Oral administration of γ-aminobutyric acid affects heat production in a hot environment in resting humans
© Miyazawa et al; licensee BioMed Central Ltd. 2012
Received: 9 June 2011
Accepted: 29 February 2012
Published: 29 February 2012
Central administration of γ-amino butyric acid (GABA) induces lower body temperature in animals in hot ambient air. However, it is still unknown whether oral GABA administration affects temperature regulation at rest in a hot environment in humans. Therefore, in the present study, we specifically hypothesized that systemic administration of GABA in humans would induce hypothermia in a hot environment and that this response would be observed in association with decreased heat production.
Eight male participants drank a 200-ml sports drink with 1 g of GABA (trial G) or without GABA (trial C), then rested for 30 minutes in a sitting position in a hot environment (ambient air temperature 33°C, relative humidity 50%).
We found that changes in esophageal temperature from before drinking the sports drink were lower in trial G than in trial C (-0.046 ± 0.079°C vs 0.001 ± 0.063°C; P < 0.05), with lower heat production calculated by oxygen consumption (41 ± 5 W/m2 vs 47 ± 8 W/m2; P < 0.05).
In this study, we have demonstrated that a single oral administration of GABA induced a larger decrease in body core temperature compared to a control condition during rest in a hot environment and that this response was concomitant with a decrease in total heat production.
Keywordssweat rate rest temperature regulation esophageal temperature
γ-aminobutyric acid (GABA) is an amino acid that is widely distributed throughout the central nervous system (CNS) and is the most important depressive neurotransmitter . GABA has important roles concerning temperature regulation in the hypothalamus. In experimental animals, it has been reported that central pharmacological stimulation of GABA in the dorsomedial hypothalamus (DMH) and the posterior hypothalamus (PH) inhibits heat production [2, 3]. On the contrary, it has been reported that central pharmacological stimulation of GABA in the preoptic (PO) area and anterior hypothalamus (AH) increases heat production [4, 5]. On the basis of these reports, it is assumed that central GABA stimulation to the hypothalamic region has some practical effect on temperature regulation.
Few studies have examined the influence of systemic GABA stimulation on temperature regulation in either experimental animals or humans because the blood-brain barrier is impermeable to GABA  and it has long been thought that systemic administration of GABA cannot affect GABA's availability in the CNS [7, 8]. However, it has been suggested that GABA could access certain areas of the brain that lack the blood-brain barrier [9–11], such as the hypothalamus. Therefore, it is expected that systemically administered GABA affects GABA's availability in the hypothalamus and may have effects on the responses of temperature regulation in humans, as reported with regard to central pharmacological stimulation in experimental animals.
On the basis of a previous study conducted in our laboratory, we have reported that oral GABA administration might induce lower core temperature during rest under a hot environment . However, because our previous study was focused on the effect of oral GABA administration during exercise, we derived insufficient data to clarify the effect of oral GABA administration during rest. For example, the elapsed time from GABA administration differed among the subjects because the beginning of the rest period was determined to be the time at which the core temperature returned to the baseline level after sample ingestion. Furthermore, it is thought that subjects were under a certain amount of mental or physical stress because they maintained a semirecumbent position with their feet on riding pedals to be ready for exercise and had a catheter inserted into the left antecubital vein for blood sampling. Such physical and/or mental stresses could affect physiological parameters. Therefore, it is still unknown whether oral GABA administration affects temperature regulation at rest in a hot environment. In the present study, we specifically hypothesized that systemic administration of GABA in humans would induce hypothermia in a hot environment and that this response would be observed in association with decreased heat production. To test these hypotheses in the present study, we compared temperature-regulatory responses in resting humans in a hot environment between two trials: after oral GABA administration and after placebo administration. If we could detect the hypothermic effect of systemic administration of GABA in a hot environment in humans, we expected that oral GABA administration would be used to prevent hyperthermia and the resulting heat disorders that occur during high-temperature conditions, such as during the summer.
Eight healthy nonsmoking men who usually exercised 3 to 5 days per week were included in this study. Their physical characteristics were age 23.5 ± 3.6 years, height 172.6 ± 3.5 cm, weight 66.9 ± 7.4 kg, body mass index 22.5 ± 2.7 kg/m2 (all means ± SD). Written informed consent was obtained from all participants before participation in this study. The study protocol and the informed consent forms, which conformed to the guidelines of the Declaration of Helsinki, were approved by the Ethics Committee of the Graduate School of Medicine at Osaka City University.
