| 其他摘要 | Part 1. Drug abuse is a problem of complex, compulsive drug administration. It will lead to drug addiction which is characterized by drug dependence, drug resistance, drug sensitivity and withdraw symptom. The most important character of drug addiction is compulsive pattern of drug-seeking and drug-taking behavior. That is, addicts loss of control in drug seeking and taking behavior. Accumulated studies have demonstrated that repeated exposure to certain drugs can produce deleterious sequelae, especially cognitive impairments, cognitive biases and emotion dysfunction, which may be the reason for drug abuse and relapse. However, the mechanisms underlying drug addiction are still unclear. Most evidences have indicated that the neural circuitry and molecular mechanisms of drug addiction and of learning and memory have converged. First, drug addiction and learning and memory are modulated by the similar neurotrophic factors, share certain neurotransmitters transmission and intracellular signaling cascades, and depend on activation of the transcription factor cAMP-response element-binding protein (CREB). Second, evidence is presented that in the process of drug addiction, memory about the environmental cues which are associated with the hedonic experiences of drug taking plays a critical role in drug craving. Clinical efforts have found that recovering addicts seemed to respond abnormally to drug-associated contextual cues represented by autonomic responses such as increased heart rate and blood pressure as well as subjective feelings of craving. Although drug abuse can lead to drug addiction and this process involved the mechanisms of learning and memory, injection of morphine impaired other kinds of learning and memory, such as one-trial inhibitory avoidance task, Morris water-maze spatial memory and fear conditioning memory. Pre-training administration of morphine impaired the learning process of passive avoidance task and spatial recognition memory. Post-training immediately injection of morphine impaired memory consolidation of fear conditioning and avoidance task. In addition, pre-retention administration of morphine blocked memory retrieval of spatial recognition memory. The purpose of the present study is to further investigate the mechanisms underlying morphine addiction and the impairing effects of morphine on spatial recognition memory. To this end, we used a series of behavior paradigms, including Morris water-maze (MWM), Y-maze and conditioning place preference (CPP), and neuropharmacological paradigm to study 1) the effects of PTZ induced status epilepticus on morphine-induced CPP and food-induced CPP. Moreover, we compared these effects with the effects of SE on MWM and Y-maze; 2) the effects of combined injection of morphine and propranolol (a beta-adrenergic receptor antagonist) on consolidation of spatial recognition memory; 3) the effects of NMDA system on morphine induced impairment of memory retrieval. We found that 1) SE had no effects on the formation of morphine CPP, however, the formation of food CPP was blocked by SE. Meanwhile, spatial memory assayed in the Morris water maze and Y-maze was impaired by SE. In addition, the data demonstrated that SE did not cause a lasting disturbance of motor activity nor a change in the mice’s appetite. These results suggested that although SE had no effects on morphine CPP, there was impaired food CPP and spatial memory in both the Morris water maze and the Y-maze; 2) post-training administration of morphine (0.25 and 2.5 mg/kg) or PROP (2, 10 and 20 mg/kg) alone did not impair memory consolidation after a 2 h inter-trial interval (ITI). However, co-administration of ineffective doses of morphine (0.25 and 2.5 mg/kg) and ineffective doses of PROP (2, 10 and 20 mg/kg) disrupted memory consolidation after a 2 h ITI. Moreover, the relatively higher dose of morphine (2.5 mg/kg) plus the relatively higher doses of PROP (10 and 20 mg/kg) more seriously disrupted memory consolidation after a 2 h ITI. Locomotor activity was not affected by any of the drug treatments; 3）pre-retention administration of morphine (1 and 10 mg/kg) and MK-801 (0.05, 0.1 and 0.2 mg/kg) dose dependently impaired memory retrieval, but administration of NMDA (1, 2 and 4 mg/kg) had no effects on memory retrieval. Co-administration of ineffective low dose of morphine (1 mg/kg) and ineffective low dose of MK-801 (0.05 mg/kg) impaired memory retrieval. In addition, co-administration of high dose of morphine (10 mg/kg) and middle dose of NMDA (2 mg/kg) blocked the impairing effects of morphine on memory retrieval Part 2. Studies of visual perception have indicated that human visual abilities decline with age. The mechanisms underlying these age-related changes are unclear. Previous studies indicate that age related changes in the retina and dorsal lateral geniculate nucleus (dLGN). Those results, however, cannot explain the declines of senescence. It has been suggested that the deficits in visual function that accompany old age result from a degradation of function in the visual cortex. In previous studies, we have found that both the orientation and direction selectivity of primary visual cortex (V1) cells are decreased in senescent monkeys and cats. These decreases are accompanied by increased visual responsiveness, increased spontaneous activity (baseline) and decreased signal to noise ratios. We also found that the visual response latencies of V1 cells were greater in old than in young monkeys. In addition, Mendelson and Wells have found the degradation of temporal sensitivity of cells in areas 17 and 18 of visual cortex in aged rats. Here we compared the spatial and temporal sensitivities of primary visual cortical (V1) cells in young and old paralyzed macaque monkeys, using extracellular single-unit in vivo recordings. Our results show that cortical neurons of old monkeys exhibit lower optimal spatial and temporal frequency, lower spatial resolution and lower high temporal frequency cut-offs than do cells in young adult monkeys. These changes of old monkeys were accompanied by increased visually evoked responses, increased spontaneous activities and decreased signal-to-noise ratios. The increased excitability of cells in old animals is consistent with an age-related degeneration of intracortical inhibition. A significant degradation of neural spatial and temporal function in striate cortex should contribute to the declines in visual function that accompany old age. |
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