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Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats

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Abstract

Background

Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance.

Methods

We examined the effects of two drugs that cause disruptions in perception and cognition in humans—the kappa-opioid receptor (KOR) agonist salvinorin A (salvA; 0.125–4.0 mg/kg) and the non-competitive NMDA receptor antagonist ketamine (0.63–20 mg/kg)—on behavior in rats using the 5-choice serial reaction time task (5CSRTT), a food-motivated test that quantifies attention. We also compared the binding profiles of salvA and ketamine at KORs and NMDA receptors.

Results

SalvA and ketamine produced the same pattern of disruptive effects in the 5CSRTT, characterized by increases in signs often associated with reduced motivation (omission errors) and deficits in processing (elevated latencies to respond correctly). Sessions in which rats were fed before testing suggest that reduced motivation produces a subtly different pattern of behavior. Pretreatment with the KOR antagonist JDTic (10 mg/kg) blocked all salvA effects and some ketamine effects. Binding and function studies revealed that ketamine is a full agonist at KORs, although not as potent or selective as salvA.

Conclusions

SalvA and ketamine have previously under-appreciated similarities in their behavioral effects and pharmacological profiles. By implication, KORs might be involved in some of the cognitive abnormalities observed in psychiatric disorders such as schizophrenia.

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Acknowledgment

This study is supported by the National Institute of Mental Health (MH063266 to WAC, and RO1DA017204 to BLR).

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Authors and Affiliations

  1. Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA

    Christina L. Nemeth, Tracie A. Paine, Cécile Béguin, Bruce M. Cohen & William A. Carlezon Jr.

  2. Department of Pharmacology and NIMH Psychoactive Drug Screening Program, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA

    Joseph E. Rittiner & Bryan L. Roth

  3. Research Triangle Institute, Organic and Medicinal Chemistry, Research Triangle Park, NC, 27709, USA

    F. Ivy Carroll

  4. Department of Psychiatry, McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA, 02478, USA

    William A. Carlezon Jr.

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  1. Christina L. Nemeth
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  2. Tracie A. Paine
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  3. Joseph E. Rittiner
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  4. Cécile Béguin
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  6. Bryan L. Roth
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  7. Bruce M. Cohen
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  8. William A. Carlezon Jr.
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Correspondence to William A. Carlezon Jr..

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Authors Nemeth and Paine denote equal authorship.

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Nemeth, C.L., Paine, T.A., Rittiner, J.E. et al. Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology 210, 263–274 (2010). https://doi.org/10.1007/s00213-010-1834-7

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  • DOI: https://doi.org/10.1007/s00213-010-1834-7

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