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Cited by 575Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchNeuropeptides and Animal Physiology

Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies

McBride, William J, Murphy, James M, Ikemoto, Satoshi·1999·Behavioural Brain Research
DOI 10.1016/s0166-4328(99)00022-4
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Abstract

Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC) methodologies have been mainly used to study drug reward mechanisms, but they have also been applied toward examining brain reward mechanisms. ICSA studies in rodents have established that the ventral tegmental area (VTA) is a site supporting morphine and ethanol reinforcement. ICPC studies confirmed that injection of morphine into the VTA produces conditioned place preference (CPP). Further confirmation that activation of opioid receptors within the VTA is reinforcing comes from the findings that the endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA. Activation of the VTA dopamine (DA) system may produce reinforcing effects in general because (a) neurotensin is self-administered into the VTA, and injection of neurotensin into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC), and (b) GABA(A) antagonists are self-administered into the anterior VTA and injections of GABA(A) antagonists into the anterior VTA enhance DA release in the NAC. The NAC also appears to have a major role in brain reward mechanisms, whereas most data from ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement processes. Rodents will self-infuse a variety of drugs of abuse (e.g. amphetamine, morphine, phencyclidine and cocaine) into the NAC, and this occurs primarily in the shell region. ICPC studies also indicate that injection of amphetamine into the shell portion of the NAC produces CPP. Activation of the DA system within the shell subregion of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D2 antagonist can block this behavior. In addition, rats will self-administer a mixture of a D1 plus a D2 agonist into the shell, but not the core, region of the NAC. The ICSA of this mixture can be blocked with the co-infusion of either a D1 or a D2 antagonist. However, the interactions of other transmitter systems within the NAC may also play key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused into the NAC. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and phencyclidine. The DA system also seems to play a role in this behavior since cocaine self-infusion into the MPF cortex can be blocked by co-infusing a D2 antagonist, or with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus. Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis) and serotonin systems of the dorsal and median raphe nuclei may also be important anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC studies indicate that there are a number of receptors, neuronal pathways, and discrete CNS sites involved in brain reward mechanisms.

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Authors
McBride, W. J., Murphy, J. M., & Ikemoto, S.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
McBride, William J
ORCID
Venue
Behavioural Brain Research
Publisher
Elsevier BV
Published
1999-06
Volume
101
Issue
2
Pages
129-152
ISSN
0166-4328 (ISSN-L)
DOI
10.1016/s0166-4328(99)00022-4
OpenAlex
W2129176481
Cited by
574
References
150
Citations by year
2026: 3 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 6 · 2021: 10 · 2020: 16 · 2019: 12 · 2018: 20 · 2017: 18 · 2016: 21 · 2015: 17 · 2014: 16 · 2013: 29 · 2012: 23
FWCI
2.40
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Behavioural Brain Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01aa009619-03)
  • National Institute on Alcohol Abuse and Alcoholism (AA-07611, AA-07462, T32AA007462, AA09619)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
ventral tegmental area, nucleus accumbens shell, dopamine, opioid receptors, met-enkephalin, conditioned place preference, drug reward, morphine, amphetamine, cocaine, dopamine D1 and D2 receptors, NMDA receptor antagonists, muscarinic receptors
MeSH terms
Animals, Brain, Conditioning, Operant, Humans, Receptors, Drug, Receptors, Cell Surface, Reinforcement, Psychology, Reward, Self Administration, Rats

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