The ventral tegmental area (VTA) refers to a group of neurons located close to the midline on the floor of the midbrain.
The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways.
The VTA’s activities include: drug and natural reward circuitry of the brain, reward cognition, motivational salience, associative learning, and positively-balenced emotions and orgasm
It activities are related to several psychiatric disorders.
Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.
The VTA lacks clear borders that separate it from adjacent regions.
The ventral tegmental area is in the midbrain between several other major areas.
The mammillary bodies and the posterior hypothalamus, both included in the diencephalon, extend rostrally from the VTA.
The red nucleus is situated laterally and oculomotor fibers are situated ventromedially to the VTA.
The pons and the hindbrain lie caudally to the VTA.
The substantia nigra is located laterally to the VTA.
There are four primary nuclei in the VTA: the nucleus paranigralis (Npn), the nucleus parabrachialis pigmentosus (Npbp), the nucleus interfascicularis (Nif), and the nucleus linearis (Nln) caudalis and rostralis.
The VTA up into four similar functional zones that are called the paranigral nucleus (PN), the parabrachial pigmented area (PBP), the parafasciculus retroflexus area (PFR), and the rostromedial tegmental nucleus (RMTg), which approximately adhere to the previous divisions.
The PN and PBP are rich in dopaminergic cells, whereas the other two regions have low densities of these neurons.
The PFR and RMTg contain a low density of tyrosine hydroxylase positive cell bodies.
The RMTg is composed mostly of GABAergic cells.
The PN and PBP consist mainly of medium to large sized tyrosine hydroxylase positive cell bodies.
Almost all areas receiving projections from the VTA project back to it, being
reciprocally connected with a wide range of structures throughout the brain.
The VTA has a role in the control of function in the highly developed neocortex, as well older limbic areas.
The VTA consists of a variety of neurons that are characterized by different neurochemical and neurophysiological properties.
Its glutamatergic and GABAergic inputs are not exclusively inhibitory nor exclusively excitatory.
It receives glutamatergic afferents, which play a key role in regulating VTA cell firing. from the: prefrontal cortex, pedunculopontine tegmental nucleus, laterodorsal tegmental nucleus, subthalamic nucleus, bed nucleus of the stria terminalis, superior colliculus, periaqueductal gray, lateral habenula, dorsal raphe nucleus, and lateral hypothalamic and preoptic areas.
When glutamatergic neurons are activated, the firing rates of the dopamine neurons increase in the VTA and induce burst firing.
Glutamatergic actions in the VTA are critical to the effects of drugs of abuse.
The tail of the ventral tegmental area projects to the VTA with GABAergic afferents, functioning as a
brake for the VTA dopamine pathways.
GABAergic inputs to the VTA include the nucleus accumbens, ventral pallidum, dorsal raphe nucleus, lateral hypothalamus, periaqueductal gray, bed nucleus of the stria terminalis, and rostromedial tegmental nucleus.
Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory.
When this pathway is disinhibited, an increase in the dopamine release in the mesolimbic pathway amplifies locomotor activity.
The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways: corresponding to the prefrontal cortex and nucleus accumbens respectively.
Other VTA projections, which utilize dopamine as their primary neurotransmitter:
Dopaminergic cell groups lack clear anatomical boundaries.
The VTA, in particular the VTA dopamine neurons, function in the reward system, motivation, cognition, and drug addiction, and may be the focus of several psychiatric disorders.
The VTA also processes various emotional outputs from the amygdala, playing a role in avoidance and fear-conditioning.
MRI studies indicate emotional states relating to intense love correlate with activity in the VTA.
The VTA has a large network of GABAergic neurons that are interconnected via gap junctions, allowing for electrical conduction, which is considerably faster than the chemical conduction of signals between synapses.
The VTA, like the substantia nigra, has melanin-pigmented dopaminergic neurons.
Dopaminergic neurons comprise 50-60% of all neurons in the VTA.
GABAergic neurons regulate the firing of their dopaminergic counterparts that send projections throughout the brain
The VTA also contains a small percentage of excitatory glutamatergic neurons.
There are major excitatory inputs from the cortex to the striatum (accumbens nucleus), the midbrain project neuromodulatory dopamine neurons to the striatum, the striatum makes internuclear connections to the pallidum, and the pallidum has outputs to the thalamus, which projects to the cortex, thus completing a loop (limbic loop).
The limbic loop is distinguished from the motor loop
The limbic loop controls cognitive and affective functioning, while the motor loop controls movement.
The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.
Its medial projection system is important in the regulation of affect and drive and plays a different role in goal-directed behavior than the lateral projection system.
The medial projection is activated not by rewarding but by noxious stimuli.
The NAC shell and the posterior VTA are the primary areas involved in the reward system.
The dopaminergic neurons of the substantia nigra and the ventral tegmental area of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways.
These two pathways causes them to be grouped together under dopaminergic projections.
Disorders result from the disruption of these two pathways: schizophrenia, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD).
The nucleus accumbens and the ventral tegmental area are
The primary sites where addictive drugs act are the nucleus accumbens and the ventral tegmental area.
Addictive agents: cocaine, alcohol, opioids, nicotine, cannabinoids, amphetamine, and their analogs alter the neuromodulatory influence of dopamine on the processing of reinforcement signals by prolonging the action of dopamine in the nucleus accumbens or by stimulating the activation of neurons there and also in the VTA.
Addictive drugs stimulate the release of dopamine, which creates both their rewarding and the psychomotor effects.
Compulsive drug-taking behavior is a result of the permanent functional changes in the mesolimbic dopamine system arising from repetitive dopamine stimulation.
Molecular and cellular adaptations that occur are responsible for a sensitized dopamine activity in the VTA and along the mesolimbic dopamine projection in response to drug abuse.
The dopamine-synthesizing enzyme tyrosine hydroxylase activity increases in the VTA as does the ability of these neurons to respond to excitatory inputs in addiction.
These changes occur with increases in the activity of the transcription factor CREB and the up regulation of GluR1, an important subunit of AMPA receptors for glutamate.
Such activated alterations in neural processing impairs the waning influence of adaptive emotional signals in the operation of decision making faculties as drug-seeking and drug-taking behaviors become habitual and compulsive.
Withdrawal symptoms occur because the deficit in reward functioning initiates a distress cycle wherein the drugs become necessary to restore the normal homeostatic state.
Even after the final stages of withdrawal have been passed, drug-seeking behavior can be restored if exposed to the drug or drug-related stimuli.