The effect of methamphetamine on serotonin and its metabolite in the suprachiasmatic nucleus: A microdialysis study

Summary The suprachiasmatic nucleus (SCN) has been identified as a major circadian pacemaker. Methamphetamine has been shown to modify the behavior of circadian rhythms. We detected extracellular serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SCN in freely moving rats, using a microdialysis method, to investigate biochemical effects of methamphetamine in the SCN. Methamphetamine infusion into the SCN dose-dependently increased extracellular 5-HT and decreased extracellular 5-HIAA.     

Quisqualate lesions of rat NBM: Selective effects on working memory in a double Y-maze

Some authors have reported that quisqualic acid lesions of the nucleus basalis magnocellularis (NBM), although producing large cortical cholinergic losses, have little effect on memory. The purpose of the present study was to investigate the effects of quisqualic acid lesions of the NBM on working and reference memory in a double Y-maze. Each trial started with placement into one of the two end arms of the first Y-maze, and the correct response was to go down the stem (reference memory). Access was then given to the second Y-maze, the correct response being conditional upon the side of the first Y-maze from which that trial had begun (working memory). Rats were trained to an 88% correct criterion and were then given either bilateral quisqualic acid (60 nM, 0.5 microliters) or sham lesions (0.9% saline, 0.5 microliters) of the NBM. One week postsurgery, rats were tested on the double Y-maze task with delays of 0, 5 or 30 seconds being introduced prior to both the working and reference memory choice. NBM lesions produced a 63.2 +/- 6.2% decrease of cortical choline acetyltransferase (ChAT) compared to unoperated controls. Delays affected only the working memory of the sham group. Rats with lesions showed a significant impairment of working memory at all delays, but no change in reference memory. Results indicate that quisqualic acid lesions of the NBM that produce significant reductions in cortical ChAT selectively impair working memory.     

Application of median-effect in quantitative analysis of antitumor drugs in vitro

Objective: To analyze quantitatively the synergistic and antagonistic effects of combined oxymatrine (OMT) and 5-fluorouracil (5-GU) on a cell line of human liver cancer (HepG2) with median-effect principle in vitro. Methods: The median-effect principle and MTT method were used in the quantitative analysis of effects of the two drugs. Results: Cytotoxic activity of the individual drugs enhanced as drug concentration increased. As fa=0.41, a CI equal to 1 indicated additivity; fa<0.41, a CI less than 1 indicated synergy; and fa>0.41, a CI greater than 1 indicated antagonism. The sequence of administration did not influence the cytotoxic activity of the combined antitumor drugs. The ratio of drug concentration was a factor that can influence the killing effect. Conclusion: The combined drugs interaction (CI<1) was synergistic at lower concentration and antagonistic at higher concentration. The ratio of drug concentration is a factor that can influence the killing effect. Biography: HE Song(1965–), male, doctor of medicine, associate professor, Chongqing Medical University, majors in gastroenterology.     

Quantitative autoradiographic study of L-glutamate binding sites in normal and atrophic human cerebellum.

In the present work the distribution of L-glutamate binding sites in the different layers of human cerebellum of normal individuals and of seven patients who died with olivopontocerebellar atrophy (OPCA) was examined with the technique of quantitative autoradiography. Specific L-[3H]glutamate binding was higher in the molecular than in the granule cell layer of normal cerebellar tissue. A significant decrease of L-[3H]glutamate specific binding was observed in the molecular layer of all OPCA tissues. In the granule cell layer L-[3H]glutamate binding was decreased only in two patients who suffered from late-onset sporadic OPCA and in one patient who suffered from a form of OPCA inherited in a dominant manner. Quisqualate-sensitive binding sites were the most abundant binding sites in the molecular layer of normal cerebella, whereas N-methyl-D-aspartic acid (NMDA)-sensitive binding sites were the most abundant type in the granule cell layer. A significant decrease of quisqualate-sensitive and an increase in NMDA-sensitive binding sites were observed in the molecular layer of OPCA cerebellar tissues. No significant changes were observed in the granule cell layer of these tissues.     

Effect of Vigabatrin on the Electroencephalogram in Rats

Vigabatrin (gamma-vinyl GABA; GVG) is a new antiepileptic drug (AED) that increases the level of the inhibitory transmitter, gamma-aminobutyric acid (GABA) in the brain. We evaluated the effect of GVG on the EEG of normal rats. GVG was administered intraperitoneally (i.p.) at a dose of 100 mg/kg once a day for 12 days. EEG was recorded at baseline, on the fourth day, at the end of the 12-day GVG period and 10 days after discontinuation of GVG. GVG increased the amplitude of delta (1-4 Hz) and theta (4-8 Hz) frequency bands and resulted in slowing of the peak frequency (Fp) and mean frequency (Fm) in both the frontal and occipital cortex, especially during waking-immobility. EEG changes normalized within 10 days after the last GVG injections. The results suggest that a relationship may exist between the EEG changes and increase in GABA levels with GVG.     

Protective effects of serotonin reuptake inhibitors, citalopram and clomipramine, against hippocampal CA1 neuronal damage following transient ischemia in the gerbil

To clarify the role of serotonin in cerebral ischemia, we examined the effects of selective serotonin reuptake inhibitors, citalopram and clomipramine, on ischemic neuronal damage in the gerbil. Pretreatment with citalopram (40 mg/kg i.p.) and clomipramine (20 mg/kg i.p.) protected against neuronal destruction of hippocampal CA1 pyramidal cells following 5 min of forebrain ischemia. Furthermore, microdialysis assays showed that a striking increase in extracellular excitatory amino acid levels during ischemia was significantly inhibited by pretreatment with citalopram and clomipramine. However, citalopram (40 mg/kg i.p.) did not alter the extracellular amino acid concentrations in normal gerbils. Thus, serotonin reuptake inhibitors have a protective effect against ischemic neuronal damage. Furthermore, the present result suggests that the protective effect is mediated through prevention of the accumulation of extracellular excitatory amino acids during and after ischemia.     

