Cited by 1,477Neurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology StudiesNeuroscience and Neuropharmacology Research

The DOI matches its Crossref record; 389 of the 389 references it cites were found in a registry or an index; 1 of the 414 sources its claims cite were checked for support.

Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex

Open access
Ikemoto, Satoshi·2007·Brain Research Reviews

Abstract

Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review refines the meso-limbic dopamine system of the rat into two ventral midbrain-to-ventral striatum projection systems: a meso-ventromedial striatal system from posteromedial VTA/central linear nucleus to medial olfactory tubercle and medial accumbens shell, and a meso-ventrolateral striatal system from lateral VTA to lateral tubercle, lateral shell, and core. It argues these systems support different roles in drug reward, action-arousal, and goal-directed learning, with the medial system especially important for reward and behavioral variation.

Key findings

  • Retrograde tracing showed the ventromedial striatum receives dopaminergic input mainly from posteromedial VTA, interfascicular nucleus, and central linear nucleus, whereas ventrolateral striatum receives mainly from lateral VTA. Table 1: medial tubercle received 45% from PBP, 28% from CL, 10% from PN; medial shell received 33% from CL, 22% from PN, 21% from PBP, 21% from IF; lateral tubercle received 81% from PBP; lateral shell 72% from PBP; core 53% from PBP and 14% from SNC; dorsal striatum 76% from SNC.
  • Most ventral midbrain neurons projecting to ventral striatum were dopaminergic: over 96% of retrogradely labeled cell-bodies after FG deposits into olfactory tubercle, nucleus accumbens, or dorsal striatum were also TH-positive, versus only 10% after diagonal band deposits.
  • Response-independent cocaine into the medial olfactory tubercle increased lever-pressing; 60 mM and 200 mM cocaine produced significantly higher lever-press rates than vehicle (F1,4 = 9.20, P < .05 and F1,4 = 16.88, P < .05, respectively).
  • The paper proposes a variation-selection hypothesis: meso-ventromedial striatal dopamine participates in action-arousal and behavioral variation, while meso-ventrolateral and meso-dorsal striatal dopamine participate in selection and associative learning.

Methods

  • Review plus original experiments in male Wistar rats. Anatomy used 11 rats for TH/Nissl cytoarchitectonic mapping and 43 rats for Fluoro-Gold retrograde tracing from medial/lateral tubercle, medial/lateral shell, core, dorsal striatum, and diagonal band, with TH co-localization.
  • Behavioral experiment used 5 male Wistar rats with unilateral cannulae aimed at medial olfactory tubercle; cocaine was delivered response-independently at fixed intervals, lever-presses illuminated a cue light, and lever-press rates were analyzed with within-subjects ANOVAs.
  • Literature review synthesized prior anatomical, electrophysiological, pharmacological, lesion, microdialysis, and behavioral studies on drug reward and motivated behavior.

Limitations

  • The paper states that the anatomical study focused on limited dimensions and did not examine other VTA projection targets, nor antero-posterior differences within the ventral striatum; it notes that anterior/posterior ventral striatum differences have been reported.
  • The paper notes methodological issues: FG/TH co-localization relied on intrinsic FG fluorescence, reducing detection by about 50% versus immunohistochemical detection, and overlapping TH immunofluorescence made co-expression sometimes difficult to determine.
  • The text also makes evident broader interpretive limits: microinjections diffuse from target sites, permanent lesions can involve functional compensation, and much of the functional discussion is explicitly heuristic or based on limited data, especially for the lateral shell and lateral olfactory tubercle.

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Integrity signals

Registry

Crossref · 10.1016/j.brainresrev.2007.05.004

Cites

389 of 389 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

227 Not checked yet · 156 Own interpretation · 51 Own result · 27 No basis given · 4 Own method · 1 Partly supported · 1 Sources not found · accuracy not yet measured

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Show all 210 claims

  • It may state two separate claims as one. 149
  • Probably not a substantial claim. 151
257 of 257
  • The paper relies on this without support.

    The variation-selection hypothesis of striatal functional organization correctly describes how the medial and lateral projection systems differ in goal-directed learning.

    “as described in the variation-selection hypothesis of striatal functional organization.”
  • The paper relies on this without support.

