Distinctions among GABA_A and GABA_B responses revealed by calcium channel antagonists, cannabinoids, opioids, and synaptic plasticity in rat hippocampus

Rationale: Hippocampal interneurons release γ-aminobutyric acid (GABA) and produce fast GABA_A- and slow GABA_B-inhibitory postsynaptic potentials (IPSPs). The regulation of GABA_B eIPSPs or the interneurons that produce them are not well understood. In addition, while both μ-opioid receptors (μORs) and cannabinoid CB1R receptors (CB1Rs) are present on hippocampal interneurons, it is not clear how these two systems interact. Objectives: This study tests the hypotheses that: (1) all interneurons can initiate both GABA_A and GABA_B inhibitory postsynaptic potentials; (2) GABA_B responses are insensitive to mGluR-triggered, endocannabinoid (eCB)-mediated inhibitory long-term depression (iLTD); (3) GABA_B responses are produced by interneurons that express μOR; and (4) CB1R-dependent and μOR-dependent response interact. Materials and methods: Pharmacological and electrophysiological approaches were used in acute rat hippocampal slices. High resistance microelectrode recordings were made from pyramidal cells, while interneurons were stimulated extracellularly. Results: GABA_B responses were found to be produced by interneurons that release GABA via either presynaptic N-type or P/Q-type calcium channels but that they are insensitive to suppression by eCBs or eCB-mediated iLTD. GABA _B IPSPs were sensitive to suppression by a μOR agonist, suggesting a major source of GABA_B responses is the μOR-expressing interneuron population. A small eCB-iLTD (10% eIPSP reduction) persisted in conotoxin. eCB-iLTD was blocked by a μOR agonist in 6/13 slices. Conclusions: GABA_B responses cannot be produced by all interneurons. CB1R or μOR agonists will differentially alter the balance of activity in hippocampal circuits. CB1R- and μOR-mediated responses can interact.