Effects of the H3 antagonist, thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats

Abstract

Rationale-Recent studies have raised the possibility that antagonists of H 3 histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia.Objectives-The purpose of this study was to determine if a prototypical H 3 antagonist, thioperamide, could alter behavioral deficits caused by the NMDA receptor antagonist, MK-801, in adult male rats. MK-801 was chosen for study since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia.Methods-The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 & 10 mg/kg) followed 20 minutes later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, & 0.30 mg/kg).Results-Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity, however its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment.Conclusions-H 3 receptors modulate responses to NMDA antagonists in behaviorally-specific ways and dependent upon the level of NMDA receptor blockade.

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

“…Also, another H 3 antagonist ciproxifan reduced hyperactivity induced in mice by 0.3 mg/kg dose of MK-801 (Faucard et al 2006). On the other hand, thioperamide can potentiate cocaine-induced hyperactivity in mice (Brabant et al 2009), while in Long-Evans rats it can either potentiate or attenuate MK-801-induced hyperactivity depending on the dose of the latter (Bardgett et al 2009). In the present study, the initial attenuating effect of thioperamide on MK-801-induced hyperactivity was followed by a potentiating effect.…”

Differential effects of histamine H3 receptor inverse agonist thioperamide, given alone or in combination with the N-methyl-d-aspartate receptor antagonist dizocilpine, on reconsolidation and consolidation of a contextual fear memory in mice

“…If such an interaction has not been reported previ- ously for reconsolidation, it has also been demonstrated for other memory phases like acquisition, retrieval and working memory in a variety of tasks (Chen et al, 1999;Orsetti et al, 2001;Huang et al, 2003Huang et al, , 2004Nishiga and Kamei, 2003;Bardgett et al, 2009Bardgett et al, , 2010.…”

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].…”