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Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA‐A Receptor δ Subunit Knockout Mice
Author(s) -
Siivonen Milo S.,
Miguel Elena,
Aaltio Juho,
Manner Aino K.,
Vahermo Mikko,
YliKauhaluoma Jari,
Linden AnniMaija,
Aittaaho Teemu,
Korpi Esa R.
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13043
Subject(s) - ventral tegmental area , conditioned place preference , gabaa receptor , pharmacology , neuroactive steroid , nucleus accumbens , dopamine , morphine , chemistry , knockout mouse , medicine , neuroscience , receptor , biology , dopaminergic
Extrasynaptic δ subunit‐containing γ‐aminobutyric acid type A receptors (δ‐ GABA A R s) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ‐ GABA A R s are functionally expressed in the ventral tegmental area ( VTA ), the cell body region of mesocorticolimbic dopamine ( DA ) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo , by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ‐ GABA A R knockout mice (δ‐ KO ). It is not known whether δ‐ GABA A R s are important for the effects of other drugs, such as opioids (that also inhibit GABA neurons) and stimulants (that primarily elevate monoamine levels). Here, we used δ‐ KO mice and conditioned place preference ( CPP ) test to study the rewarding effects of morphine (20 mg/kg), methamphetamine (1 mg/kg) and mephedrone (5 mg/kg). Morphine‐induced nociception was also assessed using tail‐flick and hot‐plate tests. We found that the δ‐ KO mice failed to express morphine‐induced CPP , but that they were more sensitive to morphine‐induced analgesia in the tail‐flick test. In contrast, stimulant‐induced CPP in the δ‐ KO mice was similar to that in the wild‐type controls. Thus, the conditioned rewarding effect by opioids, but not that of stimulants, was impaired in the absence of δ‐ GABA A R s. Further studies are warranted to assess the potential of δ‐ GABA A R antagonists as possible targets for reducing morphine reward and potentiating morphine analgesia.