Akira Takashima

Protective effect of cerulein on memory impairment induced by protein synthesis inhibitors in rats

Previous studies have demonstrated that NMDA receptor antagonists and protein kinase C inhibitors induced marked memory impairment in rats, but that peripherally administered cerulein (CER) prevented these effects. In the present study, the effect of subcutaneously administered CER on amnesia induced by protein synthesis inhibitors was examined in passive and active avoidance responses and in the Morris water maze test. Intraperitoneal injection of the inhibitors produced marked memory impairment, but the effect was abolished by combined administration with CER. The effective dose of subcutaneously injected CER was, on a molar basis, three thousand- and six thousandfold less than the dose of anisomycin, and two hundred eighty- and three thousandfold less than the dose of puromycin in the passive and active avoidance response experiments, respectively. Similarly, in the Morris water maze test, behavioral disturbances produced by the protein synthesis inhibitors were abolished by CER. These results indicate the effectiveness of CER in preventing memory impairment induced by protein synthesis inhibitors.

Pretreatment with caerulein protects against memory impairment induced by protein kinase C inhibitors in the rat

The effect of subcutaneously injected caerulein (CER) on memory impairment induced by protein kinase C (PKC) inhibitors, H-7 and melittin, was examined in rats. Intracerebroventricular injection of PKC inhibitors caused marked memory impairment in one-trial passive avoidance response and Morris water tank tasks. However, when rats were pretreated with CER at a subcutaneous dose of 1 microgram/kg 3 hours before the training trials, the reduced latency of the passive avoidance response was significantly increased, and in the Morris water pool tasks the memory deficit induced by PKC inhibitors completely disappeared. These results indicate that CER can offer protection against the effect of PKC inhibitors at least from the viewpoint of the memory processes.

Memory effect of caerulein and its analogs in active and passive avoidance responses in the rat

The memory effects of caerulein (CER) and its analogs ([des-Gln2]-CER and [Leu5,Nle8]-CER) were compared with that of cholecystokinin octapeptide (CCK-8) using active and passive avoidance responses in rats. In the active avoidance test, single subcutaneous (SC) injection of CER and its analogs immediately after the learning trials at doses of 10 and 100 ng/kg prevented extinction of learned task for 10 days, and at a dose of 1000 ng/kg for at least 15 days, but the effect of CCK-8 was somewhat weaker. In the saline control group, the number of responses decreased after 5 days. In the passive avoidance response, electroconvulsive shock (ECS)-induced amnesia was partially prevented by CCK-8 at doses of 100 and 1000 ng/kg SC, while CER and its analogs at doses of more than 100 ng/kg totally prevented the ECS-induced amnesia. Intraperitoneal administration of scopolamine caused complete amnesia which was also partially prevented by CCK-8, while CER could totally prevent the amnesia following SC injection of 2 micrograms/kg. These results indicate that CER and its analogs are more effective than CCK-8 for preventing experimental amnesia.

Effect of caerulein on decreased latency of passive avoidance response in rats treated with NMDA receptor antagonists

The effect of subcutaneous injection of caerulein on memory impairment induced by intracerebroventricular administration of NMDA receptor antagonists was examined in the passive avoidance response of the rat. When rats were treated with AP5, AP7, CPP or MK-801, the retention latencies decreased markedly. However, in rats that received caerulein immediately after the training trials, the latency increased to some extent. Pretreatment with caerulein and subsequent injection of the competitive NMDA receptor antagonists AP5, AP7 and CPP caused a more apparent increase in the latency. The noncompetitive NMDA receptor antagonist MK-801 was not affected by pretreatment with caerulein. The difference might be, at least in part, due to the sites of action of these NMDA receptor antagonists.

Effect of vasoactive intestinal peptide on dopaminergic system in the rat brain

The present study analyzed the effect of vasoactive intestinal peptide (VIP) on the content of dopamine (DA) and its main metabolite, DOPAC, in the rat brain. Intracerebroventricular administration of VIP increased the DA and DOPAC content, causing a dose-dependent increase in the DOPAC/DA ratio in various regions of the brain. The results suggest that VIP facilitates the DA metabolism in the brain.

Vasoactive intestinal peptide (VIP) causes memory impairment in passive avoidance responding of the rat

Our previous studies demonstrated that CCK-8 and its analog, cerulein (CER), have a potent preventive action on experimental amnesia, and that VIP has reciprocal action against CCK-8 and CER. Since VIP has been reported to cause amnesia, we carried out the present experiments to confirm this action and to examine the preventive effect of CER on VIP-induced amnesia. In the passive avoidance response, central administration, but not peripheral injection, of VIP caused amnesia; the effective portion of the molecule was found to be located in the N-terminus amino acid sequence. Secretin and PACAP, which have similar molecular structures to that of VIP, had no amnestic action. Preadministration of CER prevented VIP-induced memory deficit. The VIP antagonists did not affect amnesia induced by electroconvulsive shock and scopolamine. It was concluded that CER prevents VIP-induced memory deficit in the passive avoidance response of the rat.

Influence of chronic intracerebroventricular infusion of vasoactive intestinal peptide (VIP) on memory processes in Morris water pool test in the rat

In our previous study, bolus injection of VIP into the lateral cerebral ventricle, at nonphysiological high doses, has been shown to produce amnesia. Accordingly, in the present study, VIP was infused chronically into the cerebral ventricle of the rat at a rate of 10 ng per day for 2 weeks. During the infusion period, the animals were subjected to the Morris water pool test. The VIP infusion caused an apparent impairment of memory, particularly in the acquisition of new information; VIP(1-12) also caused similar impairment, but to a lesser extent. The VIP antagonists did not affect the performance of learned tasks. However, cerulein treatment prevented the VIP-induced memory impairment.

Neuropharmacological profile of V-9-M, a putative neuropeptide derived from procholecystokinin.

(1) The present review suggests that V-9-M, a putative neuromodulator derived from pro-CCK, possesses apparent sedative actions and prevents experimental amnesia in both passive and active avoidance paradigms in rats. (2) These properties are similar to CCK-8, but some differences were noticed; (i) CCK-8 is a potent appetite inhibitor, while V-9-M does not affect food intake in fasted rats, and (ii) small doses of apomorphine cause hypomotility which is abolished by CCK-8, while V-9-M decreases the motility further. (3) More important is the fact that peripheral administration of CCK-8 produces central actions, but that of V-9-M is ineffective. (4) Although CCK-8 and V-9-M are derived from the same pro-CCK, their chemical structures are quite different, and the receptors for these two peptides are not the same. (5) CCK-8 has both central and peripheral receptors, but the presence of a peripheral receptor for V-9-M is questionable. (6) The different properties may be partially explained by this. (7) However, immunochemical studies indicated the coexistence of CCK and GABA in the cortical neurons. (8) This suggests that V-9-M may be present in the GABA neurons together with other CCK fragments. (9) There might be close interaction between V-9-M and the GABAergic system.