Postsynaptic dopamine D₃ receptors selectively modulate μ-opioid receptor-expressing GABAergic inputs onto CA1...

Although the actions of dopamine throughout the brain are clearly linked to motivation and cognition, the specific role(s) of dopamine in the CA1 subfield of the ventral hippocampus (vH) is unresolved. Prior preclinical studies suggest that dopamine D₃ receptors (D₃Rs) expressed on CA1 pyramidal cells exhibit a unique capacity to modulate mechanisms of long-term synaptic plasticity, but less is known about how interneuronal inputs modulate these cells. We hypothesized that inputs from μ-opioid receptor (MOR)-expressing inhibitory interneurons selectively modulate the activity of postsynaptic D₃Rs expressed on CA1 principal cells to shape neurotransmission in the rat vH. We used the whole cell voltage-clamp technique to test this hypothesis by measuring evoked inhibitory postsynaptic currents (eIPSCs) from CA1 principal cells in vH slices or GABA_A currents from acutely dissociated vH neurons. The eIPSC response recorded from CA1 neurons in vH slices was inhibited by either the MOR agonist DAMGO or the D₃R agonist PD128907, but pretreatment with DAMGO occluded any further inhibition by PD128907. GABA_A currents measured in acutely dissociated vH CA1 neurons were inhibited by D₃R activation via PD128907, consistent with postsynaptic localization of D₃ receptors. Kinetic alterations induced by the neuromodulatory agonists are consistent with selective targeting of postsynaptic D₃Rs expressed on CA1 principal cells by MOR-expressing GABAergic inputs. Our findings suggest that postsynaptic D₃R-mediated modulation of MOR-expressing GABAergic inputs is a site at which dopaminergic and opioidergic activity may contribute to disinhibition of vH excitatory neurotransmission and, thus, influence critical physiological processes such as synaptic plasticity and network oscillations.NEW & NOTEWORTHY We report that the activity of an inhibitory synapse on CA1 pyramidal cells in the rat ventral hippocampus is shaped by heterogeneous neuromodulators. Specifically, postsynaptic dopamine D₃ receptors on ventral hippocampal CA1 pyramidal neurons are selectively targeted by an inhibitory input from µ-opioid receptor-expressing GABAergic terminals.