GABA(B), receptor antagonism: Facilitatory effects on memory parallel those on LTP induced by TBS but not HFS

The present experiments used CGP 35348, a selective GABA(B) receptor antago nist with a significantly higher affinity for post-versus presynaptic recep tors, to dissociate the role of antagonist concentration versus stimulation mode in determining whether GABA(B) receptor blockade facilitates or suppr esses long-term potentiation (LTP), The antagonist was applied by pressure ejection to one of two recording sites in area CA1 of hippocampal slices be fore LTP was induced at both sites with either theta burst or high-frequenc y stimulation (TBS or HFS), TBS produced a dose-dependent facilitation of p otentiation that turned into depression at the highest concentration tested , a result reflecting the dose-dependent balance between the drug's postsyn aptic disinhibitory effect and its action on presynaptic autoreceptors regu lating the release of GABA. In contrast, HFS-induced LTP increased monotoni cally with drug concentration, suggesting that blockade of postsynaptic GAB A(B) receptors is the only factor contributing to HFS-induced LTP. To test the relevance of the two sets of LTP results, we performed behavioral studi es examining the effect of different dosages of antagonist on spatial reten tion and found that memory was enhanced at intermediate dosages but not at very low and high concentrations, reminiscent of the bell-shaped dose-respo nse curve obtained for TBS-induced LTP. These findings are consistent with the notion that LTP induced by electrical stimulation modeled after endogen ous theta-modulated activity patterns bears more relevance to behavior than does potentiation induced by arbitrary tetanic trains.