Central cholinergic influence on self-administration of morphine and amphetamine

Atropine and methylatropine were tested in rats for an ability to alter the reinforcing action of intravenous morphine sulfate and d-amphetamine sulfate (60 μg/kg/injection). Atropine blocked the self-administration of morphine, but methylatropine did not. Similarly, atropine but not methylatropine prevented the establishment of a conditioned reinforcer based on passive intravenous infusions of morphine. Self-administration of d-amphetamine was enhanced by atropine but not by methylatropine. The results indicate that a central cholinergic system exerts an influence on the brain mechanisms which are affected by morphine or d-amphetamine to produce positive reinforcement.     

Effect of parenterally administered atropine on the percutaneous absorption of phencyclidine and methadone

The effect of parenterally administered atropine on the previously demonstrated percutaneous absorption of phencyclidine and methadone was investigated in vivo using the hairless (SKH, hr-1/hr-1) mouse as an experimental model. At both three hours and four hours following topical application of aqueous phencyclidine hydrochloride, the mean drug concentration in liver was significantly lower in mice that had received atropine sulfate by intraperitoneal injection than in mice that had received only water by this route (3 hrs: p less than 0.01; 4 hrs: p less than 0.02). Prior to three hours no statistically significant difference was noted. In contrast, parenteral administration of atropine produced no significant effect upon the percutaneous absorption of aqueous methadone hydrochloride over a four-hour period. Atropine inhibition of absorption is likely due to cutaneous dehydration, and it may be drug-specific and/or dose-related. These findings are correlated with the previously reported ethanol inhibition of percutaneous absorption. The therapeutic implications of these observations are discussed.     

Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats

Recently, we demonstrated that intrahippocampal infusion of the cyclo-oxygenase (COX)-2-specific inhibitor celecoxib impaired spatial memory retention in the Morris water maze. In the present work, we investigated the effects of nicotine, infused in the rat dorsal hippocampus several minutes after infusion of celecoxib, on memory retention in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained four trials. Test trials were conducted 48 h after surgery. As expected, bilateral intrahippocampal infusion of celecoxib (19 microg/side; 0.1 m) increased escape latency and travel distance in rats, indicating significant impairment of spatial memory retention. We also examined the effects of bilateral infusion of nicotine (0.5, 1.0 and 2.0 microg/side) on memory retention. Infusion of 1 microg nicotine significantly decreased escape latency and travel distance but not swimming speed, compared with controls, suggesting memory retention enhancement by nicotine at this concentration. In separate experiments, bilateral infusion of nicotine, infused 5 min after 0.1 m (19 microg/side) celecoxib infusion, was associated with escape latency, travel distance and swimming speed profiles very similar to those in control animals. Brain tissue sections from several of these animals were subjected to immunohistochemical staining analysis with anti-COX-2 antibodies. Quantification analysis by optical density measurements showed that the celecoxib infusion reduced the immunoreactivity of COX-2-containing neurons in the CA1 area of the hippocampus compared with controls, although this reduction was not significant. However, infusion of a combination of celecoxib and nicotine significantly increased this immunoreactivity compared with levels in control and celecoxib-infused groups. These results suggest that nicotine prevented or reversed the adverse effects of celecoxib on spatial memory retention and protected or restored the immunostaining pattern of COX-2 neurons in the rat dorsal hippocampus.     

Effect of route of atropine delivery on bronchospasm from cold air and methacholine

We undertook a study to determine whether the apparent disparity between the dose of inhaled atropine required to inhibit the bronchoconstriction induced by inhaled methacholine and the dose required to inhibit the bronchoconstriction induced by eucapnic hyperpnea with cold air is a function of the route of administration of atropine. In six subjects with asthma, we constructed dose-response curves to inhaled methacholine and to eucapnic hyperpnea with cold air after treatment with inhaled atropine (0.5 mg delivered) and intravenous placebo, with inhaled placebo and intravenous atropine (0.5 mg injected), and with inhaled and intravenous placebos. Atropine by either route shifted the dose-response curves to both cold air and to methacholine to the right. In every subject, however, inhaled atropine caused a markedly greater rightward shift of the inhaled methacholine dose-response curve than did intravenous atropine, whereas inhaled and intravenous atropine had similar effects on the cold air dose-response curve. These findings suggest that the apparent disparity between the doses of atropine required to inhibit methacholine- and cold air-induced bronchoconstriction may be a function of the route of administration of atropine and thus does not imply a nonmuscarinic action of atropine. The findings support the view that cold air causes bronchoconstriction via muscarinic pathways.     

