Hiroshi Kaneto

State dependent and/or direct memory retrieval by morphine in mice.

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.

Similar ameliorating effects of benzomorphans and 5-HT2 antagonists on drug-induced impairment of passive avoidance response in mice: comparison with acetylcholinesterase inhibitors

Mice were trained to avoid electric shocks by means of step-down type passive avoidance learning tasks, and memory retention was measured 24 h after the training session. Memory impairment (amnesia) was produced by administering eitherp-chloroamphetamine (PCA), a serotonin (5-HT) releaser or scopolamine (SCOP), a muscarinic cholinoceptor antagonist, 30 min prior to the training session. Benzomorphans, 5-HT2 antagonists and acetylcholinesterase (AChE) inhibitors were administered immediately after the training session. PCA- but not SCOP-induced amnesia was attenuated by the post-training administration of two benzomorphans, (+)N-allylnormetazocine ((+)SKF-10,047) and (±)pentazocine ((±)PTZ). Similarly, PCA-induced amnesia was reversed by the post-training administration of 5-HT2 antagonists, ritanserin (RIT) and mianserin (MIA), but SCOP-induced amnesia was not. However, the AChE inhibitors, tetrahydroaminoacridine (THA) and physostigmine (PHY) attenuated both PCA- and SCOP-induced amnesia when administered immediately after the training session. These results indicated that benzomorphans and 5-HT2 antagonists have antiamnestic effects in mice, as do AChE inhibitors. In addition, it is interesting that the patterns of ameliorating effect of benzomorphans were similar to those of 5-HT2 antagonists, which differ from those of AChE inhibitors.

Learning/memory processes under stress conditions

Using mice, changes in the learning/memory processes under various stress conditions were investigated in one-trial step-through type passive avoidance learning task. Pre-, post-training and pre-test foot shock (FS)-stress induced long-lasting, at least 96 h, facilitation of test trial latencies. Pre-training psychological (PSY)-stress induces facilitation and pre-test swimming (SW)-stress provokes impairment of test trial latencies. These effects of FS-, PSY- and SW-stress are all dependent on the timing of their exposure and due to their acute effect. Intraperitoneal administration of 1 mg/kg scopolamine 30 min pre-training caused impairment of test latencies in naive and pre-test FS-stressed animals but failed to affect both pre- and post-training FS-induced enhancement. Taken all these data together, it seems that cholinergic mechanism is partly involved in the FS-stress induced facilitation of test latencies, though the research on the changes in ACh levels at the action site in brain after FS-stress exposure is necessary for a definite conclusion.

Facilitation of memory retrieval by pretest morphine mediated by μ but not δ and κ opioid receptors

Mice were trained to avoid electric shock (0.6 mA) in a step-through type passive avoidance learning task, retention being measured 24 h after the training trial. Morphine 10 mg/kg administered 30 min before the test trial (pretest) facilitated memory retrieval, and the effect was completely antagonized by 1 mg/kg naloxone, a selective μ-opioid receptor antagonist. On the other hand, pretest administration of 0.01–10 mg/kg DTLET, a selective δ-opioid receptor agonist, did not produce the same effect as morphine. Nor-binaltorphimine, a κ-opioid receptor antagonist, did not antagonize the effect of pretest morphine, at doses of 1 and 2 mg/kg. These results suggest that the facilitation of memory retrieval by pretest morphine is mediated through μ- but not δ- or κ-opioid receptors.

Inorganic Ions: The Role of Calcium

The significant role of inorganic ions, above all, cations, in the various biological phenomena, especially in nervous activities, has been studied intensively, and it is well understood that the metabolism of the cells is regulated through the fluxes of ions at the cell membranes.

Action site of adrenergic blockers to suppress the development of tolerance to morphine analgesia

The effect of locally applied adrenergic blockers in the restricted area of the central nervous system on morphine analgesia and the development of tolerance to the analgesic effect was examined in the mouse. Intrathecal (i.t.) injection of phentolamine decreased the analgesic effect of morphine administered either subcutaneous (s.c.), intracerebroventricular (i.c.v.) or i.t., while i.t. propranolol was less potent in suppressing morphine analgesia and, in particular, did not affect the analgesic effect of i.t. morphine. I.c.v. phentolamine enhanced i.t. injected morphine analgesia; on the other hand, i.c.v. propranolol tended to reduce the analgesic effect of s.c. morphine. Compared with the effect on the analgesia, i.t. administration of both phentolamine and propranolol did not affect the development of tolerance to morphine and i.p. or i.c.v. blockers suppressed the development of tolerance to s.c. or i.t. morphine analgesia. Moreover, morphine tolerance induced by i.c.v. administration was blocked by i.c.v. phentolamine. These results not only provide further evidence for the importance of the spinal and supraspinal adrenergic systems in the analgesic effects of morphine and the development of tolerance to the effect, respectively, and also suggest the difference in both the site and mechanisms involved in the production of morphine analgesia and the development of tolerance to morphine.

