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Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040

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Abstract

Objectives

To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential.

Materials and methods

Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations.

Results

GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg.

Conclusions

The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H3 receptor antagonism versus positive symptoms is less likely, at least following acute administration.

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Acknowledgements

All the authors are employees of GlaxoSmithKline. The experiments described were conducted in GlaxoSmithKline laboratories according to United Kingdom laws and regulations.

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  1. GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex, CM195AW, UK

    Eric Southam, Jackie Cilia, Jane E. Gartlon, Marie L. Woolley, Laurent P. Lacroix, Carol A. Jennings, Jane E. Cluderay, Charlie Reavill, Claire Rourke, David M. Wilson, Lee A. Dawson, Andrew D. Medhurst & Declan N. C. Jones

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  1. Eric Southam
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  2. Jackie Cilia
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  3. Jane E. Gartlon
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  4. Marie L. Woolley
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  5. Laurent P. Lacroix
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  6. Carol A. Jennings
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  13. Declan N. C. Jones
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Correspondence to Eric Southam.

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Southam, E., Cilia, J., Gartlon, J.E. et al. Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040. Psychopharmacology 201, 483–494 (2009). https://doi.org/10.1007/s00213-008-1310-9

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