Brain-stem auditory pathways: effects of atropine]

The efferent pathways exert a control action on the function of the cochlear nucleus and hair cells. Acetylcholine is the neurotransmitter of the centrifugal system and its action can be blocked by Atropine. In order to give a contribution to the knowledge of the function of the efferent bundle, Auditory Brainstem Responses (ABRs) and Acoustic Reflex Latencies (ARLs) have been examined in 10 young normal subjects there was also a decrease in latency greater than or equal to 100 microseconds by at least other two waves. The only statistically significant difference was relative to the latency mean value of the wave III recorded in contralateral derivation at 11 pps. The ARLs, after the infusion of atropine, showed a statistically significant increase in 7 of the 10 cases; no change was recorded in the AR amplitude. It can be concluded that the pharmacological block of the olivo-cochlear bundle determines a delay in the neural conduction of the acoustic impulses; this finding means that the atropine can inhibit the facilitating activity of the efferent system on the brainstem afferent pathways.     

Effects of physical fatigue in mice on learning performance in a water maze

We investigated the effects of physical fatigue produced by swimming exercise on learning the Morris water maze in BALB/c mice. We measured the escape latency in the maze immediately after the swimming exercise. The control group was soaked in the water but not fatigued. For easier tasks, like one with an obvious cue flag, the escape latency was not changed by exercise fatigue. However, escape latency was increased after exercise fatigue for more difficult tasks of spatial learning. These results appear to suggest that physical fatigue impaired learning performance. The effects of swimming exercise fatigue on learning efficiency were then investigated. Mice were continuously fatigued during the spatial learning period. This increased escape latency between the first and third sessions. The results suggest that learning efficiency was impaired by exercise fatigue. This system may be useful for screening new foods used to enhance brain function during exercise.     

慢性束缚应激对SD和Wistar大鼠学习记忆能力的影响

目的探讨慢性束缚应激对Wistar、SD两种品系大鼠学习记忆能力的影响,为应激模型中实验动物的选择提供依据。方法对两种品系大鼠(Wistar、SD)采用每天束缚10 h,束缚28 d建立慢性应激模型。采用物体认知新物体识别实验和Morris水迷宫空间学习、工作记忆行为学检测方法,观察束缚应激对两种品系实验动物学习记忆能力的影响。结果束缚28 d后,物体识别实验中,Wistar、SD模型组的辨别指数(discrimination index,DI)均低于对照组,但只有SD两组间差异存在显著性(P0.05);水迷宫空间学习阶段,SD模型组潜伏期高于对照组,第5天差异有显著性(P0.05),而Wistar模型组与对照组间的潜伏期没有差异;水迷宫工作记忆阶段,SD大鼠模型组与正常组比较,潜伏期显著增加(P0.05),Wistar模型大鼠的潜伏期与对照组比较没有显著差异。结论新物体识别实验和水迷宫实验,这两种反应动物不同学习记忆能力的行为学实验结果都表明,慢性束缚应激(10 h,28 d)对SD大鼠学习记忆能力的损伤较Wistar大鼠明显。SD大鼠可能更适合作为慢性应激所致学习记忆损伤动物模型。     

The role of the neurotransmitters acetylcholine and noradrenaline in the pathogenesis of stress ulcers

1. Adrenergic and cholinergic mechanisms seem to be involved in the pathogenesis of stress ulcers.2. In this study, gastric ulcers were induced in rats by immobilization and cold. Prior intraperitoneal administration of both anticholinergic (atropine) as well as α-blocking medication (phenoxybenzamine) produced a very significant decrease in stress ulcers.3. Additionally, using the technique of continuous intravenous perfusion in rats, acetylcholine was shown to have a gastric ulcerogenic effect, in contrast to noradrenaline.4. It is concluded that acetylcholine is the peripheral mediator in stress ulcers, while noradrenaline intervenes at the encephalic level in stress ulcer pathogenesis.     