The effect of ginseng extract on locomotor sensitization and conditioned place preference induced by methamphetamine and cocaine in mice

Repeated i.p. injections of 2 mg/kg methamphetamine (MA) or 20 mg/kg cocaine at 48-h intervals induced reverse tolerance to their ambulation-enhancing effects (behavioral sensitization). Furthermore, the reappearance of the sensitized state was observed at the time of readministration of MA or cocaine even after a 30-day discontinuation of drug administration. A concomitant injection of ginseng extract (GE), 200 mg/kg, i.p., suppressed the development of reverse tolerance and the reappearance of sensitization to MA and cocaine. Conditioned place preference to MA (1, 2, and 4 mg/kg, i.p.) and cocaine (1, 4, 10, and 20 mg/kg, i.p.), was completely blocked by GE, 200 mg/kg, i.p. combined treatment with MA of cocaine. Meanwhile, spontaneous motor activity and place preference were not affected by GE alone. These results provide evidence that GE may be useful clinically for the prevention of adverse actions of MA and cocaine.

Evidence for the dissociation of morphine analgesia, tolerance and dependence

A single large dose of morphine produced profound analgesia accompanied by the development of tolerance and physical dependence. The tolerance developed acutely within 24 h and was further intensified, reaching a peak on the 5th day, then gradually disappeared. Partial or complete masking of morphine analgesia by naloxone inhibited the development of the acute, but could not prevent the development of the delayed, tolerance. These results suggest there are two kinds of tolerance and that the analgesic effect is separate from tolerance. Similarly, treatment with morphine produced physical dependence which was precipitated by naloxone, Unlike tolerance, dependence did not develop when morphine analgesia was completely masked by naloxone. The findings provide for the dissociation or morphine analgesia, tolerance and dependence.

FS stress induces long-lasting memory facilitation: Involvement of cholinergic pathways

We tested in vivo the hypothesis that foot-shock (FS) stress-induced prolongation of latencies in the one-trial step-through passive avoidance learning task in mice occurred through a long-term facilitation process. Whereas behavioral responses in control mice lasted for 24 h, decreasing progressively in the subsequent days, FS-stress exposure for 15 min before training (pretraining), immediately after training (posttraining), or 15 min before the test (pretest) resulted in a profound and sustained enhancement of test latencies that lasted for at least 96 h. These facilitating effects disappeared when FS exposure was delivered with a 2- or 3-h difference with respect to the training trial. Scopolamine (Scop) (1 mg/kg, intraperitoneally) 30 min before the training session caused impairment of test latencies in control and pretest stressed animals, but failed to affect both pre- and posttraining FS stress-induced enhancement. Our working hypothesis is that FS stress may increase the levels of acetylcholine in the presynaptic terminal or the firing rate of cholinergic input. Animals pretreated with FS stress daily for 1 or 4 days followed by the acute schedule described above showed no enhancements of test latencies. Pretraining Scop impaired test latencies in pre- and posttraining and pretest stressed animals, suggesting that unpredictability is a critical factor in activating behavioral long-term facilitation.

Dependency on the brain function of arginine vasopressin system of the development to and recovery from analgesic tolerance to morphine

Concomitant intracerebroventricular (i.c.v.) injection of anti-arginine vasopressin (AVP) antiserum dose-dependently suppressed the development of analgesic tolerance to daily morphine, 10 mg/kg, s.c., in mice. This suppressive effect of the antiserum was reduced by incubating the antiserum with AVP in vitro, before i.c.v. injection, suggesting that the antiserum inactivates brain AVP to result in the suppression of the development of tolerance in vivo. Similar to the antiserum, both AVP V1 and V2 antagonists given i.c.v., 10 ng and 20 ng/mouse, respectively, suppressed the development of morphine tolerance. Meanwhile, the administration of antiserum dose-dependently recovered morphine analgesia in morphine-tolerant mice and a complete recovery of analgesia was observed at the highest dose of antiserum following the second injection, and the effect of antiserum was maintained for 3 days after its withdrawal. Likewise, 10-100 ng/mouse of AVP V1 receptor antagonist given i.c.v. recovered morphine analgesia partially but significantly in a dose-dependent manner; however, AVP V2 receptor antagonist at the same doses partially recovered analgesic effect but the effect was neither significant nor dose-dependent. These findings suggest that the tolerance developed to morphine can be reversible when disturbing the function of brain AVP, but in addition to the different mechanisms of antiserum, V1 and V2 receptor antagonists, the V1 receptor-mediated mechanism may be more closely concerned in this phenomenon.