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Cited by 15Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Comparison of Antidepressant‐Like and Abuse‐Related Effects of Phencyclidine in Rats

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Hillhouse, Todd M., Porter, Joseph H., Negus, S. Stevens·2014·Drug Development Research
DOI 10.1002/ddr.21228PMC PMC4276473
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Abstract

Preclinical Research N ‐methyl‐D‐aspartate ( NMDA ) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but abuse potential of these agents is a concern. The NMDA antagonist phencyclidine has known abuse liability but undefined efficacy as an antidepressant. To further evaluate the relationship between antidepressant‐like and abuse‐related effects of NMDA antagonists, this study evaluated the effects of phencyclidine (1.0–10.0 mg/kg) in male S prague‐ D awley rats responding under two procedures that have been used to assess antidepressant‐like effects (differential‐reinforcement‐of‐low‐rate [ DRL ] 72 s schedule of food reinforcement; n = 9) and abuse‐related drug effects (intracranial self‐stimulation [ ICSS ]; n = 6). Under the DRL 72 s schedule, phencyclidine (10.0 mg/kg) increased reinforcers and decreased responses without shifting the peak location of the interresponse time ( IRT ) distribution. Ketamine (10.0 mg/kg) also increased reinforcers and decreased responses, but unlike phencyclidine, it produced a rightward shift in the peak location of the IRT distribution. The 10.0 mg/kg phencyclidine dose that decreased DRL 72 s responding also decreased rates of ICSS for 50 min after its administration; however, abuse‐related ICSS facilitation was observed at later times (100–300 min) or after a lower phencyclidine dose (3.2 mg/kg). These results suggest that phencyclidine produces weaker antidepressant‐like effects, but stronger abuse‐related effects than ketamine in these procedures.

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  • Evidence that PCP, MK-801, and memantine produce antidepressant-like effects in rodents is mixed, and clinical studies are failing or lacking.

    “Given that the evidence of PCP, MK-801, and memantine exerting antidepressant-like effects in rodents is mixed, with clinical studies either failing or lacking”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Hillhouse & Porter, 2014

    The Introduction and Discussion (pages unavailable) describe mixed rodent findings: PCP showed a partial antidepressant-like effect in this study but no effect in an earlier forced-swim test; MK-801 lacked an antidepressant-like profile in the DRL procedure, while memantine showed antidepressant-like effects in forced-swim tests. The Introduction calls the clinical literature on PCP limited, and the Discussion says PCP is unlikely to be tested clinically. The paper does not establish that clinical studies of all three drugs failed or are lacking. (LLM, conf=0.85)

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  • NMDAR antagonism may not fully account for ketamine's antidepressant effects.

    “NMDAR antagonism may not fully explain the antidepressant effects of ketamine”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Hillhouse & Porter, 2014

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Authors
Hillhouse, T. M., Porter, J. H., & Negus, S. S.
Affiliations
  • University of Michigan (US)
  • Virginia Commonwealth University (US)
Corresponding author
Negus, S. Stevens
ORCID
Venue
Drug Development Research
Publisher
Wiley
Published
2014-10-15
Volume
75
Issue
8
Pages
479-488
ISSN
  • 0272-4391 (ISSN-L)
  • 1098-2299
DOI
10.1002/ddr.21228
PMC
PMC4276473
OpenAlex
W1936652454
Cited by
15
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2022: 3 · 2021: 2 · 2018: 2 · 2016: 2 · 2015: 2
FWCI
0.97
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Drug Development Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Deep Blue (University of Michigan) (submittedVersion)
Funders
National Institutes of Health (R01 NS070715)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
phencyclidine, ketamine, NMDA receptor antagonists, antidepressant-like effects, abuse liability, major depressive disorder, differential reinforcement of low rates, intracranial self-stimulation
MeSH terms
Animals, Antidepressive Agents, Conditioning, Operant, Dose-Response Relationship, Drug, Ketamine, Male, Phencyclidine, Reinforcement Schedule, Self Stimulation, Time Factors, Rats, Sprague-Dawley, Excitatory Amino Acid Antagonists, Rats

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