GABA Site Agonist Gaboxadol Induces Addiction-Predicting Persistent Changes in Ventral Tegmental Area Dopamine Neurons But Is Not Rewarding in Mice or Baboons

Abstract

In behavioral experiments, we found neither acute reinforcement in intravenous selfadministration 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 ␦-subunit-containing GABA A receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion.

Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons

“…We first searched for slightly sedative doses of GAN after acute injections to locate the closest match to our previous study with THIP (Vashchinkina et al, 2012) that has a full agonistic profile at extrasynaptic GABA A receptors (Storustovu and Ebert, 2006). We found that GAN 30 mg/ kg produced a transient reduction in locomotor activity of young mice, whereas a 10 mg/kg dose did not affect activity (Figure 1a and b).…”

“…a-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and Nmethyl-D-aspartate (NMDA) receptor EPSCs were induced by stimulating glutamatergic afferents at 0.1 kHz frequency using a bipolar stimulus electrode (Vashchinkina et al, 2012). Neurons were clamped at þ 40 mV in the presence of GABA A receptor blocker picrotoxin (100 mM), and EPSCs were recorded for 10 min before and after the application of NMDA receptor blocker D-( À )-2-amino-5-phosphonopentanoic acid (AP5 50 mM).…”

“…The procedure was performed in eight Plexiglas cages covered with transparent lids with ventilation holes (Cunningham et al, 2006;Vashchinkina et al, 2012). Two types of preselected floor material (plastic 1.2-cm-wide flat bars separated by 0.5-cm gaps and a metal grid with 1-mm-spacing between wires) were used as conditioning stimuli.…”

“…injection of vehicle, GAN (30 mg/kg), or 4,5,6,7-tetrahydroisoxazolol[4,5-c]pyridine-3-ol (THIP, gaboxadol; 6 mg/ kg), a selective GABA-site agonist with a full agonist profile at d-subunit-containing GABA A receptors (Storustovu and Ebert, 2006). THIP has shown to induce neuroplasticity in VTA DA neurons but no reward-like behavior in CPP test in mice (Vashchinkina et al, 2012).…”

“…To determine whether GAN induces potentiation in the VTA DA neurons through insertion of new GluA2 subunit-lacking receptors in a similar manner as THIP (Vashchinkina et al, 2012), we tested the I-V relationships of AMPAR-EPSCs and calculated the rectification index (Luscher and Malenka, 2011). The pipette solution containing polyamines selectively blocks the GluA2-lacking AMPA receptors (Dingledine et al, 1999), which can be seen as increased rectification at positive holding potentials.…”