DIFFERENT MECHANISMS FOR USE-DEPENDENT DEPRESSION OF 2 GABA(A)-MEDIATED IPSCS IN RAT HIPPOCAMPUS

1. The mechanisms involved in the use-dependent depression of GABA(A,fast) and GABA(A,slow), two GABA(A)-mediated IPSCs in the rat hippocampal slice preparation, were investigated by observing the effects of paired-pulse depression and of baclofen and CGP 35348 on monosynaptic inhibitory currents recorded from CA1 pyramidal neurons. 2. The second of a pair of evoked responses that consisted of both inhibitory components was depressed and decayed more rapidly compared to the first at an interpulse interval (IpI) of 200 ms. This effect was due to a decrease in the amplitude of GABA(A,slow), with no effect on the time constant of decay or on the amplitude or time constant of GABA(A,fast). 3. The time course of paired-pulse depression of both components at IpIs ranging from 5 to 2560 ms was compared. GABA(A,slow) was depressed maximally by 55% at IpIs of 80-160 ms. GABA(A,fast) was depressed maximally by 38% at 5 ms, and recovered exponentially with a time constant of 130 ms. 4. GABA(A,slow) was more sensitive than GABA(A,fast) to depression by baclofen. GABA(A,slow) was susceptible to complete block, with an ED50 of approximately 200 nM for (+/-)-baclofen and 100 nM for the active enantiomer, (R)-(+)-baclofen. GABA(A,fast) was blocked by only 50% by the highest concentrations of baclofen tested (10-100 mu M r (R)-(+)-baclofen), with an ED50 of approximately 2 mu M for (+/-)-baclofen and 1 mu M for (R)-(+)-baclofen. Paired-pulse depression of GABA(A,fast) was not occluded by 10 or 100 mu M (R)-(+)-baclofen. 5. The GABA(B) antagonist CGP 35348 (0.4-1 mM), prevented paired-pulse depression of GABA(A,slow) at IpIs of 160 to 200 ms, and reversed the depression of GABA(A,fast) by baclofen, but had no effect on paired-pulse depression of GABA(A,fast) at IpIs of 20 to 40 ms. 6. It is concluded that use-dependent depression of GABA(A,slow), but not GABA(A,fast), is mediated by a presynaptic GABA(B) receptor. It is speculated that use-dependent depression of GABA(A,fast), which occurs only over a much faster time scale, may be due to rapid postsynaptic QABA(A) receptor desensitization.