Abstract
Activation of γ‐aminobutyric acid B (GABA~B~) and 5‐hydroxytryptamine (5‐HT) receptors produces presynaptic inhibition at glutamatergic terminals in the rat neocortex. To evaluate interactions between these metabotropic receptors, field potentials were recorded in layer 2/3 of somatosensory cortex. In addition, the paired pulse (PP) protocol was used to measure changes in the ratio of the second/first extracellular synaptic potentials (S~2~/S~1~ ratio) as an index of glutamate release probability in the area. Lowering extracellular [Ca^2+^]~o~ to 0.5 mM, increased the S~2~/S~1~ ratio by 318 ± 134%. 5‐HT (1 μM) increased the S~2~/S~1~ ratio by 61 ± 15%. In presence of the GABA~A~ antagonist bicuculline (10 μM), 5‐HT increased the S~2~/S~1~ ratio by 98 ± 15%. This effect did not desensitize after two consecutive applications of the amine, and was dose dependent in the concentration range between 0.03–1 μM (EC~50~ = 2.36 × 10^−7^ mol/L). The increase of S~2~/S~1~ ratio induced by 5‐HT (1 μM) was blocked reversibly by the 5‐HT~1A~ antagonist NAN‐190 (10–30 μM), but was unaffected by the selective GABA~B~ antagonist CGP 52432 (1 μM). The action of 5‐HT was mimicked by the 5‐HT~1A/7~ agonist 8OH‐DPAT (10 μM), increasing the S~2~/S~1~ ratio by 84 ± 2%, a response that was unaffected by the 5‐HT~2/7~ antagonist ritanserin (2 μM). The 5‐HT~1B~ agonist CP93129 (10 μM) had no effect. The GABA~B~ agonist baclofen (1 μM) increased the S~2~/S~1~ ratio up to 308 ± 33%, which is similar to that produced by low [Ca^2+^]~o~. When the effect of baclofen was maximal, application of 5‐HT (1 μM) reversed the S~2~/S~1~ ratio back to 78 ± 27%, a result that was blocked by the 5‐HT~2/7~ antagonist ritanserin (100 nM). Notably, the interaction between the GABA~B~ agonist and 5‐HT was order dependent, because enhancement of the S~2~/S~1~ ratio elicited by baclofen was not inhibited if 5‐HT was applied first. These results suggest a complex interaction between GABA~B~, 5‐HT~1A~, and 5‐HT~2~ receptors in layer 2/3 of rat somatosensory cortex. Activation of GABA~B~ receptors induces PP facilitation (inhibits glutamate release) more efficiently than does activation of 5‐HT~1A~ receptors. When the effect of GABA~B~ receptor activation is maximal, however, the influence of 5‐HT changes to the opposite direction, inhibiting PP facilitation (increasing glutamate release) through activation of 5‐HT~2~ receptors. © 2004 Wiley‐Liss, Inc.