Proteome analysis of rat hippocampus following morphine-induced amnesia and state-dependent learning

Morphine's effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry [MS and MS/MS]. Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT [Modular Approach to Software Construction Operation and Test] scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomic screen suggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity

time profile of morphine effect on different phases of inhibitory avoidance memory in rat

The amnesic effect of morphine is well known in the laboratory animals. But, it is unclear that morphine at what times can exactly affect different phases of memory, including acquisition, consolidation, and retrieval. Therefore, we investigated the time profile of morphine's amnesic effect on passive [inhibitory] avoidance learning and memory in male Wistar rats. In order to evaluate the outcomes of pre- and post-training administrations of morphine, the animals were trained in a step-through type of passive avoidance task at various time points, and were tested 24 h after training to measure memory retrieval. The results showed that acquisition of memory was impaired in the animals that received a dose of 7.5 mg/kg of morphine [Intraperitoneally] at 0, 30 min, and 1 h before training, as evidenced by a decrease in step-through latency on the test day. Post-training administrations of morphine at 30 min and 1h, 4h except for the time immediately after training, did not impair memory consolidation. The results also showed that pre-test administrations of morphine at 0 and 30 min before the test, impaired retrieval of inhibitory avoidance memory. Taken together, the results suggest that morphine, when injected at different time points before training, after training, or before testing affects different phases of inhibitory avoidance memory. With regard to the time of injections related to each phase, other experiments can be designed to investigate molecular mechanisms involved in the impairing effect of morphine in each phase

Repeated pretreatment of morphine prevents morphine-induced amnesia: a possible involvement for dorsal hippocampal NMDA receptors

Background: learning and memory processes can be affected by morphine administration. It has been previously demonstrated that the effects of morphine depend on the timing of drug administration. In the present study, the effects of microinjections of a NMDA receptor agonist and antagonist into the CA1 regions of the dorsal hippocampi [intra CA1] on repeated pretreatment of morphine-induced prevention of morphine-induced amnesia have been investigated

Methods: step-through inhibitory avoidance task of memory has been used to examine retrieval of memory formation, 24 h after training in male Wistar rats

Results: the results indicate that post-training administration of morphine [7.5 mg/kg] impaired memory retrieval, but not in the animals, which received previous repeated morphine [7.5 and 10 mg/kg] injections followed by morphine withdrawal. Repeated co-administration of NMDA [7.5 and 10 ng/rat, intra-CA1] with an ineffective dose of morphine [5 mg/kg], once daily for three days reversed morphine-induced amnesia. Repeated bilateral intra-CA1 microinjections of NMDA, once daily for three days followed by a five-day washout had no effect on the expression of amnesia produced by post-training morphine. Three-day administration of the NMDA receptor antagonist, D-AP5 [0.5 - 2 micro g/rat, intra-CA1] followed by a five-day washout had no effect on morphine-induced amnesia. On the other hand, intra-CA1 microinjections of the same doses of D-AP5 prior to injection of 7.5 mg/kg of morphine [per day×3 days] decreased the reversal of morphine-induced amnesia

Conclusion: these data imply that the dorsal hippocampal NMDA receptor mechanism[s] may modulate the effect-induced by repeated morphine administration on a challenge dose of morphine-induced amnesia

effects of histaminergic agents in the nucleus accumbens of rats in the elevated plus-maze test of anxiety

The nucleus accumbens [NAc] receives histaminergic neurons from tuberomammillary nuclei. There are also reports indicating that central histamine systems are involved in many physiological behavioral processes, including anxiety. The aim of the present study was to assess whether the histaminergic system of the NAc is involved in the anxiety-related behaviors. As a model of anxiety the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used in male Wistar rats. Intra-NAc administration of histamine [0.01, 0.1 and 1 microg/rat] increased the percentage of open arm time [%OAT] and open arm entries [%OAE] but not locomotor activity, indicating an anxiolytic response. Furthermore, bilateral microinjections of different doses of the Hi receptor antagonist pyrilamine [0.001, 0.01, 0.1 and 1 microg/rat] or the H2 receptor antagonist ranitidine [0.001, 0.01, 0.1 and 1 microg/rat] into the NAc increased%OAT and%OAE but not locomotor activity. However, both histamine and histamine receptor antagonists showed an anxiolytic-like effect, the antagonists [1 microg/rat] also decreased the histamine response. The results may indicate a modulatory effect for the Hi and H2 histamine receptors of nucleus accumbens in the anxiety behavior of rats

effects of histaminergic agents in the nucleus accumbens of rats in the elevated plus-maze test of anxiety

The nucleus accumbens [NAc] receive histaminergic neurons from tuberomammillary nuclei. There are reports indicating that central histamine systems are involved in many physiological behavioral processes, including anxiety. The aim of the present study was to assess whether the histaminergic system of the NAc is involved in anxiety-related behaviors. Rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride, plus xylazine and then were placed in a stereotaxic apparatus. In addition, two stainless-steel cannuale were placed 2 mm above the nucleus accumbens shell. Seven days after recovery from surgery, the behavioral testing was started. As a model of anxiety, the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents, was used in male Wistar rats. Intra-NAc administration of histamine [0.01, 0.1 and 1 micro g/rat] increased the percentage of open arm time [%OAT] and open arm entries [%OAE], but not locomotor activity, indicating an anxiolytic response. Furthermore, bilateral microinjections of different doses of the H1 receptor antagonist pyrilamine [0.001, 0.01, 0.1 and 1 micro g/rat] or the H2 receptor antagonist ranitidine [0.001, 0.01, 0.1 and 1 micro g/rat] into the NAc increased%OAT and%OAE, but not locomotor activity. However, both histamine and histamine receptor antagonists showed an anxiolytic-like effect; the antagonists [1 micro g/rat] also decreased the histamine response. The results may indicate a modulatory effect for the H1 and H2 histamine receptors of nucleus accumbens in the anxiety behavior of rats