Glucose attenuation of atropine-induced deficits in paradoxical sleep and memory

When administered systemically, glucose attenuates deficits in memory produced by several classes of drugs, including cholinergic antagonists and opiate agonists. Glucose also enhances memory in aged rats, mice, and humans. In addition, glucose ameliorates age-related reductions in paradoxical sleep. Because deficits in paradoxical sleep are most marked in those individual aged rats that also have deficits in memory, treatments which improve one of these functions may similarly improve the other. The present experiments show that glucose attenuates deficits in paradoxical sleep and memory after atropine administration, with similar dose-response curves for both actions. In the first experiment, rats received saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100, 250, and 500 mg/kg) 30 min before assessment on a spontaneous alternation task. In the second experiment, 3-h EEGs were assessed for spontaneous daytime sleep in rats administered saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100 and 250 mg/kg). In both experiments, glucose significantly attenuated deficits at an optimal dose of 100 mg/kg. A third experiment assessed blood glucose levels after injections of atropine + glucose (100 mg/kg) and determined that blood glucose levels were similar to those produced by other treatments which enhance memory. These results are consistent with the view that paradoxical sleep and at least one test of memory are similarly influenced by atropine and glucose.     

Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia, and high serum creatine phosphokinase level

The neuroleptic malignant syndrome (NMS) is a life-threatening complication of neuroleptic treatment. To elucidate the pathogenesis of NMS, an animal model has been developed. Experimental rabbits treated with haloperidol (1 mg/kg) by intramuscular injection, were studied for the diagnostic symptoms of increased muscle rigidity, elevated body temperature, and high serum creatine phosphokinase (CPK) level. Administration of haloperidol (1 mg/kg) and atropine (0.4 mg/kg), and exposure to high ambient temperature (35°C) induced a significant increase in electromyographic activity with muscle rigidity similar to that observed in patients with NMS. Such rabbits also showed elevated body temperature and serum CPK value. In addition to the similarity of the signs and symptoms, all parameters measured (muscle rigidity, body temperature, and serum CPK level) were normalized by dantrolene treatment. The effectiveness of dantrolene in the experimental animal partially confirms the validity of this animal model for NMS. This experimental animal model for NMS may be useful to elucidate the pathogenesis of NMS.     

Influence of acetylcholine on neuronal activity of monkey amygdala during bar press feeding behavior

Single neuron activity in the monkey amygdala was investigated during cue signalled conditioned bar press feeding behavior and the effects of electrophoretically applied acetylcholine (ACh) and atropine were analyzed. ACh increased the firing rate of one third of the neurons tested; these excitatory responses were inhibited by the muscarinic receptor antagonist atropine. No characteristic location of ACh-sensitive neurons was found, cells were diffusely distributed throughout the amygdala. Activity of ACh-sensitive neurons did not correlate with any particular event during the bar press feeding task. However, continuous application of ACh at low current intensity during the task significantly enhanced the task-related excitatory firing patterns, or markedly attenuated the inhibitory responses. Continuous application of atropine elicited or enhanced inhibitory response patterns. These results suggest that the cholinergic system of the monkey amygdala facilitates neuronal excitation but attenuates inhibition related to various phases of feeding behavior, such as to cue recognition, food aquisition and rewarding process.     

Hippocampal EEG responses induced by carbachol and atropine infusions into the septum and the hippocampus in the urethane-anaesthetized rat

Infusion of 1 μg of carbachol, a potent cholinergic agonist, into the lateral septum of the urethane-anaesthetized rat systematically caused the induction of clear-cut hippocampal theta (θ). However, infusion of an equivalent amount of the drug into the hippocampus, close to the recording electrode, failed to induce θ in 50% of the animals and produced a mixture of θ waves and desynchronized activity, resulting in atypical EEG patterns, in the remaining subjects. Both carbachol EEG effects were blocked by intraseptal infusion of the antimuscarinic agent, atropine. Our data demontrate that muscarinic receptors in the septum are predominent sites for cholinergic agonist-antagonist action capable of generating or suppressing hippocampal θ in the rat. They also indicate that intraseptal cholinergic mechanisms play an important role in the initiation and generation of this rhythm.     

Spinal cholinergic and monoamine receptors mediate the antinociceptive effect of morphine microinjected in the periaqueductal gray on the rat tail, but not the feet

The antinociceptive effects of morphine (5 μg) microinjected into the ventrolateral periaqueductal gray were determined using both the tail flick and the foot withdrawal responses to noxious radiant heating in lightly anesthetized rats. Intrathecal injection of appropriate antagonists was used to determine whether the antinociceptive effects of morphine were mediated byα₂-noradrenergic, serotonergic, opioid, or cholinergic muscarinic receptors. The increase in the foot withdrawal response latency produced by microinjection of morphine in the ventrolateral periaqueductal gray was reversed by intrathecal injection of the cholinergic muscarinic receptor antagonist atropine, but was not affected by the a2-adrenoceptor antagonist yohimbine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In contrast, the increase in the tail flick response latency produced by morphine was reduced by either yohimbine, methysergide or atropine. These results indicate that microinjection of morphine in the ventrolateral periaqueductal gray inhibits nociceptive responses to noxious heating of the tail by activating descending neuronal systems that are different from those that inhibit the nociceptive responses to noxious heating of the feet. More specifically, serotonergic, muscarinic cholinergic andα₂-noradrenergic receptors appear to mediate the antinociception produced by morphine using the tail flick test. In contrast, muscarinic cholinergic, but not monoamine receptors appear to mediate the antinociceptive effects of morphine using the foot withdrawal response.     

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.     