This study was carried out using a placebo-controlled, double-blind design. The participants randomly performed two trials, a control trial (trial C) and a GABA trial (trial G). The trials were conducted at the same time of day with an interval of at least 3 days between trials to avoid the influence of circadian variation. All experiments were conducted in the morning during the winter season (from January to March). The participants ingested a 200-ml sports drink (placebo) in trial C and a 200-ml sports drink containing 1 g of GABA (GABA drink) in trial G. The dose was the maximal consumption of GABA for a single ingestion (Japan Standard Commodity Classification 872199). Both the placebo and the GABA drink were stored at room temperature controlled at 23°C to 25°C. We checked and confirmed that the temperature of each fluid was 21°C to 23°C before the participants drank it. The sports drink (200 ml) provided 30 kcal of energy, 7.4 g of carbohydrate, 0 g of protein and 0 g of fat.
The participants were requested to refrain from consuming food or drink for at least 12 hours and to avoid caffeinated beverages, alcohol and strenuous physical activity for at least 24 hours before each experiment. Consumption of drinking water was permitted as required. The participants reported to the laboratory at 10:00 AM. They were asked to drink water (200 ml) and then sit for 30 minutes to achieve a normal body fluid balance. They then voided, were weighed in the nude and were provided a pair of shorts. They then swallowed an esophageal thermistor. Subsequently, they entered the climatic chamber (TBR-6W2S2L2M; ESPEC Corp, Osaka, Japan) maintained at an ambient temperature (Ta) of 33°C and 50% relative humidity. The participants sat for 1 hour on chairs without backrests while measurement devices were positioned. After baseline data correction for 5 minutes and confirmation of stable physiological responses before drinking, the participants ingested the placebo in trial C and the GABA drink in trial G within 1 minute. They were then instructed to rest in a sitting position for 30 minutes. Because we had confirmed that plasma GABA concentration increased after oral administration of GABA, peaked 20 to 40 minutes after ingestion and maintained significantly higher levels than the baseline for at least 1 hour , we set the rest period for 30 minutes in this study. During the rest period, an examiner in close proximity to each subject paid close attention to prevent a reduction in the subject's arousal level by checking the subject's heart rate and facial expression. After the rest period, the monitoring instruments were promptly removed, and the participants exited the chamber, wiped themselves down and were weighed again in the nude to estimate total sweat loss.
Ta was measured using a thermister (LT-ST08-12; Gram Co) in the climate chamber at the same level of the chest thermister. The precision of LT-ST08-11 and LT-ST08-12 was ± 0.01°C. Heart rate (HR) measured by electrocardiography and blood pressure measured by oscillometry were measured noninvasively every minute (BSM-4103; Nihon-Kohden, Tokyo, Japan). Mean arterial pressure (MAP) was calculated as one-third of the pulse pressure plus the diastolic blood pressure. Skin blood flow was measured on the chest (SkBFchest) on the left side by laser Doppler flowmetry (ALF21D; Advance, Tokyo, Japan). Sweat rate was measured on the chest (SRchest) on the left side using the ventricular capsule method (SS-100ΙΙ; K and S, Aichi, Japan). The flow rate and duration of air ventilation before starting measurement were 0.3 ml/minute and 10 minutes, respectively. The precision of the SS-100ΙΙ for SR measurements was ± 3% within the range of 0 to 5 mg/cm2/minute. For each participant, the probe and capsule were placed on the skin at identical sites in both trials. Data for Tes, skin temperature, Ta, SkBFchest and SRchest were collected at intervals of 1 second using a 16-channel computerized data acquisition system (Intercross-310; Intercross Co, Tokyo, Japan) and stored in data files on a laboratory computer (JPA32301WP; Hewlett-Packard Japan Ltd, Tokyo, Japan). Oxygen consumption (VO2) was measured at 20-second intervals using a metabolic gas analyzer system (Vmax Encore 29 System; VIASYS Healthcare, Inc, Yorba Linda, CA, USA). The coefficient of variation for VO2 measurement by the Vmax Encore 29 System was 3%. Total sweat loss was estimated by determining the change in dry body weight (BW), which was measured immediately before and after the experiment as (BWbefore) - (BWafter) + 200 g (weight of drink). There was no significant difference in BWbefore between trial C and trial G (66.96 ± 7.47 kg vs 66.88 ± 7.45 kg; P = 0.36).
