Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Robert W. Gould, Russell J. Amato, Michael Bubser, Max E. Joffe, Michael T. Nedelcovych, Analisa D. Thompson, Hilary H. Nickols, Johannes P. Yuh, Xiaoyan Zhan, Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Frank W. Byers, Jerri M. Rook, John S. Daniels, Colleen M. Niswender, P. Jeffrey Conn, Kyle A. Emmitte, Craig W. Lindsley, Carrie K. Jones

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-Administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-To-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.

Original languageEnglish
Pages (from-to)1166-1178
Number of pages13
JournalNeuropsychopharmacology
Volume41
Issue number4
DOIs
StatePublished - 1 Mar 2016

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Metabotropic Glutamate 5 Receptor
Cocaine
Cocaine-Related Disorders
Therapeutics
Self Administration
Anti-Anxiety Agents
Therapeutic Uses
Psychotic Disorders
Antidepressive Agents
Substance-Related Disorders
Comorbidity
Anxiety
Public Health
Clinical Trials
Depression

Cite this

Gould, R. W., Amato, R. J., Bubser, M., Joffe, M. E., Nedelcovych, M. T., Thompson, A. D., ... Jones, C. K. (2016). Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects. Neuropsychopharmacology, 41(4), 1166-1178. https://doi.org/10.1038/npp.2015.265
Gould, Robert W. ; Amato, Russell J. ; Bubser, Michael ; Joffe, Max E. ; Nedelcovych, Michael T. ; Thompson, Analisa D. ; Nickols, Hilary H. ; Yuh, Johannes P. ; Zhan, Xiaoyan ; Felts, Andrew S. ; Rodriguez, Alice L. ; Morrison, Ryan D. ; Byers, Frank W. ; Rook, Jerri M. ; Daniels, John S. ; Niswender, Colleen M. ; Conn, P. Jeffrey ; Emmitte, Kyle A. ; Lindsley, Craig W. ; Jones, Carrie K. / Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects. In: Neuropsychopharmacology. 2016 ; Vol. 41, No. 4. pp. 1166-1178.
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abstract = "Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-Administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-To-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.",
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Gould, RW, Amato, RJ, Bubser, M, Joffe, ME, Nedelcovych, MT, Thompson, AD, Nickols, HH, Yuh, JP, Zhan, X, Felts, AS, Rodriguez, AL, Morrison, RD, Byers, FW, Rook, JM, Daniels, JS, Niswender, CM, Conn, PJ, Emmitte, KA, Lindsley, CW & Jones, CK 2016, 'Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects', Neuropsychopharmacology, vol. 41, no. 4, pp. 1166-1178. https://doi.org/10.1038/npp.2015.265

Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects. / Gould, Robert W.; Amato, Russell J.; Bubser, Michael; Joffe, Max E.; Nedelcovych, Michael T.; Thompson, Analisa D.; Nickols, Hilary H.; Yuh, Johannes P.; Zhan, Xiaoyan; Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D.; Byers, Frank W.; Rook, Jerri M.; Daniels, John S.; Niswender, Colleen M.; Conn, P. Jeffrey; Emmitte, Kyle A.; Lindsley, Craig W.; Jones, Carrie K.

In: Neuropsychopharmacology, Vol. 41, No. 4, 01.03.2016, p. 1166-1178.

Research output: Contribution to journalArticle

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AU - Joffe, Max E.

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AU - Morrison, Ryan D.

AU - Byers, Frank W.

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AU - Daniels, John S.

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