Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia.
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.
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. jordan.brown@abbott.com
Jordan W
JW
Brown
Caroline A
CA
Whitehead
Ana M
AM
Basso
Lynne E
LE
Rueter
Min
M
Zhang
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000523:psychology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054828:Histamine H3 Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles; D008297:Male; D020318:Rats, Long-Evans; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D054828:Histamine H3 Antagonists; D007093:Imidazoles; C029899:imidazole