Regulation of neurotransmitter enzyme by quisqualate subtype glutamate receptors in cultured cerebellar and hippocampal neurons

The possible involvement of ionotropic and metabotropic quisqualate (QA) receptors in neuronal plasticity was studied in cultured glutamtergic cerebellar or hippocampal cells in terms of the specific activity of phosphate-activated glutaminase, an enzyme important in the synthesis of the putative neurotransmitter pool of glutamate. When cerebellar of hippocampal neurons were treated with QA, it elevated the specific activity of glutaminase in a dose-dependent manner. The half-maximal effect was obtained at about 0.1 μM, the maximum increase was at about 1 μM, but levels higher than 10 μM QA produced progressive reduction in glutaminase activity. In contrast, QA had little effects on the activities of lactate dehydrogenase and aspartate aminotransferase and the amount of protein, indicating that the increase in glutaminase was relatively specific. The QA-mediated increase in glutaminase was mimicked by the ionotropic QA receptor agonist -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; EC₅₀, about 0.5 μM), but not by the metabotropic QA receptor agonist trans-(±)-1-aino-cyclopentyl-1,3,dicarboxyalte (t-ACPD; up to 0.5 mM). The specific ionotropic QA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited QA- and AMPA-mediated increases in glutaminase activity in a dose-dependent manner, whereas other glutamate receptor antagonists, -2-amino-5-phosphonovalerate, γ- -glutamyl aminomethyl sulphonic acid and γ- -glutamyl diethyl ester were ineffective. The elevation of neurotransmitter enzyme was Ca²⁺-dependent. The increase in Ca²⁺ influx essentially through the activation of L-type voltage-operated Ca²⁺ channels, and not the mobilization of internal Ca²⁺ stores, was responsible for these QA receptor-mediated long-term plastic changes in hippocampal and cerebellar neurons.     

锰超氧化物岐化酶模型配合物的研究

为探索天然超氧化物岐化酶（ＳＯＤ）岐化超氧离子的机理，及用于临床的可能性，我们合成了乳酸、柠檬酸和酒石酸的锰（Ⅱ）配合物作为Ｍｎ－ＳＯＤ的模拟物，用光照法测定了它们的活性，得到了有意义的结果：锰配合物作为Ｍｎ－ＳＯＤ的模拟物，有肯定的活性，其中以乳酸锰配合物活性最高。     

Evidence for differential effects of 8-OH-DPAT on male and female rats in the Anxiety/Defense Test Battery

The Proxemics/Activity test and the Eat/Drink test, two components of the Anxiety/Defense Test Battery, were developed to measure defensive reactions to situations associated with a natural predator (cat). In the present studies the behavioral effects of 8-OH-DPAT treatment (0.01–1.0 mg/kg, SC) were entirely consistent with anxiety/fear reduction. These effects included an increase in time spent near the cat compartment, and a complimentary decrease in time spent farthest from this compartment, together with an increase in transits and locomote behavior. 8-OH-DPAT (1.0 mg/kg) also increased eat frequencies and durations (highly preferred food) both during and following cat presentation, without influencing drinking. This finding is discussed with reference to previous findings with 8-OH-DPAT in studies assessing both food intake and anxiolysis. Interestingly, 8-OH-DPAT was more potent in a majority of its effects in female subjects, a finding consistent with recent neurochemical data. These findings provide important behavioral evidence for a sexual differentiation in 5-HT function, and support the case for greater emphasis on female subjects in animal models of anxiety.Supported by NIH MH42803 and RCMI Grants RR03061 and RR01825     

5-Hydroxytryptamine increases excitability of CA1 hippocampal pyramidal cells.

In the presence of spiperone to block the 5-HT1A-mediated inhibition of pyramidal cell activity, 5-hydroxytryptamine (serotonin, 5-HT) produces a rapid transient increase in amplitude of the extracellularly recorded population spike from area CA1 of the hippocampus. Intracellular recording techniques in area CA1 of rat hippocampal slices were used to identify the ionic mechanism and to characterize the 5-HT receptor mediating this excitatory response to 5-HT. Most of the experiments were conducted in the presence of spiperone to block the 5HT1A hyperpolarization. Since spiperone also has high affinity for 5-HT2 receptors, any response mediated by 5-HT2 receptors would also be blocked. Bath perfusion of the slice with 5-HT increased the rectification of pyramidal cells in the subthreshold region, increased the resistance, and increased the amplitude of subthreshold excitatory postsynaptic potentials (EPSPs) to initiate spike firing. The 5-HT2,1C-selective agonist DOI mimicked this effect of 5-HT, and the 5-HT2,1C antagonist ketanserin (1 microM) blocked the effect of DOI. There was no change in the amplitude of the slow afterhyperpolarization (sAHP) or the amplitude of evoked inhibitory postsynaptic potentials (IPSPs). The increase in rectification and EPSP amplitude by 5-HT occurred even in the presence of the 5-HT4-selective antagonist BRL 24924 to prevent the decrease in amplitude of the sAHP by 5-HT. We conclude that 5-HT produces a fast excitatory response by increasing subthreshold conductance in CA1 hippocampal pyramidal cells. The identity of the receptor mediating this response was not conclusively identified, but resembled the 5-HT1C receptor.