To the Editor: 

We have read with great interest the recent article “Anesthetic Ketamine Impairs Rats' Recall of Previous Information: The Nitric Oxide Synthase N -nitro-L-arginine Methylester Antagonizes this Ketamine-induced Recognition Memory Deficit,”1and we would like to address some comments. This study stresses that nitric oxide metabolism may modify the anesthetic effects of ketamine. Although this relation has been described previously, the approach using the N -nitro-L-arginine methylester (a nonselective nitric oxide synthase inhibitor) to influence the cognitive deficits induced by the posttraining administration of ketamine was interesting. Moreover, these effects were observed only when associated with a change in room temperature, suggesting that this change is a key factor in this study.

This article referred to the hypothermic properties of ketamine; however, hypothermia is usually induced in laboratory animals by anesthetics in general. Boultadakis and Pitsikas suggested that the effects of ketamine in cognition were dependent on the room temperature. Importantly, body temperature values for the tested animals were not shown in this study; instead, the authors forward the readers to a previous article, in which initial and 120-min postadministration temperatures in similar conditions were reported.2Although we agree that the body temperature values for animals tested in this study are probably within the same interval as those reported previously, we strongly disagree that these measures may be sufficient. Mild hypothermia values were observed at 120 min after anesthesia in the ketamine group kept at 21°C when animals were already recovered. However, it is highly probable that these values may have been lower during the anesthesia period. Therefore, body temperature curves throughout time should have been registered. The report of the body temperature curve would also dissipate the doubts about a potential hypothermic period in the animals anesthetized in a room at 25°C. Moreover, it would be helpful to have the body temperature of the animals that received only N -nitro-L-arginine methylester, because this substance may have an effect on thermoregulation.3Ulugol and colleagues showed that high doses of ketamine and N -nitro-L-arginine methylester may cause hypothermia, indicating an involvement of the N -methyl-D-aspartate receptor and nitric oxide in the thermoregulation pathway.3The authors suggested that ketamine hypothermic properties at a room temperature of 21°C may exert neuroprotection; however, it would be interesting to consider the room temperature increase from 21°C to 25°C as a potential stressful event that increases brain vulnerability and may potentiate ketamine-induced deficit.4 

It is important to notice that in laboratory animal practice, anesthesia must always be performed under controlled temperature by using a homeothermic blanket connected to a rectal probe. However, the measurement of rectal temperature in awake animals could cause stress and consequently may influence body temperature.5To avoid the stress of a rectal probe, the temperature data of an awake rat could be obtained using subcutaneous probes or digital scanners.6 

Clinical observations, such as respiratory rate, heart rate, and blood pressure, should have been reported because N -nitro-L-arginine methylester may induce hypertension; moreover, these hemodynamic parameters may influence the outcome of the study because of potential differences between groups.

Finally, we would like to highlight some differences between humans and animals. This article stresses the hypothermic properties of ketamine and its negative impact on the information previously learned by rats, whereas in humans, ketamine revealed no impairment in retrieval7and is known to reduce the possibility of hypothermia.8 

In summary, our main concerns are related with the lack of data regarding body temperature and clinical information. Possible differences between temperature evolution within groups during the 120-min period may have influenced the results of the study.

Boultadakis A, Pitsikas N: Anesthetic ketamine impairs rats' recall of previous information: The nitric oxide synthase inhibitor N -nitro-L-arginine methylester antagonizes this ketamine-induced recognition memory deficit. ANESTHESIOLOGY 2011; 114:1345–53
Boultadakis A, Pitsikas N: Effects of the nitric oxide synthase inhibitor L-NAME on recognition and spatial memory deficits produced by different NMDA receptor antagonists in the rat. Neuropsychopharmacology 2010; 35:2357–66
Ulugol A, Dost T, Dokmeci D, Akpolat M, Karadag CH, Dokmeci I: Involvement of NMDA receptors and nitric oxide in the thermoregulatory effect of morphine in mice. J Neural Transm 2000; 107:515–21
Kiyatkin EA, Brown PL, Wise RA: Brain temperature fluctuation: A reflection of functional neural activation. Eur J Neurosci 2002; 16:164–8
Poole S, Stephenson JD: Core temperature: Some shortcomings of rectal temperature measurements. Physiol Behav 1977; 18:203–5
Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Barata JC, Fernandes E, Bastos Mde L, Tavares MA, Carvalho F: Monoamine oxidase-B mediates ecstasy-induced neurotoxic effects to adolescent rat brain mitochondria. J Neurosci 2007; 27:10203–10
Morgan CJ, Curran HV: Acute and chronic effects of ketamine upon human memory: A review. Psychopharmacology 2006; 188:408–24
Ikeda T, Kazama T, Sessler DI, Toriyama S, Niwa K, Shimada C, Sato S: Induction of anesthesia with ketamine reduces the magnitude of redistribution hypothermia. Anesth Analg 2001; 93:934–8