Behavioral sensitization to psychostimulants is associated with changes in dopamine (DA), glutamate, and GABA within the mesocorticolimbic and nigrostriatal DA systems. Because GABA(A) receptors are highly expressed within these systems, we examined the role of these receptors containing a delta 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 delta-GABA(A) 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 mu mol/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 mu mol/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 delta-containing GABA(A) 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 GABA(A) delta-subunit containing receptors in cocaine sensitization.