title: Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons.
abstract: Opiate activation of mu-opioid receptors (muORs) in the ventral tegmental area (VTA) modulates gamma-aminobutyric acid (GABA) neurotransmission within the mesocorticolimbic dopamine (DA) reward system. We combined in vivo extracellular electrophysiological recordings in anesthetized and freely behaving rats with intracellular Neurobiotin filling and immunocytochemistry to characterize the effects of opiates on VTA GABA neurons, evaluate their discharge activity during opiate self-administration, and identify the cellular sites for opiate activation. We identified a subpopulation of VTA GABA neurons that was characterized by location, spike discharge profile, activation by microelectrophoretic DA, and response to internal capsule (IC) stimulation. Systemic administration of heroin or microelectrophoretic application of the selective muOR agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) reduced VTA GABA neuron firing rate (heroin IC(50) = 0.35 mg/kg) and was blocked by the muOR antagonist naloxone. Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons. The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin. Electrophysiologically characterized VTA GABA neurons were filled with Neurobiotin and labeled dendrites contained plasmalemmal muOR immunoreactivity. Dually labeled muOR dendrites contained dendrodendritic appositions characteristic of gap junctions. These findings indicate that inhibition of this population of GABAergic neurons by opiates acting on dendritic muORs has implications for modulation of electrical coupling between VTA GABA neurons and dopamine (DA) neurotransmission in the VTA and terminal field regions.
authors.affiliation: Department of Psychology (1050 SWKT), Brigham Young University, Provo, UT 84602, USA. scott_steffensen@byu.edu
authors.forename: Scott C
authors.initials: SC
authors.lastname: Steffensen
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Stobbs
authors.forename: Eric E O
authors.initials: EE
authors.lastname: Colago
authors.forename: Rong-Sheng
authors.initials: RS
authors.lastname: Lee
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Roger A
authors.initials: RA
authors.lastname: Gallegos
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Henriksen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D003932:Heroin / Q000008:administration & dosage* / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012646:Self Administration / Q000379:methods; D017557:Ventral Tegmental Area / Q000166:cytology*; D014851:Wakefulness; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; C070614:neurobiotin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D001710:Biotin; D003932:Heroin; D004298:Dopamine