title: Direct bidirectional μ-opioid control of midbrain dopamine neurons.
abstract: The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic μ-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 μM) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 μM, n = 5) and ω-agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca(2+) channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ± 7 mV and inhibitions were blocked by the K(+) channel blocker BaCl2 (100 μM, n = 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons.
authors.affiliation: Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143, and elyssa.margolis@ucsf.edu.
authors.forename: Elyssa B
authors.initials: EB
authors.lastname: Margolis
authors.affiliation: Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143, and.
authors.forename: Gregory O
authors.identifier: http://orcid.org/0000-0003-1968-2729
authors.initials: GO
authors.lastname: Hjelmstad
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Wakako
authors.identifier: http://orcid.org/0000-0001-7109-3417
authors.initials: W
authors.lastname: Fujita
authors.affiliation: Department of Neurology, The Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143, and.
authors.forename: Howard L
authors.identifier: http://orcid.org/0000-0002-5989-0760
authors.initials: HL
authors.lastname: Fields
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
keywords: VTA; calcium channel; midbrain; opioid