Voluntary alcohol intake after noise exposure in adolescent rats: Hippocampal-related behavioral alterations.

Different physical or chemical agents, such as noise or alcohol, can induce diverse behavioral and biochemical alterations. Considering the high probability of young people to undergo consecutive or simultaneous exposures, the aim of the present work was to investigate in an animal model if noise exposure at early adolescence could induce hippocampal-related behavioral changes that might be modified after alcohol intake. Male Wistar rats (28-days-old) were exposed to noise (95-97 dB, 2 h). Afterwards, animals were allowed to voluntarily drink alcohol (10% ethanol in tap water) for three consecutive days, using the two-bottle free choice paradigm. After that, hippocampal-related memory and anxiety-like behavior tests were performed. Results show that whereas noise-exposed rats presented deficits in habituation memory, those who drank alcohol exhibited impairments in associative memory and anxiety-like behaviors. In contrast, exposure to noise followed by alcohol intake showed increases in exploratory and locomotor activities as well as in anxiety-like behaviors, unlike what was observed using each agent separately. Finally, lower levels of alcohol intake were measured in these animals when compared with those that drank alcohol and were not exposed to noise. Present findings demonstrate that exposure to physical and chemical challenges during early adolescence might induce behavioral alterations that could differ depending on the schedule used, suggesting a high vulnerability of rat developing brain to these socially relevant agents.

D-serine: a new word in the glutamatergic neuro-glial language.

Gliotransmission is a process in which astrocytes are dynamic elements that influence synaptic transmission and synaptogenesis. The best-known gliotransmitters are glutamate and ATP. However, in the past decade, it has been demonstrated that D-serine, a D-amino acid, acts as a gliotransmitter in glutamatergic synapses. The physiological relevance of D-serine is sustained by the way in which it modulates the action of glutamatergic neurotransmission, neuronal migration and long-term potentiation (LTP). In addition, the synthesis and degradation mechanisms of D-serine have been proposed as potential therapeutic targets for the treatment of Alzheimer's disease, schizophrenia and related disorders. In the present review, detailed information is provided about the physiological and physiopathological relevance of D-serine, including metabolic and regulation aspects.

Memory consolidation and reconsolidation of an inhibitory avoidance task in mice: effects of a new different learning task.

CF-1 male mice were trained in an inhibitory avoidance task using a high footshock (1.2mA, 50Hz, 1 s) in order to reduce the influence of extinction on retention performance. A single session of 5 min exposure to a hole-board (nose-poke behavior), either immediately after training or the first retention test (memory reactivation) impaired retention performance over two consecutive days. The effects were time-dependent since they were not observed when the exposure to the hole-board was delayed 3 h. When mice were habituated to the hole-board (5 min/day, 5 days), and then trained in an inhibitory avoidance task, the immediately post-training or memory reactivation exposure to the hole-board did not modify retention performance over two consecutive days. The effects of the post-reactivation acute exposure to the hole-board were long-lasting (21 days). Reinstatement was not observed in our experimental conditions. The non-spontaneous recovery of retention performance over 21-days and the lack of reinstatement, suggest that the impairment of retention performance observed was not probably due to a deficit in memory retrieval. These findings suggest that the exposure to a potential new learning situation impairs not only memory consolidation but also memory reconsolidation of the original learning task.

Memory consolidation and reconsolidation of an inhibitory avoidance response in mice: effects of i.c.v. injections of hemicholinium-3.

The immediate post-training i.c.v. administration of hemicholinium-3 (HC-3) (1 microg), a specific inhibitor of the high-affinity choline uptake (HACU) in brain cholinergic neurons, impaired retention test performance of a one-trial step-through inhibitory avoidance response in adult male CF-1 mice. The effect was observed in mice that received a footshock (0.8 mA, 50 Hz, 1 s) on the learning trial, and not only 48 h after training, but also 7 days after it. After the completion of the retention test at each of the training-test interval that were studied, the HACU in the hippocampus of HC-3-treated mice was not significantly different from that of saline-injected (1 microl) control groups. Mice that were over-reinforced (1.2 mA, 50 Hz, 1 s) on the learning trial, exhibited a high retention performance 48 h after training. The immediate i.c.v. injection of HC-3 (1 microg) after the retention test, that is, after memory reactivation, significantly impaired retention performance over 4 consecutive days, whereas the saline-injected control group shown a slight, but significant performance decrease only at the last retention test. Retention performance was unchanged in HC-3-treated mice not undergoing memory reactivation session. These results, taken together, indicate that HC-3, not only impaired consolidation, but also reconsolidation of an inhibitory avoidance task in mice, suggesting a critical participation of central cholinergic mechanisms in both memory processes.

Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate.

Benzodiazepines are anxiolytic, anticonvulsant, sedative and hypnotic compounds usually prescribed on a long-term basis. Chronic treatment with these compounds induces tolerance, which has been extensively attributed to modifications in the GABAergic neurotransmission. However, a compensatory increase in the excitatory response, named as an oppositional response, has also been put forward as a means for explaining such tolerance. Changes in the excitatory neurotransmission have been found in withdrawn rats after a long treatment with benzodiazepines but these modifications have not been conclusively studied during tolerance. In this work we studied several parameters of the glutamatergic neurotransmission in rats made tolerant to the sedative effect of 3 mg/kg (i.p.) of lorazepam (LZ). We found a decrease in the affinity of cortical NMDA receptors for (3)H-glutamate (K(D): 124.4 +/- 13.3 nM in tolerant rats, 71.6 +/- 10.4 nM in controls, P<0.05) together with a decrease in the in vitro 60 mM K(+)-stimulated cortical glutamate release (59+/- 12% vs. 153 +/- 38%, tolerant rats vs. controls, P<0.05). We conclude that tolerance to the sedative effect of LZ correlates with a decreased sensitivity for glutamate that may in turn diminish the cortical response to a chemical stimulus. Our findings constitute an evidence against the oppositional model of pharmacodynamic tolerance in this experimental condition.

Memory improving actions of gabapentin in mice: possible involvement of central muscarinic cholinergic mechanism.

Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately post-training, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation.

Diazepam fails to potentiate GABA-induced chloride uptake and to produce anxiolytic-like action in aged rats.

The pharmacological response to benzodiazepines has been demonstrated to be different in aged individuals in comparison to adults. We studied the age-dependent changes in some of the in vitro and behavioral effects of diazepam in aged (24 months old) rats, comparing them to adults (3 months old). We evaluated the in vitro gamma-aminobutyric acid (GABA)-induced 36Cl- uptake and the diazepam potentiation of GABA-stimulated 36Cl- uptake in microsacs from cerebral cortex of both groups of animals. We found no differences in the GABA-stimulated 36Cl- uptake between adult and aged animals, and diazepam failed to potentiate GABA-induced 36Cl- flux in the aged cortical microsacs. We also examined the effect of 0.03-10 mg of diazepam on locomotor activity in an open-field test and the anxiolytic-like action of diazepam in doses ranging from 0.03 to 1 in a dark-light transition test. We observed no anxiolytic-like action of the drug in the dark-light transition test in the aged rats, while there was a shift to the left in the diminution of locomotor activity evaluated by the open-field test. We conclude that the pharmacodynamic changes observed in cortical GABA(A) receptors in aged rats could partially explain the lack of anxiolytic-like action but not the oversedation evidenced in this group of animals.

A possible interaction between CCKergic and GABAergic systems in the rat brain.

Cholecystokinin sulfated octapeptide (CCK-8S) was given to rats i.p. at single doses of 10 and 100 nmol/kg, respectively. It produced a modification in GABA levels in several areas of the rat brain. After 30 min of injection, the lower dose (10 nmol/kg) increased GABA levels in striatum by 31% (P<0.05). The higher dose (100 nmol/kg) enhanced GABA levels either in hippocampus by 78% (P<0.05) or in frontal cerebral cortex by 81% (P<0.05) and decreased in olfactory bulbs by 57% (P<0.01). Thus, these results show that systemic injection of CCK-8S, produced regional specific changes on GABA levels in brain, and these effects were dose-dependent. Systemic pretreatment with the CCK(B) receptor antagonist, PD 135,158, 1 mg/kg i.p., on the endogenous levels of GABA in certain regions was also studied. The selective CCK(B) receptor antagonist, PD 135,158, did not have an effect per se on the endogenous levels of GABA but prevents the action induced by the neuropeptide. We suggest that the action of CCK may be mediated via a selective action on the CCK(B) receptor subtypes.

