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JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats

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Abstract

Rationale

A few recent studies suggest that brain histamine levels and signaling via H3 receptors play an important role in modulation of alcohol stimulation and reward in rodents.

Objective

The present study characterized the effects of a novel, selective, and brain penetrant H3 receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.

Methods

The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.

Results

Subcutaneous administration of the selective H3 receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.

Conclusions

These results indicate that blockade of H3 receptor should be considered as a new attractive mechanism for the treatment of alcoholism.

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Acknowledgements

The assistance of Dr. Kevin Sharp and his staff at Johnson & Johnson Pharmaceutical Research & Development L.L.C. (San Diego, CA) is gratefully acknowledged.

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Authors and Affiliations

  1. Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA

    Leah Aluisio, Brian Lord, Ian Fraser, Jamin Boggs, Natalie Welty, James R. Shoblock, S. Timothy Motley, Michael A. Letavic, Nicholas I. Carruthers, Christine Dugovic, Timothy W. Lovenberg & Pascal Bonaventure

  2. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA

    Amir H. Rezvani & Edward D. Levin

  3. Bristol Myers-Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA

    Ruggero Galici

Authors
  1. Ruggero Galici
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  2. Amir H. Rezvani
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  3. Leah Aluisio
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  4. Brian Lord
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  5. Edward D. Levin
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  6. Ian Fraser
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  7. Jamin Boggs
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  8. Natalie Welty
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  9. James R. Shoblock
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  10. S. Timothy Motley
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  11. Michael A. Letavic
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  12. Nicholas I. Carruthers
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  13. Christine Dugovic
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  14. Timothy W. Lovenberg
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  15. Pascal Bonaventure
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Corresponding author

Correspondence to Pascal Bonaventure.

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Galici, R., Rezvani, A.H., Aluisio, L. et al. JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats. Psychopharmacology 214, 829–841 (2011). https://doi.org/10.1007/s00213-010-2092-4

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  • DOI: https://doi.org/10.1007/s00213-010-2092-4

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