ENDOGENOUS ACTIVATION OF MU-OPIOID AND DELTA-1-OPIOID RECEPTORS IS REQUIRED FOR LONG-TERM POTENTIATION INDUCTION IN THE LATERAL PERFORANT PATH - DEPENDENCE ON GABAERGIC INHIBITION

Opioid peptides costored with glutamate have emerged as powerful regul ators of long-term potentiation (LTP) induction in several hippocampal pathways. The objectives of the present study were twofold: (1) to id entify which opioid receptor types (mu, delta, or kappa) regulate LTP induction at lateral perforant path-granule cell synapses and (2) to t est the hypothesis that endogenous opioids regulate LTP induction via modulation of GABAergic inhibition. LTP of lateral perforant path-evok ed field EPSPs was induced selectively by high-frequency stimulation a pplied to the outer third of the molecular layer of the dentate gyrus of rat hippocampal slices. No changes in medial perforant path respons es occurred. LTP was blocked when high-frequency stimulation was appli ed in the presence of the mu receptor antagonist CTAP, the selective d elta-1 receptor antagonist BNTX, or the delta-1 and delta-2 receptor a ntagonist naltrindole. By contrast, the kappa-1 opioid receptor antago nist NBNI had no effect on LTP induction. The role of GABAergic inhibi tion was investigated by comparing the effect of naloxone on LTP induc tion in slices maintained in standard buffer and picrotoxincontaining buffer. Naloxone blocked LTP in standard buffer, whereas normal LTP wa s induced in picrotoxin-treated, disinhibited slices. Finally, NMDA re ceptor blockade completely inhibited LTP in both standard and disinhib ited slices. The results show that mu and delta-1 opioid receptors reg ulate LTP induction and that this mechanism critically depends on GABA ergic inhibition. A key issue then becomes how endogenous opioids fine -tune the activity of intact inhibitory networks in the dentate gyrus, effectively gating synaptic plasticity in specific dendritic strata.