shown to increase extracellular levels of dopamine within
the mesolimbic pathway, preferentially within the nucleus accumbens.
The mechanisms by which these drugs do so vary depending on the drug
prototype. For example, cocaine precludes the re-uptake of synaptic
dopamine through blocking the presynaptic dopamine transporter.
Another stimulant, amphetamine, reverses the dopamine transporter and
induces the release of dopamine from synaptic vesicles. Non-stimulant
drugs typically bind with ligand-gated channels or G protein-coupled
receptors. Such drugs include alcohol, nicotine, and
tetrahydrocannabinol (THC).
Addictive Drugs and their Molecular Interactions
!Type   !Target !Examples
|Alcohol        |GABAA Receptor, NMDA Receptor  |Beer, wine, and other
beverages
|Cannabinoids   |Cannabinoid Receptor   |Marijuana
|Nicotine       |Nicotinic Acetylcholine Receptor       |Tobacco
|Opiates        |μ Opioid Receptor     |Morphine, heroin
|Phencyclidine  |NMDA Receptor  |PCP
|Stimulants     |Dopamine Transporter   |Cocaine, amphetamine,
methamphetamine
These dopaminergic activations of the mesolimbic pathway are
accompanied by the perception of reward. This stimulus-reward
association shows a resistance to extinction and creates an increased
motivation to repeat that same behavior that caused it. Additionally,
drug intake changes synaptic plasticity in the ventral tegmental area
and the nucleus accumbens. Repeated exposure to the drug can lead to
lasting changes in the brain that gives rise to addictive behavior.


Relation to other neurological and psychological disorders
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The mesolimbic pathway is implicated in schizophrenia, depression, and
Parkinson's disease. It is also theorized to be implicated in overuse
of digital media, although it could simply be a consequence of a
sedentary lifestyle. Each involves distinct structural changes within
the mesolimbic pathway.


                      Other dopamine pathways
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* Mesocortical pathway
* Nigrostriatal pathway
* Tuberoinfundibular pathway


                              See also
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* Antipsychotic
* Tardive dyskinesia
*Tolerance
*Withdrawal
*Motivational salience
*Apathy
*Abulia
*Akinetic mutism


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