Antagonists of H(3)-type
histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of
antipsychotic activity in normal animals. The present study determined if a prototypical H(3) antagonist,
ciproxifan, could reverse the behavioral effects of
MK-801, a
drug used in animals to mimic the hypoglutamatergic state suspected to exist in
schizophrenia. Four behaviors were chosen for study, locomotor activity,
ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by
dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a
subcutaneous injection of
ciproxifan or vehicle followed 20 min later by a
subcutaneous injection of
MK-801 or vehicle. Three doses of
MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of
ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of
MK-801, but suppressed the effect of the high dose.
Ciproxifan (3.0 mg/kg) enhanced the effects of
MK-801 (0.1 & 0.3 mg/kg) on fine movements and
ataxia. Deficits in PPI were observed
after treatment with
MK-801 (0.05 & 0.1 mg/kg), but
ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by
MK-801 (0.1 mg/kg) at a longer delay, and
ciproxifan (3.0 mg/kg) alleviated this impairment. These results indicate that some H(3) antagonists can alleviate the impact of
NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors.