Nicotinic receptors in the brain

Although the psychological and physiological effects of nicotine have long suggested that nicotine exerts specific actions in the brain, the identification of neuronal nicotinic receptors (nAChRs) only began in the past few years with the development of molecular genetics. It is now clear that neuronal nAChRs form a family of highly heterogenous receptor subtypes, as evidenced by the number of genes encoding nAChR subunits, the diversity of immunopurified receptor proteins, and the multiple functional types of ligand-gated ion channels. Neuronal nAChRs have discrete localizations within the brain, and are involved in modulating neuronal firing and transmitter release. Cumulative evidence from animal and human studies indicates that nicotinic systems play a major role in higher cognitive functions and dysfunctions. In particular, the loss of cortical nAChRs is a neurochemical hallmark of Alzheimer (AD) and Parkinson (PD) diseases. In addition, nicotine improves memory and attention in AD and PD. Our recent studies using electrophysiological biochemical and behavioral approaches suggest that the prefrontal cortex is a major target site for the cognitive actions of nicotine.     

Maps,routes, and the hippocampus: A neural network approach

This study describes hippocampal participation in maze navigation in terms of a real-time, biologically plausible neural network. The system is composed of (1) a goal-seeking mechanism, (2) a cognitive map system, and (3) a route system. The goal-seeking mechanism displays exploratory behavior until either the goal is found or a sufficiently strong prediction of the goal is generated. The cognitive map is a topological map that stores associations between places and views of accessible places, and between places and reward. The route system establishes associations between cues and reward. Both systems compete with each other to establish associations with the reward, with the cognitive system generally overshadowing the route system. In agreement with previous models, it is assumed that the hippocampus modulates the storage of cognitive maps in cortical areas and mediates the competition between cognitive maps and route systems. In agreement with previous models, it is assumed that the hippocampus modulates the storage of cognitive maps in cortical areas and mediates the competition between cognitive maps and route systems. After hippocampal lesions, animals navigate through mazes making use of the route system. Computer simulations show that the network effectively describes latent learning, detour behavior, and place learning in normal and hippocampal-and cortical-lesioned animals.     

Simultaneous blockade of non-NMDA ionotropic receptors and NMDA receptor-associated ionophore partially protects hippocampal slices from protein synthesis impairment due to simulated ischemia

A large body of evidence exists to demonstrate that excitatory amino acids (EAA) and their receptors are involved in the pathophysiological mechanisms linking several acute brain insults, such as cerebral ischemia, to neuronal degeneration and death. Accordingly, the use of EAA receptor antagonists can be beneficial in attenuating or preventing the neuronal irreversible damage subsequent to various neuropathological syndromes. We have investigated the effect of 15 min of simulated ischemic conditions, i. e., oxygen/glucose deprivation, on hippocampal slices preparation measuring, as neurotoxicity indexes, both the amino acids efflux in the incubation medium, detected by HPLC, and the inhibition of protein synthesis, evaluated as ³H-Leucine incorporation into proteins. Accumulation of neurotransmitter amino acids was measured in the medium during the “ischemic” period. Glutamate increased 30-fold over the basal level while aspartate was sevenfold and GABA 12-fold higher than in normal conditions. After a reoxygenation period of 30 min, the rate of protein synthesis of hippocampal slices subjected to “ischemia” was reduced to 35–50% of controls. The non-competitive NMDA antagonist MK-801 (100 μM) and the competitive NMDA antagonist CGP 39551 (100–250 μM) as well as the non-NMDA receptor antagonist NBQX (100 μM) and AP3 (300 μM) were unable to counteract the metabolic impairment when they were present alone in the incubation fluid during simulated “ischemia.” An incomplete, but highly significant (p < 0.001), protection from protein synthesis impairment was achieved in the presence of an equimolar concentration (100 μM) of MK-801 and NBQX. A similar protective effect could be reproduced using 100 μM NBQX in concomitance with a high Mg⁺⁺ (20 μM) voltage-dependent block of the NMDA receptor-associated channel but not exposing the slices to a NBQX (100 μM) and CGP 39551 (100–250 μM) mixture. The recovery of protein synthesis in the presence of the MK-801/NBQX effective combination was not paralleled by a detectable decrease in the amount of amino acids released in the incubation medium during the “ischemic” period. Taken together, the present data allow new insights into neurotoxicity-mediating mechanisms, suggesting that multiple additive processes are involved and that antagonists acting at different sites on excitatory amino acid receptor subtype can show different neuroprotective potency. © 1995 Wiley-Liss, Inc.     