    The central linear nucleus provides heavy dopaminergic inputs to the ventromedial striatum.

    “The central linear nucleus, into which rats quickly learn to self-administer nicotine or the GABAA receptor agonist muscimol (Ikemoto et al., 1998; Ikemoto et al., 2006), provides heavy dopaminergic inputs to the ventromedial striatum.”
  • The paper relies on this without support.

    Associative learning depends on temporal contiguity.

    “because in most cases associative learning depends on temporal contiguity*.”
  • The paper relies on this without support.

    Motivation and affect concern tonic states.

    “because motivation and affect concern tonic states.”
  • The paper relies on this without support.

    The meso-ventromedial striatal dopamine system is sensitized by regulatory imbalances and activated when animals detect incentive stimuli and especially when procurement of reward is uncertain.

    “This dopamine system is sensitized by regulatory imbalances (e.g., hunger) and activated when animals detect incentive stimuli and especially when procurement of reward is uncertain.”
  • The authors state this as an assumption.

    The reinforcement concept holds that behavioral response leading to drug delivery is reinforced by the direct pharmacological actions of the drug, and contingent drug delivery is essential for learning self-administration.

    “It is generally assumed that behavioral response leading to drug delivery is reinforced by the direct pharmacological actions of the drug, and contingent drug delivery is thought to be essential for learning self-administration.”
  • The paper relies on this without support.

    The medial olfactory tubercle serves similar functions to the medial shell.

    “The loss of medial shell function may be compensated during the “recovery” period (typically a week or more) from surgery by remaining mechanisms including the medial olfactory tubercle, which serves similar functions to the medial shell.”
  • The paper relies on this without support.

    Retrograde tracer FG deposits confined to a region are taken up by neurons projecting to that region and do not spread to adjacent regions or fibers of passage in a way that confounds the labeling.

    “FG deposits in fourteen rats were found in in-between regions including core-dorsal striatum (n = 1), core-medial shell (n = 3), medial shell-medial tubercle (n = 5), medial shell-diagonal band (n = 3), medial tubercle-diagonal band (n = 1), and ventral shell-lateral tubercle (n = 1); the sections from these rats were studied, but not included for analysis.”
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Citations

Cites

Research works printed but not linked: 3

  1. Brog, 1993, The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported Fluoro-Gold, J. Comp. Neurol., 338, 255, 10.1002/cne.903380209 · DOI · Paper page
  2. Brown, 1968, Autoshaping of the pigeon's keypeck, J. Exp. Anal. Psychol., 11, 1
  3. Swanson, 1987, The hypothalamus, vol. 5, 1

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Metadata

Authors
Ikemoto, S.
Affiliations
National Institutes of Health (US)
Corresponding author
Ikemoto, Satoshi
Venue
Brain Research Reviews
Publisher
Elsevier BV
Published
2007-11
Volume
56
Issue
1
Pages
27-78
ISSN
0165-0173 (ISSN-L)
OpenAlex
W1980571433
Cited by
1,477
References
389
Citations by year
2026: 43 · 2025: 54 · 2024: 56 · 2023: 62 · 2022: 54 · 2021: 82 · 2020: 82 · 2019: 85 · 2018: 92 · 2017: 99 · 2016: 85 · 2015: 94 · 2014: 97 · 2013: 116 · 2012: 84
FWCI
5.68
Type
journal article
Language
en
Open access
Locations
  • Brain Research Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Drug Abuse (Z01DA000480, Z01DA000439)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
mesolimbic dopamine system, ventral tegmental area, nucleus accumbens, olfactory tubercle, ventral striatum, reward, cocaine, amphetamine, nicotine, opiates, goal-directed learning, arousal, rats
MeSH terms
Central Nervous System Stimulants, Animals, Brain Mapping, Cocaine, Dopamine, Efferent Pathways, Fluorescent Dyes, Immunohistochemistry, Male, Models, Neurological, Nucleus Accumbens, Olfactory Pathways, Psychotropic Drugs, Reward, Tyrosine 3-Monooxygenase, Rats, Wistar, Ventral Tegmental Area, Dopamine Uptake Inhibitors, Rats

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