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The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the
brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...
. The pathway connects the
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
in the
midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
to the
ventral striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutama ...
of the
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
in the
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three prima ...
. The ventral striatum includes the
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
and the olfactory tubercle.
Figure 3: The ventral striatum and self-administration of amphetamine
/ref> The release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates
incentive salience Motivational salience is a cognitive process and a form of attention that ''motivates'' or propels an individual's behavior towards or away from a particular object, perceived event or outcome. Motivational salience regulates the intensity of be ...
(e.g. motivation and desire for rewarding stimuli) and facilitates
reinforcement In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher fr ...
and reward-related motor function learning; it may also play a role in the subjective perception of
pleasure Pleasure refers to experience that feels good, that involves the enjoyment of something. It contrasts with pain or suffering, which are forms of feeling bad. It is closely related to value, desire and action: humans and other conscious anima ...
. 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 Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
.


Anatomy

The mesolimbic pathway is a collection of dopaminergic (i.e.,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
-releasing) neurons that project from the
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
(VTA) to the
ventral striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutama ...
, which includes the
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
(NAcc) and olfactory tubercle.Figure 3: The ventral striatum and self-administration of amphetamine
/ref> 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 The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
and consists of dopaminergic,
GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...
, and glutamatergic
neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
s. The dopaminergic neurons in this region receive stimuli from both cholinergic neurons in the
pedunculopontine nucleus The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus (PPT or PPTg) is a collection of neurons located in the upper pons in the brainstem. It lies caudal to the substantia nigra and adjacent to the superior cerebellar peduncle ...
and the laterodorsal tegmental nucleus as well as glutamatergic neurons in other regions such as the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA ...
. The nucleus accumbens and olfactory tubercle are located in the
ventral striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutama ...
and are primarily composed of medium spiny neurons.Purves D et al. 2008. Neuroscience. Sinauer 4ed. 754-56 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 The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
,
amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex v ...
, and
medial prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA4 ...
. When they are activated by these inputs, the medium spiny neurons' projections release GABA onto the ventral pallidum.


Function

The mesolimbic pathway regulates
incentive salience Motivational salience is a cognitive process and a form of attention that ''motivates'' or propels an individual's behavior towards or away from a particular object, perceived event or outcome. Motivational salience regulates the intensity of be ...
, motivation, reinforcement learning, and fear, among other cognitive processes. The mesolimbic pathway is involved in
motivation Motivation is the reason for which humans and other animals initiate, continue, or terminate a behavior at a given time. Motivational states are commonly understood as forces acting within the agent that create a disposition to engage in goal-dire ...
al 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.


Clinical significance


Mechanisms of addiction

The mesolimbic pathway and a specific set of the pathway's output neurons (e.g. D1-type
medium spiny neurons Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary ...
within the nucleus accumbens) play a central role in the neurobiology of
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
. 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 Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
,
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
, 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 Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
, 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 receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s. Such drugs include alcohol, nicotine, and
tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
(THC). These dopaminergic activations of the mesolimbic pathway are accompanied by the perception of reward. This stimulus-reward association shows a resistance to
extinction Extinction is the termination of a kind of organism or of a group of kinds ( taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed ...
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 neurological and psychological disorders

The mesolimbic pathway is implicated in
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
, depression,Diaz J. 1996. How Drugs Influence Behavior: A Neurobehavorial Approach. Prentice Hall and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. 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

* Mesocortical pathway *
Nigrostriatal pathway The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain. It is one of th ...
* Tuberoinfundibular pathway


See also

*
Antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
*
Tardive dyskinesia Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
*
Tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
*
Withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * '' Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from ...
* Motivational salience *
Apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of inter ...
* Abulia * Akinetic mutism


References


External links

{{Use dmy dates, date=April 2017 Central nervous system pathways Addiction Dopamine