哌甲酯、氯安酮长期作用对大鼠海马游离氨基酸和皮层下组织多巴胺的影响

本研究利用高效液相色谱分析法测定经两种不同作用机制的拟精神病药（哌甲酯、氯安酮）长期作用后（６周）的大鼠海马游离氨基酸和皮层下组织多巴胺及代谢物的含量。结果发现，哌甲酯和氯安酮长期作用后大鼠海马的γ－氨基丁酸、甘氨酸、天门冬氨酸、游离氨含量降低；氯安酮还使谷氨酸增高、精氨酸降低。两种药物均有使皮层下组织多巴胺活动增高的趋势，且哌甲酯尤明显。     

Learning and memory after adrenalectomy-induced hippocampal dentate granule cell degeneration in the rat

Adrenalectomy (ADX) of normal adult rats causes selective hippocampal dentate granule cell degeneration that is prevented by corticosterone. The ability to destroy this one hippocampal cell type noninvasively made it possible to address the role of the dentate granule cells in learning and memory. Four months after ADX, 31 of 45 rats failed to show obvious granule cell loss and displayed behavior in the Morris water maze that was similar to 16 sham-operated control rats and 16 ADX rats maintained on corticosterone throughout the study. Conversely, 14 of the 45 ADX rats experienced a loss of granule cells that varied from minimal to extensive. Although there were no obvious differences between groups in motoric and motivational characteristics or search strategies, ADX rats with moderate to extensive granule cell loss acquired place learning slightly slower than controls or ADX rats with minimal or no obvious cell loss. Furthermore, the ADX rats with moderate to extensive cell loss were temporarily impaired following alteration of either intramaze or extramaze cues compared to controls. In contrast, the rats with granule cell loss remembered an old place and learned a new place as quickly as controls. These results suggest that a normal complement of dentate granule cells may not be necessary for the acquisition or retention of spatial information in the Morris water maze.     

Activation,travel distance,and environmental change influence food carrying in rats with hippocampal,medial thalamic and septal lesions: Implications for studies on hoarding and theories of hippocampal function

Rats transport food from exposed areas to covered areas where they eat it or leave it. Although there is evidence that limbic structures play a role in food transport, their role is controversial. Here it was found that although many rats with large hippocampal, septal/diagonal band of Broca or dorsomedial thalamic lesions did not carry food but ate it where they found it, a few presentations of an auditory stimulus could restore food carrying. Once restored, most features of food carrying in hippocampal rats were normal in relation to food presentation schedules, deprivation levels, ambient illumination, circadian cycles, food size, and eating times. Nevertheless, food carrying impairments reemerged when the testing environment was changed. Hippocampal rats were also excessively responsive to increases in travel distance and stopped carrying food at distances over which control rats would still carry large food pellets. Auditory stimulation did not restore food carrying over long travel distances. The findings that sensory stimulation, environmental change, and travel distance influence food carrying probabilities in rats with limbic system lesions is discussed in relation to research on limbic control of food hoarding and theories of limbic system function.     

Localization of taurine transporters, taurine, and (3)H taurine accumulation in the rat retina, pituitary, and brain.

The nervous system contains an abundance of taurine, a neuroactive sulfonic acid. Antibodies were generated against two cloned high-affinity taurine transporters, referred to in this study as TAUT-1 and TAUT-2. The distribution of such was compared with the distribution of taurine in the rat brain, pituitary, and retina. The cellular pattern of [(3)H] taurine uptake in brain slices, pituitary slices, and retinas was examined by autoradiography. TAUT-2 was predominantly associated with glial cells, including the Bergmann glial cells of the cerebellum and astrocytes in brain areas such as hippocampus. Low-level labeling for TAUT-2 was also observed in some neurones such as CA1 pyramidal cells. TAUT-1 distribution was more limited; in the posterior pituitary TAUT-1 was associated with the pituicytes but was absent from glial cells in the intermediate and anterior lobes. Conversely, in the brain TAUT-1 was associated with cerebellar Purkinje cells and, in the retina, with photoreceptors and bipolar cells. Our data suggest that intracellular taurine levels in glial cells and neurons may be regulated in part by specific high-affinity taurine transporters. The heterogeneous distribution of taurine and its transporters in the brain does not reconcile well with the possibility that taurine acts solely as a ubiquitous osmolyte in nervous tissues.     