Ovariectomy ameliorates dextromethorphan--induced memory impairment in young female rats

We have previously found that dextromethorphan (DM), over-the-counter cough suppressant, impairs memory retention in water maze task, when it is repeatedly administrated to adolescent female rats at high doses. In this study we examined first if ovariectomy ameliorates the DM-induced memory impairment in female rats, and then whether or not the DM effect is revived by estrogen replacement in ovariectomized female rats. Female rat pups received bilateral ovariectomy or sham operation on postnatal day (PND) 21, and then intraperitoneal DM (40 mg/kg) daily during PND 28-37. Rats were subjected to the Morris water maze task from PND 38, approximately 24 h after the last DM injection. In probe trial, goal quadrant dwell time was significantly reduced by DM in the sham operated group, however, the reduction by DM did not occur in the ovariectomy group. When 17beta-estradiol was supplied to ovariectomized females during DM treatment, the goal quadrant dwell time was significantly decreased, compared to the vehicle control group. Furthermore, a major effect of estrogen replacement was found in the escape latency during the last 3 days of initial learning trials. These results suggest that ovariectomy may ameliorate the adverse effect of DM treatment on memory retention in young female rats, and that estrogen replacement may revive it, i.e. estrogen may take a major role in DM-induced memory impairment in female rats.     

Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior

A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents.     

Effects of atropine on operant test battery performance in rhesus monkeys.

The acute behavioral effects of atropine sulfate were assessed using a battery of complex food-reinforced operant tasks that included: temporal response differentiation (TRD, n = 7); delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 8), incremental repeated acquisition (IRA, n = 8), and conditioned position responding (CPR, n = 8). Performance in these tasks is thought to depend primarily upon specific brain functions such as time perception, short-term memory and attention, motivation, learning, and color and position discrimination, respectively. Atropine sulfate (0.01-0.56 mg/kg iv), given 15-min pretesting, produced significant dose-dependent decreases in the number of reinforcers obtained in all tasks. Response rates decreased significantly at greater than or equal to 0.03 mg/kg for the learning and discrimination tasks, at greater than or equal to 0.10 mg/kg for the motivation and short-term memory and attention tasks, and at greater than or equal to 0.30 mg/kg for the time perception task. Response accuracies were significantly decreased at doses greater than or equal to 0.10 mg/kg for the learning, discrimination, and short-term memory and attention tasks, and at greater than or equal to 0.30 mg/kg for the time perception task. Thus, the order of task sensitivity to any disruption by atropine is learning = color and position discrimination greater than time perception = short-term memory and attention = motivation (IRA = CPR greater than TRD = DMTS = PR). Thus in monkeys, the rates of responding in operant tasks designed to model learning and color and position discrimination were the most sensitive measures to atropine's behavioral effects. Accuracy in these same task was also disrupted but at higher doses. These data support the hypothesis that cholinergic systems play a greater role in the speed (but not accuracy) of performance of our learning and discrimination tasks compared to all other tasks. Accuracy of responding in these and the short-term memory task, all of which involve the use of lights as visual stimuli, was more sensitive to disruption by atropine than those tasks which did not utilize such strong visual stimuli.     

Moderate prenatal carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats

The effects of moderate (150 +/- 2 ppm) prenatal carbon monoxide (CO) exposure (maternal HbCO concentrations of 15.6 +/- 1.1%) on learning and memory were assessed in young and aged adult rats using a two-way active avoidance paradigm. In experiment 1, the prenatal CO-exposed rats at 120 days of age acquired a conditioned avoidance response equally well as control animals in a 100-trial session. However, following a 24-hr interval the CO-exposed rats failed to demonstrate significant retention of the task as indicated by the absence of significant improvement in performance over the indicated by the absence of significant improvement in performance over the previous day; control subjects did show significant retention. In experiment 2, in which 120-day-old animals received 50 training trials per day until a criterion of ten consecutive avoidance responses was met, the prenatal CO-exposed subjects again acquired the task as well as control animals. When tested for retention 28 days later, a significant memory impairment was again observed in terms of trials required to reattain the avoidance criterion as well as in total percent avoidance responding. In neither experiment did an analysis of initial or average latency to escape the footshock stimulus reveal any significant alterations. These latter results suggest that the observed performance impairment reflected a memory deficit and not a disruption of sensory, motor, or motivational factors. In experiment 3, prenatal CO-exposed rats approximately 1 year of age (300-360 days of age) showed impairment relative to air-exposed controls in both the original learning and retention of the two-way avoidance response. Again, however, there was no evidence for alterations in performance factors per se. Collectively these data indicate that while young adult rats prenatally exposed to 150 ppm CO demonstrate an associative deficit restricted to memory impairment, aged adults similarly exposed during the prenatal period display a more pronounced deficit similar to that recently reported for animals tested as juveniles. The importance of parametric manipulations in uncovering long-term toxicity is also discussed.     

