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Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia.
- Source :
- International Journal of Neuropsychopharmacology; May2013, Vol. 16 Issue 4, p889-904, 16p
- Publication Year :
- 2013
-
Abstract
- Cognitive deficits associated with schizophrenia (CDS) are implicated as a core symptom cluster of the disease and are associated with poor daily life functioning. Unfortunately, current antipsychotic agents provide little alleviation of CDS, representing a critical unmet therapeutic need. Here we investigated the effects of ABT-239 and A-431404, non-imidazole histamine H<subscript>3</subscript> receptor (H<subscript>3</subscript>R) antagonists, in animal models with relevance to CDS. As N-methyl-D-aspartate receptor hypofunction is considered an important factor in the pathogenesis of schizophrenia, acute administration of ketamine or MK-801 was used to induce cognitive impairments. The assays employed in the current studies were spontaneous alternation in cross-maze, used as an indication of working memory, and inhibitory avoidance (IA), used to assess long-term memory retention. Risperidone and olanzapine were also tested to directly compare the effects of H<subscript>3</subscript>R antagonists to two widely used antipsychotics. ABT-239 and A-431404, but not risperidone and olanzapine, attenuated ketamine-induced deficits on spontaneous alternation in cross-maze, while none of these compounds affected alternation performance on their own. ABT-239 and A-431404 also attenuated MK-801-induced impairments in IA; no effects were observed when given alone. Risperidone and olanzapine, however, failed to attenuate MK-801-induced deficits in IA and produced dose-dependent impairments when given alone. ABT-239 was also investigated in methylazoxymethanol acetate (MAM) treated rats, a neurodevelopmental model for schizophrenia. Chronic, but not acute, treatment with ABT-239 significantly improved spontaneous alternation impairments in MAM rats tested in cross-maze. In summary, these results suggest H3R antagonists may have the potential to ameliorate CDS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14611457
- Volume :
- 16
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- International Journal of Neuropsychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 87344609
- Full Text :
- https://doi.org/10.1017/S1461145712000739