Ventral Tegmental Area

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Substantia Nigra pars Compacta     

K&W don't consider the ventral tegmental area as a distinct part of the 
Tegmentum .     

Ventral tegmental area (Wiki)   
    "The ventral tegmentum (tegmentum is Latin for covering), better known as the ventral tegmental area (VTA), is a group of neurons located close to the midline on the floor of the midbrain (mesencephalon).  
    The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and is widely implicated in the drug and natural reward circuitry of the brain.  
    It is important in cognition, motivation, drug addiction, intense emotions relating to love, and several psychiatric disorders.  
    The VTA contains neurons that project to numerous areas of the brain, from the prefrontal cortex (PFC) to the caudal brainstem and several regions in between.
The VTA has been shown to have a large network of GABAergic neurons that are interconnected via gap junctions. This network allows for electrical conduction, which is considerably faster than the chemical conduction of signals between synapses.
The VTA, like the substantia nigra (SN), is populated with melanin-pigmented dopaminergic neurons [1]. Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA,[1] which is contrary to previous evidence which noted 77% of neurons within the VTA to be dopaminergic.[2] Additionally, there is a sizable population of GABAergic neurons in the VTA. These GABAergic neurons regulate the firing of their dopaminergic counterparts and send projections throughout the brain to, but not limited to, the following regions: the prefrontal cortex, the nucleus accumbens, and the locus coeruleus. The VTA also contains a small percentage of excitatory glutamatergic neurons.
All studies since 1964 have emphasized the impressive general similarity between the VTA of all mammals from rodents to humans. These studies have focused their efforts on rats, rabbits, dogs, cats, opossum, non-human primates, and humans.

    The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways. Three less important pathways also exists: the mesostriatal, the mesodiencephalic, and the mesorhombencephalic pathways. Below is a brief summary of where each pathway originates and terminates:

    The large mesolimbic pathway projects primarily to the NAC and the olfactory tubercle. The projection is so named to contrast it with the nigro-striatal dopamine system that runs parallel to it but connects the substantia nigra to the dorsal striatum.

    Other projections of the VTA dopamine neurons include the limbic-related regions (i.e. septum, hippocampus, amygdala, and prefrontal cortex).

    The mesocortical pathway projects to sensory, motor, limbic, and polysensory association cortices. The prefrontal, orbitofrontal, and cingulate cortices receive the majority of innervation from the VTA. Most of these connections are unilateral, but some project to one or more area."   


    Almost all areas receiving projections from the VTA project back to it. Thus, the ventral tegmentum is reciprocally connected with a wide range of structures throughout the brain suggesting that it has a role in the control of function in the phylogenetically new and highly developed neocortex, as well as that of the phylogenetically older limbic areas.

    There are excitatory glutamatergic afferents that arise from almost every structure that projects into the VTA, except the NAC and the lateral septum. These glutamatergic afferents play a key role in regulating VTA cell firing. When the glutamatergic neurons are activated, the firing rates of the dopamine neurons increase in the VTA and induce burst firing. Studies have shown that these glutamatergic actions in the VTA are critical to the effects of drugs of abuse.

    Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory. There is a substantial pathway from the subpallidal area to the VTA. When this pathway is disinhibited, an increase in the dopamine release in the mesolimbic pathway amplifies locomotor activity." 

    "Limbic loop

    "The “limbic loop” is very similar to the direct pathway motor loop of the basal ganglia. In both systems, 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 the loop. The limbic loop is distinguished from the motor loop by the source and nature of the cortical input, the division of the striatum and pallidum that process the input, the source of the dopaminergic neurons form the midbrain, and the thalamic target of the pallidal output." 

CA3 loop

    "Linking context to reward is important for reward seeking. Recently a group of researchers documented a VTA-CA3 loop that uses the lateral septum as an intermediary. They used a pseudo-rabies virus (PRV) as a transsnyaptic tracer, and injected it into the VTA. They found that unilateral injection into the VTA resulted in bilateral PRV labeling in CA3 beginning 48 hours after injection. Lesions of the caudodorsal lateral septum (cd-LS) prior to VTA PRV injection resulted in significantly less PRV labeled neurons in CA3. Theta wave stimulation of CA3 resulted in increased firing rates for dopamine cells in the VTA, and decreased firing rates for GABA neurons in the VTA. The identity of VTA neurons was confirmed by biotin labeling of the recording neuron, and then histological staining for tyrosine hydroxylase (TH). Temporary inactivation of CA3 via GABA agonists prevented context induced reinstatement of lever pressing for intravenous cocaine.[3]

    The authors propose a functional circuit loop where activation of glutamatergic cells in CA3 causes activation of GABAergic cells in cd-LS, which inhibits GABA interneurons in the VTA, releasing the dopamine cells from the tonic inhibition, and leading to an increased firing rate for the dopamine cells.

Reward system

    "The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.

    First, the posteromedial VTA and central linear raphe cells selectively project to the ventromedial striatum, which includes the medial olfactory tubercle and the medial NAC shell.