Atropine depresses release of neurotensin and its effect on the exocrine pancreas

In this study the effect of 10 and 20 μg · kg^?1 · h^?1 atropine sulfate on release and pancreatic effects of neurotensin was studied in 4 dogs. Neurotensin plasma levels rose significantly when a liquid fat preparation was infused intraduodenally. This rise was almost completely abolished by simultaneous infusion of atropine. Atropine further suppressed basal and fat-stimulated output of pancreatic volume, protein, and bicarbonate; it also reduced pancreatic secretion stimulated by an intravenous infusion of low doses (2.5 to 20 pmol · kg^?1 · min^?1) neurotensin. The effect of higher doses (80 and 240 pmol · kg^?1 · min^?1) of neurotensin was less affected.As neurotensin plasma levels in contrast to normal oral feeding did not rise after sham feeding, our findings suggest that release and action of neurotensin may at least in part be dependent on a cholinergic, non-cephalic mechanism.     

Effect of atropine sulfate on the phenomena of follicular growth induced by a total anterior pituitary gonadotropic preparation during the estrus cycle in the rat

The question whether atropine inhibits follicular growth in rats induced by Gonadormone Byla was tested. 52 rats of strain WI, and 48 WII rats about 20 gm heavier, were injected at 1700 in diestrous I with 2.5 mouse units of gonadotropin per 100 gm body weight and 28 of each group also with 70 mg atropine sulfate sc, then serial ovarian sections were prepared at 1700 of proestrus. Atropine reduced the mean number of follicles 400 mcm in diameter or above (p less than .02), but did not affect their size distribution. A 2nd series of 48 rats were injected at 1700 of diestrous II with 1.5 units of gonadotropin per 100 gm body weight and half the rats with atropine. Again, atropine reduced the number of developing follicles (p less than .05) without affecting their mean diameter or size distribution.     

Low (20 cGy) doses of 1 GeV/u (56)Fe--particle radiation lead to a persistent reduction in the spatial learning ability of rats

Exposure to galactic cosmic radiation (GCR) is considered to be a potential health risk in long-term space travel, and it represents a significant risk to the central nervous system (CNS). The most harmful component of GCR is the HZE [high-mass, highly charged (Z), high-energy] particles, e.g. (56)Fe. In previous ground-based experiments, exposure to high doses of HZE-particle radiation induced pronounced deficits in hippocampus-dependent learning and memory in rodents. Recent data suggest that glutamatergic transmission in hippocampal synaptosomes is impaired after low (60 cGy) doses of 1 GeV/u (56)Fe particles, which could lead to impairment of hippocampus-dependent spatial memory. To assess the effects of mission-relevant (20-60 cGy) doses of 1 GeV/u (56)Fe particles on hippocampus-dependent spatial memory, male Wistar rats either received sham treatment or were irradiated and tested 3 months later in the Barnes maze test. Compared to the controls, rats that received 20, 40 and 60 cGy 1 GeV/u (56)Fe particles showed significant impairments in their ability to locate the escape box in the Barnes maze, which was manifested by progressively increasing escape latency times over the 3 days of testing. However, this increase was not due to a lack of motivation of the rats to escape, because the total number of head pokes (and especially incorrect head pokes) remained constant over the test period. Given that rats exposed to X rays did not exhibit spatial memory impairments until >10 Gy was delivered, the RBE for 1 GeV/u (56)Fe-particle-induced hippocampal spatial memory impairment is ～50. These data demonstrate that mission-relevant doses of 1 GeV/u (56)Fe particles can result in severe deficits in hippocampus-dependent neurocognitive tasks, and the extreme sensitivity of these processes to 1 GeV/u (56)Fe particles must arise due to the perturbation of multiple processes in addition to killing neuronal cells.     

Effect of L-asparaginase on retention of maze learning in mice

Long-term memory impairment has been described previously in mice receiving inhibitors of protein synthesis. In the present work, the enzyme L-asparaginase was injected into mice by an intrathecal or by an intraperitoneal route and produced a significant impairment of memory. Glutamine and asparagine prevented the effect of asparaginase when injected by the intraperitoneal route.     

The effect of the parasympathetic autonomic nervous system on auditory fatigue.

Volunteers with normal hearing were tested for vegetative balance with the aid of vegetative reflexes and with the aid of the atropine test. The effect of white noise stimulated on hearing thresholds was then investigated together with their recovery. The vegetative system was affected experimentally by intravenous administration of atropine, and the beginning and recession of hearing fatigue was observed. Atropine caused a small change only. In a similarly arranged experiment, 1% pilocarpin administered subcutaneously in a dose of 1.4 minus 1.6 ml, resulted in increased hearing fatigue and retarded recovery at higher frequencies. The effect of pilocarpin is explained by the fact that it supports the inhibitory processes checked by the parasympathetic nervous system on the periphery.     

