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) agonist, on single and paired-pulse responses in the dentate gyrus of urethane-anesthetized rats, in vivo. Baclofen (10 mg/kg) significantly increased the duration of single excitatory responses. This increase was blocked by the GABA(B) receptor antagonist, CGP 35348, indicating that baclofen was acting through GABA(B) receptors. To determine the mechanism underlying this increase in response duration, the NMDA antagonist, D-2-amino-5-phosphonopentanoic acid (D-APV), was administered intracerebroventricularly (i.c.v.) after baclofen. D-APV by itself had no effect on the duration of the population excitatory post-synaptic potential (EPSP). However, when infused after baclofen, D-APV blocked the baclofen induced increase in EPSP duration. This indicates the prolonged 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. Baclofen attenuated paired-pulse inhibition of population spike amplitudes at a 25 ms interstimulus interval. CGP-35348 reduced the effect of baclofen on paired-pulse inhibition, indicating that baclofen suppressed paired-pulse inhibition by acting on GABA(B) receptors. In contrast to its disinhibitory effect at the 25 ms interval, baclofen had an inhibitory 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 evoked by the second stimulus were enhanced. Baclofen suppressed this enhancement. We conclude that GABA(B) receptor activation by baclofen reduces short interval inhibition and this reduction of inhibition leads to an enhanced NMDA-receptor mediated response. We also conclude that by reducing inhibition, baclofen occludes paired-pulse disinhibition found at longer interstimulus intervals. In contrast, CGP-35348 directly blocks paired-pulse disinhibition. Thus, GABA(B) receptor activation can regulate synaptic inhibition, in turn influencing NMDA receptor activation and synaptic transmission. Thus, pharmacologic manipulation of GABA(B) receptors may provide a powerful approach for regulating synaptic transmission in the hippocampus.