Gabapentin, an antiepileptic drug, improves memory storage in mice.

Male CF-1 mice were tested 48 h after training in a one-trial step-through inhibitory avoidance task. Immediately post-training i.p. injections of the antiepileptic drug gabapentin (1-aminomethyl cyclohexaneacetic acid) (GBP; 5, 10, 50, and 100 mg/kg) induced a dose-dependent enhancement of retention performance. Gabapentin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of GBP on retention were not due to non-specific proactive effects on response latencies. The effects of GBP (10 mg/kg) were time-dependent, and the administration of GBP (10 mg/kg) 30 min before training also enhanced retention performance. However, the administration of GBP (10 mg/kg) 30 min prior to the retention test did not modify retention latencies of mice that had received either saline or GBP (10 mg/kg) immediately after training. Altogether, the results suggest that GBP influences retention by modulating time-dependent processes involved in memory storage, although the mechanism(s) of this action remain to be established.

Administration of cholecystokinin sulphated octapeptide (CCK-8S) induces changes on rat amino acid tissue levels and on a behavioral test for anxiety.

1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety.

Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain.

1. The in vitro effect of valproic acid (VA) (10(-6) to 10(-3) M) on glutamic acid decarboxylase (GAD) activity in whole brain and cerebral cortex (CC) of neonates and of adult rats was examined. 2. VA did not induce changes on GAD activity either in CC or in the rest of the brain (RB) of adult animals. 3. But at 10(-3) M, VA induced an increase in GAD activity in homogenates of noncortical brain areas of neonates; no increments were found in CC of these animals. This latter increase was detected in the membrane-bound fraction of the enzyme and was not due to physicochemical nonspecific changes related to the potential solvent activity of VA at this high concentration. 4. We may conclude that VA induces changes on GAD activity in neonatal stages of development but not in adult brain. Therefore, although a direct enhancement of GAD activity may play a role in the mechanism of action of VA in pediatric patients, this cannot be verified in the adult population.

Chronic administration of valproic acid induces a decrease in rat striatal glutamate and taurine levels.

The effect of acute and chronic (10 days) administration of 200 mg/kg (i.p.) of valproic acid (VPA) on endogenous levels of aspartate, glutamate, alanine, glycine and taurine in the cerebral frontal cortex and corpus striatum of rats was studied. Quantification of the amino acid levels was performed by HPLC.Valproic acid (VPA) did not either induce changes on these neurotransmitters contents in corpus striatum after acute treatment. After chronic administration we found a decrease on the endogenous levels of glutamic acid (24%, p < 0.05) which was related to an increase (250%, p < 0.02) of the in vitro KCl evoked release of glutamate. We found decrements in taurine endogenous levels (22%, p < 0.05) which was not associated with an increase of its release.In cerebral frontal cortex there was not found any change neither under the acute nor under the chronic condition.Thus, it may be conclude that chronic treatment with VPA produces decreases on the endogenous levels of glutamate and taurine. However the relevance of this effect concerning it therapeutic action remains unclear.

[Role of excitatory amino acids in neuropathology]. / Papel de los aminoácidos excitatorios en la neuropatología.

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.

Papel de los aminoácidos excitatorios en la neuropatología. / [Role of excitatory amino acids in neuropathology]

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.

GABAA receptors mediate the changes produced by stress on GABA function and locomotor activity.

(1) This study shows the effects of bicuculline pretreatment on the GABAergic system in certain areas of the rat brain after acute ether and cold stress. (2) The spontaneous locomotor activity was diminished by either ether stress or cold stress or bicuculline. (3) Acute ether stress enhanced GABA concentration in the hypothalamus (69%) and in the frontal cerebral cortex (26%). Bicuculline prevented the increase in GABA levels induced by ether stress in both areas. (4) Acute cold stress decreased GABA concentration in the corpus striatum (29%). Bicuculline prevented the decrease in GABA levels induced by cold stress. (5) It is concluded that there is a GABAA receptor involved in stress induced changes on endogenous GABA levels as well as on locomotor activity.

Area-dependent changes in GABAergic function after acute and chronic cold stress.

