GABA(B) RECEPTORS MODULATE SYNAPTICALLY-EVOKED RESPONSES IN THE RAT DENTATE GYRUS, IN-VIVO

We assessed the effects of systemically injected baclofen, a GABA(B) a gonist, on single and paired-pulse responses in the dentate gyrus of u rethane-anesthetized rats, in vivo. Baclofen (10 mg/kg) significantly increased the duration of single excitatory responses. This increase w as blocked by the GABA(B) receptor antagonist, CGP 35348, indicating t hat baclofen was acting through GABA(B) receptors. To determine the me chanism underlying this increase in response duration, the NMDA antago nist, D-2-amino-5-phosphonopentanoic acid (D-APV), was administered in tracerebroventricularly (i.c.v.) after baclofen. D-APV by itself had n o effect on the duration of the population excitatory post-synaptic po tential (EPSP). However, when infused after baclofen, D-APV blocked th e baclofen induced increase in EPSP duration. This indicates the prolo nged EPSP duration caused by baclofen resulted from an enhancement of an NMDA receptor mediated component of the response. We then examined the effect of baclofen on population responses to paired stimuli. Bacl ofen attenuated paired-pulse inhibition of population spike amplitudes at a 25 ms interstimulus interval. CGP-35348 reduced the effect of ba clofen on paired-pulse inhibition, indicating that baclofen suppressed paired-pulse inhibition by acting on GABA(B) receptors. In contrast t o its disinhibitory effect at the 25 ms interval, baclofen had an inhi bitory effect on responses evoked at a 150 ms interstimulus interval. Under control conditions, we observed that when stimuli were delivered 150 ms apart, both the EPSP duration and population spike amplitude e voked by the second stimulus were enhanced. Baclofen suppressed this e nhancement. We conclude that GABA(B) receptor activation by baclofen r educes short interval inhibition and this reduction of inhibition lead s to an enhanced NMDA-receptor mediated response. We also conclude tha t by reducing inhibition, baclofen occludes paired-pulse disinhibition found at longer interstimulus intervals. In contrast, CGP-35348 direc tly blocks paired-pulse disinhibition. Thus, GABA(B) receptor activati on can regulate synaptic inhibition, in turn influencing NMDA receptor activation and synaptic transmission. Thus, pharmacologic manipulatio n of GABA(B) receptors may provide a powerful approach for regulating synaptic transmission in the hippocampus.