title: GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons.
abstract: Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA(A) receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non-benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5-c]pyridine-3-ol (THIP) (also known as gaboxadol) that acts preferentially via high-affinity extrasynaptic GABA(A) receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABA(A) receptor δ(-/-) mice, which have a loss of extrasynaptic GABA(A) receptors. In behavioral experiments, we found neither acute reinforcement in intravenous self-administration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic δ-subunit-containing GABA(A) receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Elena
authors.initials: E
authors.lastname: Vashchinkina
authors.forename: Anne
authors.initials: A
authors.lastname: Panhelainen
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Vekovischeva
authors.forename: Teemu
authors.initials: T
authors.lastname: Aitta-aho
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Ator
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects*; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D010215:Papio; D016133:Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000187:drug effects; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology; D012201:Reward; D012646:Self Administration; D019966:Substance-Related Disorders / Q000473:pathology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; C015542:gaboxadol