title: Effects of gaboxadol on the expression of cocaine sensitization in rats.
abstract: Behavioral sensitization to psychostimulants is associated with changes in dopamine (DA), glutamate, and GABA within the mesocorticolimbic and nigrostriatal DA systems. Because GABAA receptors are highly expressed within these systems, we examined the role of these receptors containing a δ subunit in cocaine behavioral sensitization. Experiment 1 examined the effects of Gaboxadol (GBX, also known as THIP [4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol]), a selective δ-GABAA receptor agonist, on the locomotor responses to acute cocaine. GBX at 1.25 mg/kg produced locomotor depression in female rats alone. We then examined the effects of GBX on the expression of cocaine-induced locomotion and stereotypy in female and male rats treated with 5 days of cocaine (15 mg/kg) followed by cocaine challenge 7 days later. We administered systemic (Experiment 2) or intranucleus accumbens (intra-NAC; Experiment 3) injections of GBX (0, 1.25, 2.5, 5, or 10 mg/kg subcutaneously, or 1 μmol/L or 1 mM intra-NAC, respectively) prior to cocaine challenge (10 mg/kg). In our experiments females were robustly sensitized to cocaine at low dose whereas males did not show such sensitization-limiting comparisons between the 2 sexes. Sensitized females showed a biphasic response to low (1.25 mg/kg and 1 μmol/L) and high (10 mg/kg and 1 mM) dose GBX whereas nonsensitized males showed this pattern only following intra-NAC injection. Immunohistochemical analysis of the NAC revealed that females have more δ-containing GABAA receptors than do males and that following chronic cocaine injections this difference persisted (Experiment 4). Together, our results support the notion of the key role of extrasynaptic GABAA δ-subunit containing receptors in cocaine sensitization.
authors.affiliation: Graduate Program in Neural and Behavioral Science, SUNY Downstate Medical Center.
authors.forename: Nora Siegal
authors.initials: NS
authors.lastname: Silverman
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center.
authors.forename: Susanna
authors.initials: S
authors.lastname: Popp
authors.affiliation: INSERM.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vialou
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Astafurov
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Graduate Program in Neural and Behavioral Science, SUNY Downstate Medical Center.
authors.forename: Diana
authors.initials: D
authors.lastname: Dow-Edwards
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D003042:Cocaine; C015542:gaboxadol