The absolute values and the changes from baseline of Tes and Tsk between 30 minutes of rest were compared between trials. SkBFchest values were expressed as percentage changes from the value before drinking (%SkBFchest = (SkBFchest/before drinking SkBFchest) × 100) because absolute values within an individual can vary markedly over the surface of the skin . We averaged the recorded signals in 5-minute time windows.
where RER is the respiratory exchange ratio, VO2 is oxygen uptake, Ad is body surface area and 5.873 is oxygen energy equivalent. Heat loss and production were calculated every 1 minute and averaged over time windows of 5 minutes and per 30 minutes.
Two-way (trial-by-time) repeated-measures analysis of variance (ANOVA) was performed to test the effects of GABA administration over time. Subsequent post hoc tests to determine significant differences in the various pairwise comparisons were performed using Tukey's post hoc test. There was a transient reduction in Tes after drinking. This response may be due to the sample ingestion and may not be related to GABA effect. Furthermore, this outlier might disturb the interpretation of our statistical analysis. Therefore, the data for Tes at 5 minutes were excluded from statistical analyses. A paired t-test was used to assess differences in heat production, heat loss and total sweat loss between trials. These statistical analyses were computed using SigmaStat version 3.5 software (Systat Software Inc, Chicago, IL, USA). P < 0.05 was considered statistically significant. The data are presented as means ± SD unless stated otherwise.
125 ± 49
112 ± 19
0.14 ± 0.05
0.22 ± 0.13
0.27 ± 0.20
0.23 ± 0.12
70 ± 7
71 ± 12
72 ± 11
75 ± 14
80 ± 9
71 ± 9b
78 ± 9
70 ± 10b
The major findings of the present study are that oral administration of GABA induced a decrease in body core temperature compared to control conditions during rest in a hot environment and that this response was concomitant with a decrease in total heat production.
The most intriguing result of the present study is that the ΔTes values in trial G at 25 to 30 minutes were significantly lower than those in trial C, as shown in Figure 1, suggesting that oral administration of GABA induced responses to decrease body core temperature in resting humans in a hot environment. In the conditions of the present study, body core temperature was determined by the balance of heat production with resting metabolism and heat gain from or loss to the environment, such as by radiant, convective and evaporative heat exchange . As shown in Figures 4 and 5, although there were no significant differences in the time course of heat production between trial C and trial G, we observed that heat production averaged per 30 minutes in trial G was lower than that in trial C. Furthermore, although there were no significant differences, the mean data of VO2 in trial G were lower than those in trial C from 15 minutes (Figure 3). These data suggest that oral administration of GABA decreased heat production with lowering resting metabolism and therefore decreased the body core temperature. However, it is still unknown how the differences in heat production contribute to the differences in body core temperature. Further studies are needed to more clearly explain the relation between heat production and body core temperature changes.
The responses of ΔTes and heat production with oral administration in the present study are experimentally similar to previous observations in animals by showing that central pharmacological stimulation of GABA in the DMH and PH inhibits heat production [2, 3]. Neurons in the DMH play key roles in temperature regulation. The activation of DMH elevates core temperature and sympathetic activity to interscapular brown adipose tissue in conscious rats. Microinjection of the GABAA receptor agonist muscimol into DMH suppresses increases in sympathetic nerve activity to interscapular brown adipose tissue. In a similar way, the PH can activate an autonomic mechanism controlling heat production in brown adipose tissue. Furthermore, the neural mechanism in the PH mediating this effect is tonically inhibited by GABA. Thus the observations that we present indirectly support the hypothesis that orally administered GABA circulates in the bloodstream and affects GABA concentration and/or the activation of GABA function in the CNS through the region which lacks the blood-brain barrier [9–11] and induces the same effects for the region relating to temperature regulation, such as DMH and PH. However, we found no evidence that orally administered GABA affected central GABA concentration or function in either animals or humans. Additionally, it has been reported in animal studies that when the GABA agonist muscimol perfuses into the PO/AH, heat production and body core temperature are increased in various environmental conditions [4, 5]. Therefore, further studies are necessary to elucidate the relationship between the oral administration of GABA and central GABA function in humans as well as in animals.
The present study has some limitations. First, we did not measure plasma GABA concentrations. We confirmed that plasma GABA concentrations increased after oral administration of GABA, peaked 20 to 40 minutes after ingestion and maintained significantly higher levels than the baseline for at least 1 hour . Therefore, to diminish any subject's stress as a result of placing the catheter, we set a rest period of 30 minutes in this study by reference to the previous study. Second, we verified the effect of only one amount of GABA. To clarify the whole picture of the effect of GABA, it is necessary to investigate the effect of other amounts of GABA and reveal the concentration dependency.
