title: A novel opioid receptor-mediated enhancement of GABAA receptor function induced by stress in ventral tegmental area neurons.
abstract: Opioid receptors are G-protein-coupled receptors (GPCRs) that modulate synaptic function. Depending upon their nervous system site of action, opioid receptor agonists alter food consumption, pain perception, responses to stress, and drug reward. Opioid receptors signal primarily via G(i/o)-proteins that modulate ion channels to directly inhibit neurons or decrease neurotransmitter release from nerve terminals. Here we report that following stress, activating δ opioid receptors (DORs) on midbrain ventral tegmental area (VTA) neurons causes a novel synaptic effect: the augmentation of GABA(A) receptor (GABA(A)R)-mediated inhibitory postsynaptic currents. Most neurons showing this augmentation were identified as dopaminergic. In addition, in both stressed and unstressed animals, DOR activation decreases GABA(A)R currents in some VTA neurons. Surprisingly, both augmentation and inhibition were also observed when we bypassed the presynaptic terminal by iontophoretically applying GABA, indicating that postsynaptic mechanisms are responsible for both effects. Using a variety of blockers we determined that the augmentation is probably due to insertion of GABA(A)Rs into the synapse by a mechanism that is G-protein independent and mediated by activation of Akt via PI3K. GABA(A)Rs are inserted into the extra-synaptic plasma membrane before trafficking to the synapse, a mechanism consistent with our observation that the DOR-mediated increase in GABA(A)R signalling occurs significantly earlier in iontophoretically applied than in electrically evoked synaptic GABA. This G-protein-independent signalling pathway is not only a novel mechanism of opioid receptor-mediated inhibition, but it also represents the first reported link between activation of a GPCR and insertion of GABA(A)Rs into the plasma membrane.
authors.affiliation: Ernest Gallo Clinic and Research Centre, 5858 Horton Street, Suite no. 200, Emeryville, CA, USA. elyssam@gallo.ucsf.edu
authors.forename: Elyssa B
authors.initials: EB
authors.lastname: Margolis
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mitchell
authors.forename: Gregory O
authors.initials: GO
authors.lastname: Hjelmstad
authors.forename: Howard L
authors.initials: HL
authors.lastname: Fields
mesh_terms: D000818:Animals; D009474:Neurons; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011963:Receptors, GABA-A; D011957:Receptors, Opioid / Q000378:metabolism; D017557:Ventral Tegmental Area
chemical_list: D011963:Receptors, GABA-A; D011957:Receptors, Opioid; D019869:Phosphatidylinositol 3-Kinases