Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine

Abstract

Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this H(1) antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine.

Figure 1

The interaction of pyrilamine and prepulse intensity was not significant nor was the main effect of pyrilamine, when PPI% was analyzed for the pyrilamine data. Increasing prepulse intensity significantly increased %PPI.

Figure 2

Dizocilpine significantly decreased %PPI compared to saline alone (denoted by the bar). There was also a significant dizocilpine × pyrilamine interaction for %PPI. Pyrilamine at 10 mg/kg and 20 mg/kg significantly attenuated the dizocilpine-induced PPI impairment, while the 40 mg/kg dose of pyrilamine did not quite reach significance. Data are presented collapsed across prepulse intensity because the three-way interaction of dizocilpine, pyrilamine and prepulse intensity was not significant. ** denotes a difference from dizocilpine alone at p<0.001, + denotes a difference from dizocilpine alone at p<0.1.

Figure 3

There was a significant interaction of error type and pyrilamine. Pyrilamine tended to increase working memory (WM) errors, while it dose-dependently decreased reference memory (RM) errors, * denotes a difference from saline controls at p<0.05, + denotes a difference from saline controls at p<0.1.