Alterations in the density of excrescences in CA3 neurons of hippocampus in rats subjected to self-stimulation experience

Self-stimulation (SS) rewarding experience induced alterations in the density of excrescences in the apical dendrites of CA3 neurons were studied in adult male Wistar rats. SS experience was provided daily for an hour over a period of 10 days, through bipolar stainless steel electrodes implanted bilaterally in lateral hypothalamus and substantia nigra-ventral tegmental area. The results revealed a significant (P<0.001) increase in the number of excrescences in both main shaft and sub branches of the apical dendrites in SS experienced group compared to control groups of rats. The increased number of excrescences in CA3 neurons might be due to an enhancement in the synaptic transmission in the mossy fiber pathway following SS experience.     

Differential expression of glycans in the hippocampus of rats trained on an inhibitory learning paradigm

The glycan chains of glycoconjugates play important roles in cell–cell and cell–matrix interactions. In the CNS, previous studies on learning and memory suggest the importance of oligosaccharides attached to glycoconjugates in the modulation of synaptic connections. We studied the hippocampal glycan distribution of rats subject to an inhibitory avoidance task. The expression of glycans was examined by lectin‐histochemistry using Vicia villosa lectin (VVL) for terminal α/β N‐acetylgalactosamine (α/β GalNAc); Galanthus nivalus lectin (GNL) for terminal mannose α‐1,3 (Man α‐1,3); Peanut agglutinin (PNA) for galactose β‐1,3N‐acetylgalactosamine (Gal β‐1,3 GalNAc); Erythrina cristagalli lectin (ECL) for galactose β‐1,4 N‐acetylglucosamine (Gal β‐1,4 GlcNAc); Sambucus nigra lectin (SNA) for sialic acid α‐2.6 galactose (SA α‐2,6 Gal); Maackia amurensis lectin II (MAL II) for sialic acid α‐2,3 (SA α‐2,3); Wheat germ agglutinin (WGA) for terminal N‐acetylglucosamine with/without sialic acid (GlcNAc wo SA); succynilated WGA (sWGA) for terminal N‐acetylglucosamine without sialic acid (terminal GlcNAc without SA); Griffonia simplicifolia lectin II (GSL II) for terminal α/β N‐acetylglucosamine (α/β GlcNAc terminal); and Lotus tetragonolobus lectin (LTL) α–fucose. Two groups of 10 animals were examined: non‐trained (Control) and Trained rats. ECL, sWGA and GSL II were negative for both groups in all the hippocampal subfields studied. For both groups, VVL was negative in CA4 and granular cells of the Dentate Gyrus (DG) and LTL was negative in the CA4 subfield. Expression of α/β GalNAc, α ‐fucose and GlcNAc in other hippocampal subfields was positive, with no differences between groups. However, expression of Man α‐1,3 was significantly higher in the CA1, CA2, CA3, and CA4 subfields in the Trained group. On the other hand, expression of Gal β‐1,3 GalNAc was significantly low in CA4 and DG in the Trained group. In conclusion, the results here presented indicate that the exposure of rats to an associative behavioral paradigm related to declarative memory, involves some regulatory mechanism/s for the differential patterns of glycan expression.     

梭曼中毒对大鼠脑组织ATP酶及腺苷酸代谢的影响

目的　研究梭曼中毒后大鼠脑组织能量代谢的变化特点。方法　Wistar大鼠以 72 μg kg的剂量梭曼皮下中毒 ,分离海马及小脑并以生化法检测Na+ ,K+ ATPase、Ca2 + ATPase、Mg2 + ATPase的活性 ,HPLC法检测全脑ATP、ADP及AMP含量。结果　梭曼中毒 10～ 2 0min 3种ATP酶活性均显著升高 (P <0 .0 5 ) ,1～ 6h酶活性逐渐下降并低于对照组 ,于中毒后 48h恢复至正常对照水平。ATP含量于中毒 12h显著低于对照组 ,随着时间延长呈逐渐升高的趋势。AMP含量中毒 12h升高显著 (P <0 .0 1) ,其后于 48h恢复正常。结论　梭曼对脑组织ATP酶和能量代谢均产生广泛的影响