Inhibits the Induction of Long-Term Potentiation in the Dentate Gyrus of Rats In Vivo

Ming Chang, Hiroshi Saito and Kazuho Abe*

Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan

Received March 21, 1997 Accepted April 28, 1997

ABSTRACT-We investigated the effect of cimetidine, a clinically used H2-, on the induction of long-term potentiation (LTP) in the dentate gyrus of anesthetized rats. Intracerebroventricular injection of cimetidine (50-100 nmol) inhibited the induction of LTP in a dose-dependent manner. The inhibitory effect of cimetidine was not mimicked by other H2-receptor antagonists (, ) or the H1-receptor antagonist or the H3-receptor antagonist thioperamide. These results suggest that cimetidine inhibits hippocampal synaptic plasticity by a novel brain mechanism unrelated to H1, H2 or H3 receptors.

Keywords: Cimetidine, Long-term potentiation, Hippocampus

Histamine plays many important roles as a neurotrans stereotaxicaiiy piacea in the iert entorninai cortex to mitter or neuromodulator in the central nervous system. stimulate the medial perforant path, and the evoked For example, is involved in circadian rhythms, potential was extracellularly recorded from the granule sleep-wake cycle and various motivated behaviors (1). cell layer of the ipsilateral, dorsal dentate gyrus. A single There is also evidence that the system is test stimulus (0.08-msec duration) was applied at intervals involved in learning and memory (2, 3). of 30 sec, and the stimulus intensity was set at a level There are three classes of histamine receptors, i.e., H1, that evoked a population spike of 50% the maximum. H2 and H3 receptors (4). It has been reported that H1 The evoked population spike amplitude was measured receptors are involved in the memory facilitation by as shown in Fig. IA. After stable baseline values were histamine (5), but the role of H2 receptors in learning obtained at least for 15 min, the vehicle saline or the drug and memory are not well-understood. Long-term potenti solution was injected in a volume of 5 ;al into the con ation (LTP) of synaptic transmission in the hippocam tralateral ventricle using a microsyringe with injection pus is a form of activity-dependent synaptic plasticity time for 2.5 min. Tetanic stimulation (30 pulses at 60 Hz) and is believed to be the cellular basis of learning and was applied at the same intensity through the same elec memory (6). To examine whether H2 receptors are trodes as used for test stimulation. The effects of drugs involved in learning and memory, we investigated the were assessed on the time course curves of potentiation of effects of H2-receptor antagonists on LTP in the dentate population spike after tetanic stimulation. In order to gyrus of anesthetized rats in vivo. Here we report that compare and summarize several data sets of time course cimetidine, a clinically used H2-receptor antagonist, in curves of potentiation, we calculated the area under the hibited the induction of hippocampal LTP. curve (AUC) from 5 to 60 min after tetanic stimulation as Recording of evoked potential was made as described shown in Fig. 113. All data are represented as the in our previous paper (7). Briefly, male Wistar rats (7 to means±S.E.M. 9-weeks old) were anesthetized with a combination of First we investigated the influence of cimetidine on the urethane (1 g/kg, i.p.) and a-chloralose (25 mg/kg, i.p.) basal evoked potential. As shown in Fig. IA, the synaptic and then fixed in a stereotaxic frame. In this anesthetic potential evoked by low-frequency test stimulation was condition, we could record stable field potentials for observed up to 85 min after intracerebroventricular more than 2 hr. A bipolar stimulating electrode was (i.c.v.) injection of cimetidine (100 nmol), but there was no significant change in the basal synaptic responses. * To whom correspondence should be addressed . Next the effect of cimetidine on the induction of LTP was investigated. In the saline-injected group, the evoked lation, and LTP was generated in all cases tested (Fig. potential was greatly potentiated following tetanic stimu 1B). I.c.v. injection of 100 nmol cimetidine 25 min prior to tetanic stimulation significantly inhibited the induction of LTP (Fig. 1B). The inhibitory effect of cimetidine on LTP induction was dose-dependent (Fig. 2A). We also investigated the effect of cimetidine on the maintenance phase of LTP. LTP was induced by tetanic stimulation, and then cimetidine (100 nmol) was i.c.v. injected 20 min after tetanic stimulation. As shown in Fig. 1C, cimetidine had no effect on the pre-established LTP, indicating that the inhibitory effect of cimetidine is specific for the LTP induction mechanism. To examine if the inhibitory effect of cimetidine on LTP is due to the blockade of H2 receptors, the effects of other antagonists were investigated. Test agents were the furane-derived H2-receptor antago nist ranitidine, guanididothiazol-derived H2-receptor an tagonist famotidine, H1-receptor antagonist diphen

Fig. 1. Effects of cimetidine on basal synaptic transmission and LTP in the dentate gyrus of anesthetized rats. A: Changes in basal responses after i.c.v. injection of 100 nmol cimetidine without ap plication of tetanus (n = 5). The inset shows a typical evoked poten tial recorded in the dentate gyrus granule cell layer. The amplitude of the population spike was defined as (a+b)/2. For comparison with the data in B and C, 25 min after drug injection was defined as 0 min and the population spike amplitude was expressed as a per centage of the value at 0 min. B: The tetanus-induced potentiation of the population spike in the dentate gyrus of rats injected i.c.v. with saline (0, n = 8) or 100 nmol cimetidine (0, n = 6). Saline or cimetidine was injected 25 min before tetanus (30 pulses at 60 Hz). Population spike amplitude was expressed as a percentage of the Fig. 2. Comparison of effects of cimetidine (A), famotidine (A), baseline value immediately before tetanus (0 min). *P<0.05, ranitidine (A), diphenhydramine (B) and thioperamide (B) on LTP **P<0 .01 vs control group (0); Student's t-test. The shaded por induced by tetanus. AUC from 5 to 60 min after tetanus was calcu tion in B corresponds to the AUC from 5 to 60 min after tetanus. lated as shown in Fig. 1B and employed as an index of the magnitude C: Effect of cimetidine on the maintenance phase of LTP (n=5). of LTP. The numbers of observations are indicated in parentheses. LTP was induced by application of tetanus (time 0), and 100 nmol *P<0 .05, **P<0.01 vs saline-injected group (CON); Duncan's cimetidine was i.c.v. injected 20 min after tetanus. multiple range test. hydramine and H3-receptor antagonist thioperamide. histamine, but not 48/80, causes posttraining memory facilita However, none of them had a significant effect on the tion in the rats. 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