Stress represents an important factor in mood and anxiety disorders. We have shown that stress results in stressor- and brain region-specific changes in serotonin and that the corticotropin-releasing factor (CRF) system plays an important role herein [1]. Another important neurotransmitter implicated in controlling emotion and the stress response is the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Recent studies have shown that GABA in the hippocampus, a limbic brain structure instrumental in the coordination of the stress response, not only inhibits postsynaptic neurons via synaptic inhibition but also exerts a form of tonic inhibition via extrasynaptic receptors. Although extracellular GABA levels will represent a key determinant for tonic inhibition, until now it is largely unknown whether, and via which mediators, stress affects extracellular GABA. Thus, we designed a microdialysis study to characterise the effects of stress on hippocampal extracellular GABA. Wistar rats were equipped with a guide cannula and 7 days later a microdialysis probe was inserted into the hippocampus (both procedures under isoflurane anaesthesia). Two days later rats were, after collection of baseline samples, subjected to stress (30 min exposure to a novel cage or 15 min forced swimming) or left undisturbed. To investigate the possible role of the CRF system, separate rats were i.c.v. pretreated with the CRF receptor antagonist D-Phe-CRF_12-41 (5 µg) or vehicle before being exposed to novelty. GABA was measured by HPLC/electrochemical detection. ANOVA with repeated measures and post hoc contrasts corrected for multiple comparisons were used for statistical analysis. Novelty caused a significant increase (maximal effect 120 ± 3.8% of baseline; n=6) in extracellular GABA. The opposite effect was observed during swim stress at 25°C, i.e. a significant decrease in GABA levels (n=7; maximal effect 68.2 ± 3.9% of baseline; interaction between time and stressor: P < 0.001). Profound decreases in body temperature have been observed during swim stress at 25°C. Therefore, to discriminate between the psychological and the physical aspects of this stressor, another group of rats (n=6) was subjected to swim stress at 35°C (with only minor effects on body temperature, thereby alleviating its physical impact). In these rats, GABA levels increased to 154.4 ± 12.2% of baseline, suggesting that the psychological component of swim stress results in a rise in GABA levels, corresponding with the observed effect of novelty. The effects of novelty on hippocampal GABA could not be blocked by pretreatment with D-Phe-CRF_12-41 (P > 0.05). From these data we conclude that hippocampal extracellular GABA responds to stress in a stressor-specific manner. Moreover, CRF receptors seem not to be involved in the novelty-induced increase in GABA. Elucidation of the mediators modulating the effects of stress on hippocampal GABA will be subject of further study.