Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists

Abstract

Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.

Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo

“…In spite of the great interest raised by H 3 R inverse agonists and the high density of H 3 Rs in limbic areas (Arrang 2007), we found no evidence for antipsychotic-like properties of H 3 R inverse agonists administered acutely to rodents and they did not amplify the effect of haloperidol at therapeutic doses (Burban et al 2010). However, further studies are needed to evaluate their effects in the long-term treatment of psychiatric disorders, inasmuch as repeated administration of a H 3 R inverse agonist decreases methamphetamine-induced behavioral sensitization in mice (Motawaj and Arrang 2011).…”

The other side of the histamine H3 receptor

“…Although it is not entirely clear whether a disruption of pre-pulse inhibition (PPI) is really a model for psychosis, at least in rats and mice, the dopamine agonist-induced disruption of PPI is highly sensitive to D2R antagonists [54]. Most studies thus far have failed to find an effect of H3R antagonists on dopamine agonist-(or glutamate antagonist-) induced disruption of PPI [55,56]. Indeed, there have only been two notable exceptions: the H3R antagonist GSK207040 was able to reverse the isolation rearing-induced deficit in rats [52], and thioperamide was able to increase the naturally low PPI in DBA1 mice (though not the very low PPI in BS2 and CF-1 mice) [57].…”

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

“…Effects in preclinical models of PPI suggest that compounds of various classes, including H 3 R antagonists may have utility in the treatment of schizophrenia (Browman et al, 2004;Fox et al, 2005;Flood et al, 2011). However, whereas the DBA/2 mouse PPI model is sensitive to H 3 R antagonists, other preclinical models relevant to schizophrenia do not robustly respond to H 3 R antagonists (Burban et al, 2010;Flood et al, 2011). Although CEP-26401 effectively increased the PPI response in DBA/2 mice, fully efficacious doses (Fig.…”