In this study, we have demonstrated that a single oral administration of GABA induced a decrease in body core temperature compared to control condition during rest in a hot environment and that this response was concomitant with a decrease in total heat production.
rate of convective heat loss
central nervous system
rate of evaporative heat loss
γ-amino butyric acid
convective coefficient of heat transfer
evaporative coefficient of heat transfer
conductive coefficient of heat transfer
radiant coefficient of heat transfer
rate of conductive heat loss
metabolic energy production
mean arterial pressure
vapor pressure of room air
saturated vapor pressure
rate of radiant heat loss
respiratory exchange ratio
chest skin blood flow
chest sweat rate
upper-arm skin temperature
chest skin temperature
leg skin temperature
mean skin temperature
thigh skin temperature
We thank the subjects for participating in this study. We also thank Dr Okumoto for the helpful comments on and discussion of this study.
- Awapara J: Occurrence of free γ-aminobutyric acid in brain and its formation from L-glutamic acid. Tex Rep Biol Med. 1950, 8: 443-447.PubMedGoogle Scholar
- Dimicco JA, Zaretsky DV: The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol. 2007, 292: R47-R63.View ArticlePubMedGoogle Scholar
- Amir S: Activation of brown adipose tissue thermogenesis by chemical stimulation of the posterior hypothalamus. Brain Res. 1990, 534: 303-308. 10.1016/0006-8993(90)90145-2.View ArticlePubMedGoogle Scholar
- Ishiwata T, Saito T, Hasegawa H, Yazawa T, Kotani Y, Otokawa M, Aihara Y: Changes of body temperature and thermoregulatory responses of freely moving rats during GABAergic pharmacological stimulation to the preoptic area and anterior hypothalamus in several ambient temperatures. Brain Res. 2005, 1048: 32-40. 10.1016/j.brainres.2005.04.027.View ArticlePubMedGoogle Scholar
- Osaka T: Cold-induced thermogenesis mediated by GABA in the preoptic area of anesthetized rats. Am J Physiol Regul Integr Comp Physiol. 2004, 287: R306-R313. 10.1152/ajpregu.00003.2004.View ArticlePubMedGoogle Scholar
- Kuriyama K, Sze PY: Blood-brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals. Neuropharmacology. 1971, 10: 103-108. 10.1016/0028-3908(71)90013-X.View ArticlePubMedGoogle Scholar
- Roberts E, Baxter CF: Metabolic studies of γ-aminobutyric acid. Neurology. 1958, 8: 77-78.View ArticlePubMedGoogle Scholar
- Tsukada Y, Nagata Y, Hirano S: Active transport of γ-aminobutyric acid in brain cortex slices, with special reference to phosphorus-32 turnover of phospholipids in cytoplasmic particulates. Nature. 1960, 186: 474-475. 10.1038/186474a0.View ArticlePubMedGoogle Scholar
- Van Gelder NM, Elliott KA: Disposition of γ-aminobutyric acid administered to mammals. J Neurochem. 1958, 3: 139-143. 10.1111/j.1471-4159.1958.tb12620.x.View ArticlePubMedGoogle Scholar
- Biswas B, Carlsson A: The effect of intraperitoneally administered GABA on brain monoamine metabolism. Naunyn Schmiedebergs Arch Pharmacol. 1977, 299: 47-51. 10.1007/BF00508636.View ArticlePubMedGoogle Scholar
- Cavagnini F, Invitti C, Pinto M, Maraschini C, Di Landro A, Dubini A, Marelli A: Effect of acute and repeated administration of γ aminobutyric acid (GABA) on growth hormone and prolactin secretion in man. Acta Endocrinol (Copenh). 1980, 93: 149-154.Google Scholar
- Miyazawa T, Kawabata T, Suzuki T, Imai D, Hamamoto T, Yoshikawa T, Miyagawa T: Effect of oral administration of GABA on temperature regulation in humans during rest and exercise at high ambient temperature. Osaka City Med J. 2009, 55: 99-108.PubMedGoogle Scholar
- Ramanathan NL: A new weighting system for mean surface temperature of the human body. J Appl Physiol. 1964, 19: 531-533.PubMedGoogle Scholar
- Johnson JM, Taylor WF, Shepherd AP, Park MP: Laser-Doppler measurement of skin blood flow: comparison with plethysmography. J Appl Physiol. 1984, 56: 798-803. 10.1063/1.334009.View ArticlePubMedGoogle Scholar
- Gagge AP, Gonzalez RR: Mechanisms of heat exchange: biophysics and physiology. Handbook of Physiology, Section 4. Environmental Physiology. Edited by: Fregly MS, Blatteis CM. 1996, New York: Oxford University Press, 45-84.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.