Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia.
Int J Neuropsychopharmacol
; 16(4): 889-904, 2013 May.
Article
in En
| MEDLINE
| ID: mdl-22906530
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(3) receptor (H(3)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(3)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 H(3)R antagonists may have the potential to ameliorate CDS.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Schizophrenia
/
Schizophrenic Psychology
/
Antipsychotic Agents
/
Cognition Disorders
/
Histamine H3 Antagonists
/
Imidazoles
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Int J Neuropsychopharmacol
Journal subject:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Year:
2013
Document type:
Article
Affiliation country:
Estados Unidos