Correspondence  |   January 2012
In Reply
Author Affiliations & Notes
  • Nikolaos Pitsikas, Ph.D.
  • *School of Medicine, University of Thessaly, Larissa, Greece.
Article Information
Correspondence   |   January 2012
In Reply
Anesthesiology 1 2012, Vol.116, 227-229. doi:10.1097/ALN.0b013e31823d0d7a
Anesthesiology 1 2012, Vol.116, 227-229. doi:10.1097/ALN.0b013e31823d0d7a
We thank Dr. Valentim et al  . for their comments about our article.1 In that work, we did not seek to determine the effects produced by hypothermic ketamine on memory. We sought to investigate the effects of posttraining administration of anesthetic ketamine on rats' recognition memory and to evaluate whether the nitric oxide synthase inhibitor N  -nitro- L-arginine methylester (L-NAME) was able to reverse the expected behavioral effects produced by anesthetic ketamine. In designing and performing this study, we had two main targets: (1) a clinically relevant amnestic animal model and (2) producing a behavioral outcome not confounded by other not cognitive parameters (hypothermia, sensory motor factors, etc  .). Therefore, anesthetic ketamine's effects on rats' memory abilities were evaluated using the novel object recognition task, a behavioral procedure that reflects episodic memory in rodents,2 a type of memory impaired by ketamine in humans.3 Moreover, because ketamine induces hypothermia in rodents, but not in humans,4 it was mandatory for us to assess the effects of anesthetic ketamine on rats' recognition memory using a condition in which the drug did not display a hypothermic profile. This issue has been investigated in a previous study in which it was revealed that maintaining the animals for 2 h after drug administration at 25°C, but not at 21°C, caused recognition memory deficits without inducing hypothermia.5 Because the condition of 25°C seems to produce results similar to those obtained in humans,3,4 it was chosen for the current experiment.1 Data presented here are in line with studies carried out in humans3 and in rats.5 
We do not agree with the authors' assertion that “this study stresses that nitric oxide metabolism may modify the anesthetic effects of ketamine. Although this relation has been described previously ….” Valentim et al  ., did not provide any source of information about their statement (where has this relation been described?). In contrast to this assertion, the findings reported in our article are innovative because it is the first time to our knowledge that the effects of anesthetic ketamine on posttraining memory components (storage and/or retrieval of information) were studied in a recognition memory task in the rat.
Valentim and colleagues correctly claim that rectal temperatures of rats were not recorded in the current work. We did not record animals' body temperatures because our electrical thermometer was out of order. Thus, we referred readers to a previous study of ours5 (reference 2 of the Letter to Editor by Valentim et al  . is incorrect) in which the rectal temperatures of animals were registered.
Valentim et al  . underlined the absence of animals' body temperature curves throughout time in our work. This was not the aim of our study. For us, it was of high priority to establish an environmental condition in which anesthetic ketamine did not induce hypothermia and produced memory impairments in rats. However, we recognize that it would be useful to consider additional experiments that expand our understanding of the role of hypothermia on the effects exerted by anesthetic ketamine on cognition.
Valentim et al  . pointed out a potential action exerted by L-NAME on thermoregulation. They cited a report6 in which L-NAME was found to induce hypothermia in mice at 30 and 100 mg/kg, much higher doses than those we used (1–10 mg/kg) in rats in the current article. Moreover, studies carried out in rats have demonstrated that L-NAME has no effect on rats' body temperatures.7,8 The latter reports7,8 were unfortunately overlooked by Dr. Valentim and colleagues. This issue has been commented on in the Discussion section of our article.
Concerning the issue that shifting the room temperature from 21°C to 25°C might be a potentially stressful event, this cannot be excluded. This potential stressful effect could occur in all animals independently of treatment if this hypothesis is valid. We previously observed that vehicle-treated animals did not display higher rectal temperatures at 25°C with respect to those expressed by vehicle-treated rats at 21°C.5 In addition, there is no experimental evidence that ketamine could act in this way.
We agree with the authors' observation that “measurement of rectal temperature in awake animals could cause stress and consequently may influence body temperature”. Unfortunately, we did not have available the means (isothermic blankets, subcutaneous probes, or digital parameters) to conduct these measurements. However, we believe that this stress might be common for all rats independently of treatment.
Valentim et al  . observed that we did not report clinical information concerning the effects of L-NAME on blood pressure. That L-NAME produces hypertension and bradycardia both in humans and rodents is well known. However, we do not intend to report available clinical information about the effects of this nitric oxide synthase inhibitor on blood pressure. The aim of our work was to evaluate whether a potential hypertensive action of L-NAME might have confounded the behavioral outcome of the current study. Thus, the hypertensive properties of L-NAME were taken into consideration in our work and extensively commented on in the Discussion section of our article. The results of our study demonstrated that behavioral consequences caused by a potential L-NAME–induced hypertensive effect likely can be excluded.
A further point is that Valentim et al  . wonder why we did not include information on the effects of ketamine upon human memory in our article (see the excellent review by Morgan et al  .).3 This point is well taken. We did not comment on clinical studies for several reasons. First, those studies do not deal with the amnestic effects of anesthetic ketamine. Second, we preferred to discuss our data with respect to available literature on the role exerted by anesthetic ketamine on rodents' memory.
Finally, the authors correctly report that ketamine does not disrupt retrieval of information in healthy volunteers.3 The role of ketamine on retrieval abilities of rodents is not yet clarified. In our article, we assessed whether anesthetic ketamine affected the retention trial of the novel object recognition test. Because treatment was applied just after the last sample trial and retention was studied 24 h later, it was impossible to determine on which specific posttraining memory component (storage and/or retrieval) ketamine was acting. Thus, in our work we always strictly referred to “posttraining memory components.”
In short, it must be realized that, based on the available clinical information, the purpose of our study was first, to create an adequate amnestic animal model, with good clinical relevance, with the aim of studying the effects of anesthetic ketamine and L-NAME on rats' recognition memory, and second, to obtain a behavioral outcome not confounded by factors other than cognitive ones.
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