(1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after acute and chronic cold stress. (2) GABA concentration, [3H]GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. (3) Acute stress: (a) reduced GABA concentration in the corpus striatum (29%); (b) decreased GAD activity (under non-saturating substrate concentration) in the olfactory bulbs (24%); (c) diminished neuronal uptake of [3H]GABA in the frontal cerebral cortex (65%), hypothalamus (86%) and olfactory bulbs (82%). (4) Chronic stress: (a) reduced the endogenous levels of GABA in the frontal cerebral cortex (51%), hypothalamus (26%) and olfactory bulbs (15%); (b) decreased GAD activity in the corpus striatum (32%) and olfactory bulbs (34%); (c) decreased neuronal uptake of [3H]GABA in the hypothalamus (83%). (5) These findings suggest that compensatory changes may develop in the GABAergic system after chronic stress.

Effects of baclofen on amino acid release.

This study showed the effects of baclofen on endogenous excitatory (Glu and Asp) and non-excitatory (Tau, Gly and Ala) amino acid release. (A) Release was stimulated by K+ 30 mM in rat frontal cortex slices in vitro (evoked release in ng/g tissue per 5 min): 3739 +/- 215 (Asp), 3429 +/- 357 (Glu), 763 +/- 181 (Tau), 945 +/- 71 (Ala), 468 +/- 44 (Gly). (B) Release was largely Ca(2+)-dependent for all amino acids but Ca(2+)-independent release was observed for Asp and Glu (29 and 32%, of total evoked release respectively). (C) Ca(2+)-dependent release was inhibited by baclofen 100 microM (% of inhibition taking as 100%, the Ca(2+)-dependent release in the absence of baclofen): 46 (Asp), 96 (Glu) (85% inhibition by baclofen 10 microM), 100 (Tau), 77 (Ala). Ca(2+)-independent release was inhibited: 87 and 88% (Asp), 85 and 95% (Glu) by baclofen 10 and 100 microM respectively. It is concluded that baclofen at a high concentration inhibits the evoked release of Glu, Asp, Tau and Ala due to inhibition of the Ca(2+)-dependent fraction and also of the Ca(2+)-independent component in the case of Glu and Asp. Baclofen at a low concentration inhibits only Glu- and Asp-evoked release (total release) due to inhibition of both Ca(2+)-dependent and -independent fractions in the case of Glu and to inhibition of the Ca(2+)-independent fraction in the case of Asp. The possibility that baclofen might affect the Ca(2+)-independent carrier-mediated release of Glu-Asp is discussed.

Changes in GABAergic function after chronic chemical stress.

1. The function of the gamma-aminobutyric acid (GABA)-ergic system in certain areas of the rat brain was investigated after chronic chemical stress (exposure to either vapours 30 sec/day for 20 days). 2. GABA concentration, [3h] -GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. 3. Chronic stress: (a) reduced neuronal uptake of [3H] -GABA in the frontal cerebral cortex (43%) and increased non-neuronal uptake of [3H] -GABA in the hypothalamus (62%); (b) enhanced the activity of GAD (under subsaturating substrate concentration) in the frontal cortex (91%) and in the corpus striatum (69%); (c) did not modify GABA endogenous concentration; (d) did not affect the animals' body weight increase or produce any signs of toxicity. 4. The stimulation of GAD and reduction of [3H] -GABA neuronal uptake in the frontal cortex might suggest the stimulation of GABAergic neurotransmission induced by chronic stress in this area of the rat brain. Together with previous findings the frontal cortex would appear to be a key area in chronic stress processing.

Chemical stress and GABAergic central system.

1. The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after acute (30 sec) ether stress. 2. GABA endogenous concentrations, uptake of [3H]GABA and the activity of glutamate decarboxylase were measured in different brain areas. 3. After 30 sec of exposure to ether vapour, GABA concentration and total [3H]GABA uptake in the frontal cerebral cortex were increased. In contrast, stress increased GABA concentration in the hypothalamus, but reduced total [3H]GABA uptake. 4. Since the neuronal component of [3H]GABA uptake was increased in the frontal cerebral cortex this might be responsible for the increase in total [3H]GABA uptake. The increase in the endogenous concentration of GABA in the hypothalamus probably resulted from its enhanced synthesis because GAD activation was observed in the hypothalamus after stress. 5. In conclusion, the present study shows that acute ether stress induces rapid and quickly reversible changes in the GABAergic system according to the area of brain. The characteristics of these changes as related to their quick appearance and reversibility might suggest an effect upon neuronal activity due to acute stress exposure.