    Secondly, the lateral VTA largely projects to the ventrolateral striatum, which includes the NAC core, the medial NAC shell, and the lateral olfactory tubercle.

    These pathways are respectively called the meso-ventromedial and the meso-ventrolateral striatal dopamine systems. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed behavior than the lateral projection system. Unlike the lateral part, the medial one is activated not by rewarding but by noxious stimuli.[4] Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system.

    Normally, the dopaminergic neurons are only phasically active. When they are excited they fire a barrage of action potentials and dopamine is released in the NAC. The medium spiny neurons of the NAC are much more responsive to this increase in dopamine if there is coincident excitatory input form the telencephalic structures such as the amygdala and orbital-medial prefrontal cortex.  

    The activated striatal neurons (NAC neurons) then project to the ventral pallidum where they inhibit the inhibitory GABA neurons. This inhibition in the pallidum disinhibits the thalamic target of the limbic loop, which is the mediodorsal nucleus. The thalamus then innervates the cortical division of the limbic forebrain. This final connection is reinforced by activity in direct cortical projections from the dopaminergic neurons of the VTA." 

Drug addiction

    "The NAC and the VTA are the primary sites where drugs of abuse act. The following are commonly considered abused drugs: heroin, cocaine, alcohol, opiates, marijuana, nicotine, amphetamine and their synthetic analogs.  
    These drugs alter the neuromodulatory influence of dopamine on the processing of reinforcement signals by prolonging the action of dopamine in the nucleus accumbens or by potentiating the activation of neurons in the VTA and NAC.  
    The most common drugs of abuse stimulate the release of dopamine, which creates both their rewarding and the psychomotor effects. Compulsive drug taking behaviors are a result of the permanent functional changes in the mesolimbic dopamine system arising from repetitive dopamine stimulation. Molecular and cellular adaptations are responsible for a sensitized dopamine activity in the VTA and along the mesolimbic dopamine projection in response to drug abuse.
    In the VTA of addicted individuals, the activity of the dopamine-synthesizing enzyme tyrosine hydroxylase increases, as does the ability of these neurons to respond to excitatory inputs. The latter effect is secondary to increases in the activity of the transcription factor CREB and the up regulation of GluR1, and important subunit of AMPA receptors for glutamate. These alterations in neural processing could account for 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.

    Experiments in rats have shown that animals learn to press a lever for the administration of drugs such as nicotine, carbachol, opiates, cocaine, and ethanol into the posterior VTA more readily than into the anterior VTA. Other studies have shown that microinjections of dopaminergic drugs into the NAC shell increase locomotor activity and exploratory behaviors, conditioned approach responses, and anticipatory sexual behaviors.

    The withdrawal phenomenon occurs because the deficit in reward functioning causes the organism to enter a distress cycle where the drugs become necessary to restore the normal homeostatic state. Recent research has shown that even after the final stages of withdrawal have been passed, an organism will reinstate the drug-seeking behavior if exposed to the drug or drug-related stimuli." 

Searching Google for "A-10 cell bodies" yielded 31,400,000 references. 

Ventral tegmental area (Wiki)   
    "Because of the selective limbic-related afferents to the VTA, the cells of the VTA are given the designation A10 to differentiate them from surrounding cells."  

1980    511<518  
The pattern of termination of ventral tegmental afferents into nucleus accumbens: an anterograde HRP analysis.
The input pattern from the ventral tegmental area (VTA) to the nucleus accumbens was examined using the anterograde transport of HRP. Following an injection of HRP into the VTA, marked heterogeneity was seen in accumbens especially in caudal regions. Here, the terminals were restricted for most part in the dorsal portions of accumbens. In rostral accumbens, the pattern was more uniform across accumbens. Glyoxylic acid induced histofluorescence supported these findings. The present results demonstrate considerable complexity in the rostral-caudal termination pattern of A10 afferent within the nucleus accumbens."  

1981    508<518  
Inhibition from ventral tegmental area of nucleus accumbens neurons in the rat.  
The role of the ventral tegmental area (VTA), which is rich in dopamine-containing cell bodies, on nucleus accumbens (Acc) neurons was examined. In Acc neurons receiving input from parafascicular nucleus (Pf) of thalamus, VTA conditioning stimulation produced an inhibition of spike generation with Pf stimulation. In contrast, VTA conditioning stimulation did not affect Acc neurons receiving input from limbic structures such as the amygdala nucleus and hippocampus."  

1984    493<518 
Microiontophoretic studies of the dopaminergic inhibition from the ventral tegmental area to the nucleus accumbens neurons.  