Marked locomotor stimulation in monoamine-depleted mice following treatment with atropine in combination with clonidine

Summary The present study demonstrates that the muscarinic antagonist atropine and the -adrenergic agonist clonidine, though ineffective when administered separately, produced a pronounced locomotor stimulation in monoamine-depleted mice when combined. The atropine + clonidine-induced locomotor stimulation was counteracted by both the ₂-adrenoceptor antagonist idazoxan and the acetylcholinesterase inhibitor physostigmine. Thus, it is clear that simultaneous manipulations with cholinergic and adrenergic systems are as effective in restoring locomotion in monoamine-depleted mice as increasing central dopaminergic tone. This finding may have implications for the treatment of a movement disorder like Parkinson's disease.     

Effects of Atropine and Β-blockade on temperature regulation and performance during prolonged exercise

Summary The effects of intravenous injections of Atropine (1.8 mg) and practolol (15 mg) on the thermoregulatory responses to 1 h of exercise on a motordriven treadmill have been investigated on six healthy subjects.The results show that -blockade had little effect on thermal responses to work except for a small but significant (p<0.05) decrease in mean skin temperature (¯T _sk ) and peripheral tissue heat conductance (K). Metabolic (M) and total heat (H) production, and evaporative sweat loss (E) and rectal temperature (T _re ) were similar to control values. In contrast, atropine, particularly at work loads beyond 60% maximal aerobic power output (VO_{2 max}), raised T _re (p<0.001), ¯T _sk (p<0.001) and reduced E by approximately 50%. At the highest work loads T _re increased as a linear function of time during the latter part of exercise, and at the 60th min was almost independent of relative stress (expressed as % VO_{2 max}) imposed on the subjects. At the lower work loads the majority of subjects reached thermal equilibrium before the end of exercise by maintaining their convective heat transfer from core to periphery by increasing peripheral blood flow (as indicated by K), and raising their heat losses to environment by convection and radiation. The latter pathways for heat dissipation were enhanced by the subjects ability to sustain a ¯T _sk 4 C above control values independently of M. Atropine had no effect on M or H but greatly affected work performance, no subject was able to exercise at loads >70% VO_{2 max} for 1 h. These results demonstrate the ability of the thermoregulatory system to adapt to -adrenergic and to parasympathetic blockade during light exercise, and underline the effects of a reduction in the capacity of the sweating mechanism on physiological performance at higher rates of work.List of Abbreviations used in the Text M Metabolic heat production - H Total heat production - E Evaporative sweat loss - T _re Rectal temperature - ¯T _sk Mean skin temperature - K Peripheral tissue heat conductance - PBF Peripheral blood flow - VO_{2 max} Maximal aerobic power output - f _H Cardiac frequency     

血液灌流对硫线磷和硫酸阿托品的吸附作用

目的 定量研究血液灌流对有机磷农药硫线磷和其解毒药阿托品的吸附作用.方法 模拟临床血液灌流装置,对含硫线磷和硫酸阿托品的血样进行灌流吸附,分别用毛细管气相色谱法和高效液相色谱法测定硫线磷和硫酸阿托品的残留量.结果 吸附剂用量为0.5、1.0和1.5 g,包膜活性炭在灌流2.0 h后硫线磷的清除率均能达到90%以上,硫酸阿托品的清除率依次为61.9%、84.9%和88.9%;HA230树脂在灌流1.5 h后硫线磷清除率都达到90%以上,硫酸阿托品的清除率也依次高达88.0%、97.2%和98.4%;包膜活性炭灌流3.0h后,硫酸阿托品与硫线磷的比值最高为灌流前的10.1倍,而HA230树脂灌流后,此比值最高为灌流前的6.7倍.结论 包膜活性炭和HA230吸附树脂血液灌流1.5～2.0 h均能清除血中大部分硫线磷,而且均能增加血中硫酸阿托品和硫线磷浓度的比值.     

Muscarinic modulation of calcium dependent plateau potentials in rat neostriatal neurons

Intracellular recording from neostriatal neurons in rat brain slices revealed effects of the acetylcholine (ACh) agonist carbachol (Cch, 1–10 mol/l), of the anticholinesterase physiostigmine (10 mol/l) and of the muscarinic antagonist atropine (10 mol/l) on plateau potentials elicited in the presence of K-blockers were Cadependent, elicited in the presence of K-blockers were Cadependent, since they persisted in Na-free solution, were resistant to tetrodotoxin (TTX, 3 mol/l) and blocked by Cd (0.1–0.5 mmol/l). Cch reduced the duration of the plateau potentials and made them more susceptible to fatigue. These effects were antagonized by atropine (1–10 mol/l), but not by Ba (100–200 mol/l) or 4-aminopyridine (4-AP, 0.5 mmol/l). Physostigmine (10 mol/l) had the same atropine-sensitive effects as Cch on the plateau potential. Atropine (10 mol/l), by itself, prolonged the duration of the plateau potential. High concentrations (100 mol/l) of Cch did not further reduce the duration of the plateau potential, instead, the duration re-increased with prolonged exposure. The re-increase of the plateau-spike duration was later masked by bursting activity. The opposing effects of low and high concentrations of Cch on the plateau potential duration corresponded to effects of this drug on intrastriatally evoked EPSPs in that low concentrations of Cch reduced the EPSP amplitude, but high concentrations re-increased it after a transient decrease. It is concluded that the muscarinic effect of Ach in the neostriatum is to modulate Ca-influx and that this effect is exerted in a tonic manner. On leave from absence from: Clinica Neurologica II, Universita di Roma. Tor Vergata, Roma, Italy.