Dynorphin A (1-13) in the brain suppresses epinephrine-induced ventricular premature complexes and ventricular tachyarrhythmias.

The objectives of this study were to test the hypothesis that dynorphin in the central nervous system modulates epinephrine-induced cardiac arrhythmias and that central cholinergic mechanisms are operative in this action of dynorphin. Cardiac arrhythmias were produced by continuous intravenous infusion of epinephrine, in Wistar rats, previously instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Epinephrine produced ventricular premature complexes and later the development of fatal ventricular fibrillation. Dynorphin A (1-13), 5 or 20 micrograms (3 or 12 nM) administered into the lateral cerebral ventricle (ICV), significantly (P less than 0.05) increased the threshold for development of cardiac arrhythmias. Dynorphin A (1-13), 20 micrograms, increased the epinephrine dose at the occurrence of ventricular premature beats to 171 +/- 8 (mean +/- 1 S.E.M.) compared to 120 +/- 5 micrograms epinephrine/kg in the control group and increased the dose at the onset of fatal arrhythmias to 186 +/- 8 compared to 141 +/- 10 micrograms epinephrine/kg in the control group. The action of dynorphin was significantly (P less than 0.05) antagonized by the kappa opioid antagonist MR2266. Atropine sulfate, administered ICV or intravenously, produced a dose dependent antagonism of this action of dynorphin A (1-13). This was not due to the peripheral effects of atropine, as atropine methylnitrate, which does not cross the blood brain barrier, did not oppose the effects of dynorphin A (1-13). These data indicate (i) dynorphin A (1-13) increases the threshold for or suppresses the manifestations of epinephrine-induced ventricular arrhythmias, (ii) dynorphin's action on cardiac arrhythmias is mediated through central cholinergic rather than peripheral parasympathetic mechanisms (iii) dynorphin may play a role as an endogenous opioid within the brain that modulates cardiac arrhythmias in circumstances of elevated circulating epinephrine concentration.     

Antidote effect of sodium fluoride against organophosphate poisoning in mice

Pretreatment of mice with atropine (17.4 mg/kg) + NaF (5 or 15 mg/kg) had a significant antidotal effect over atropine alone against the lethality produced by soman and sarin. Atropine + NaF (15 mg/kg) was effective against tabun, whereas the lower dose of NaF was not. An effect of NaF on organophosphate inhibited acetylcholinesterase could not account for the antidotal action of NaF. NaF had no effect on liver somanase activity but inhibited aliesterase activity. Aliesterase activity in NaF pretreated somanpoisoned mice was significantly (p < 0.05) higher than in those receiving atropine alone. In CBDP-pretreated mice NaF did not significantly attenuate the toxicity of soman. It is hypothesized that the antidotal effect of NaF versus organophosphate poisoning is due to its antidesensitizing action at nicotinic receptors in the neuromuscular junction and/or sympathetic ganglia in addition to the proposed increased hydrolysis of sarin and direct detoxification of tabun.     

香水莲花提取物对东莨菪碱诱导记忆障碍小鼠学习记忆能力的影响

探究香水莲花提取物(Nymphaea hybrid extract,NHE)对东莨菪碱诱导记忆障碍小鼠的学习记忆能力的影响。采用腹腔注射东莨菪碱建立记忆障碍模型,Morris水迷宫实验测定小鼠空间学习和记忆能力。水迷宫实验结束后,断头处死小鼠,进行生化指标的测定。结果表明,与模型组小鼠相比,NHE干预后,小鼠的逃避潜伏期明显缩短(P <0. 01),目标象限停留时间百分比和穿越平台次数增加(P <0. 05或P <0. 01),小鼠海马和皮质区的SOD和GSH-PX活力显著升高(P <0. 01或P <0. 05),MDA含量极显著降低(P <0. 01),ACh E活性显著降低(P <0. 01),ACh含量增加(P <0. 01或P <0. 05)。同时,免疫印迹结果表明,NHE能够改善东莨菪碱引起小鼠海马和皮质中ERK、CREB磷酸化水平和BDNF蛋白表达的减少。综上,香水莲花提取物可以提高东莨菪碱诱导的记忆障碍小鼠的学习记忆能力,具体机制涉及缓解大脑的氧化应激损伤,平衡胆碱能系统,激活ERK-CREB-BDNF信号通路。