Microiontophoretic studies using chloral hydrate-anesthetized rats were performed to determine whether excitation of a dopaminergic pathway originating in the ventral tegmental area (VTA) inhibits neurons on the nucleus accumbens (Acc). In 13 of 17 Acc neurons which failed to respond to hippocampal stimulation, the spike generation produced by stimulation of the parafascicular nucleus of thalamus was inhibited by both VTA conditioning stimulation and iontophoretically applied dopamine. The inhibition induced by the VTA conditioning stimulation was antagonized by iontophoretic application of haloperidol in 10 of 13 Acc neurons tested. In contrast, spike generation induced by stimulation of the hippocampus was not affected by VTA conditioning stimulation in 14 of 15 Acc neurons, although iontophoretically applied dopamine produced an inhibition in 4 of those 15 Acc neurons. Spikes generated by stimulation of the VTA were obtained in 23 of 102 neurons and were not affected by iontophoretically applied haloperidol. These results strongly suggest that dopamine derived from VTA inhibits Acc neurons receiving input from the parafascicular nucleus of thalamus but not from the hippocampus."

1987    350<354   
Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity.  
The VTA contains the A10 group of DA containing neurons. These neurons have been grouped into nuclei to be found on the floor of the midbrain tegmentum--Npn, Nif, Npbp and Nln rostralis and caudalis.  
    The VTA is traversed by many blood vessels and nerve fibers. Close to its poorly defined borders are found DA (A8, A9, A11) and 5-HT containing neurons (B8). Efferent projections of the VTA can be divided into 5 subsystems.  
    The mesorhombencephalic projects to other monoaminergic nuclei, the cerebellum and a fine projection descends to other tegmental nuclei as far as the inferior olive. Fibers to the spinal cord have not been demonstrated.  
    The mesodiencephalic path projects to several thalamic and hypothalamic nuclei and possibly the median eminence. Functionally important examples are the anterior hypothalamic-preoptic area, N. medialis dorsalis and reuniens thalami. These two subsystems are largely non-dopaminergic.  
    A minor mesostriatal projection is overshadowed by the large mesolimbic projection to the accumbens, tuberculum olfactorium, septum lateralis and n. interstitialis stria terminalis.  
    There are also mesolimbic connections with several amygdaloid nuclei (especially centralis and basolateralis), the olfactory nuclei and entorhinal cortex. A minor projection to the hippocampus has been detected.  
    The mesocortical pathway projects to sensory (e.g. visual), motor, limbic (e.g. retrosplenial) and polysensory association cortices (e.g. prefrontal). Prefrontal, orbitofrontal (insular) and cingulate cortices receive the most marked innervation from the VTA.  
     A more widespread presence of DA in other cortices of rodents becomes progressively more evident in carnivores and primates. Most but not all projections are unilateral. Some neurons project to more than one area in mesodiencephalic, limbic and cortical systems. The majority of these fibers ascend in the MFB. Most areas receiving a projection from the VTA (DA or non-DA) project back to the VTA.  
    The septohippocampal complex in particular and the limbic system in general provide quantitatively much less feedback than other areas. The role of the VTA as a mediator of dialogue with the frontostriatal and limbic/extrapyramidal system is discussed under the theme of circuit systems. The large convergence of afferents to certain VTA projection areas (prefrontal, entorhinal cortices, lateral septum, central amygdala, habenula and accumbens) is discussed under the theme of convergence systems."  

1989    457<518            
Ventral tegmental area-mediated inhibition of neurons of the nucleus accumbens receiving input from the parafascicular nucleus of the thalamus is mediated by dopamine D1 receptors.   

Microiontophoretic experiments were performed to determine whether inhibition mediated by the ventral tegmental area neurons of the nucleus accumbens, receiving input from the parafascicular nucleus of thalamus, is mediated by dopamine D1 or D2 receptors, using rats anesthetized with chloral hydrate.
    Spikes, elicited by test stimuli applied to the parafascicular nucleus were inhibited by conditioning stimuli to the ventral tegmental area, given 30 msec before the test stimuli. This inhibition was antagonized by iontophoretic application of SCH 23390, a D1 antagonist, in 18 of 25 neurons of the nucleus accumbens, but in only 3 of 22 neurons of the nucleus accumbens during application of domperidone, a D2 antagonist. The reduction by conditioning stimulation of the ventral tegmental area of the mean number of spikes of the 25 neurons upon stimulation of the parafascicular nucleus, was abolished by SCH 23390. In contrast, domperidone did not affect the mean number of spikes of the 22 neurons upon stimulation of the parafascicular nucleus in the presence of conditioning stimulation of the ventral tegmental area. In addition, spikes elicited by stimulation of the parafascicular nucleus were dose-dependently inhibited by iontophoretic application of both SKF 38393, a D1 agonist and bromocriptine, a D2 agonist.  
    These results suggest that inhibition by dopamine, derived from the ventral tegmental area of neurons of the nucleus accumbens, receiving input from the parafascicular nucleus, is mediated mainly by dopamine D1 receptors, although both D1 and D2 receptors are expressed on the same neuron of the nucleus accumbens, which is also inhibited by exogenously applied D2 agonists."  

Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids.
It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens.  
    The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA.  
    Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m).  
    Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10(-5) m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10(-5) m).  
     The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase."  

VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons   
The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons. "