AbstractThe role of neuroactive steroids and GABAAreceptors in the generation of spontaneous spike‐and‐wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐TH PROG) were increased in the WAG/Rij rat at 2 months of age compared with those in control (Wistar) rats. In contrast, the brain and peripheral levels of 3α,5α‐tetrahydrodeoxycorticosterone (3α,5α‐TH DOC) did not differ between the two rat strains at this age. At 6 months of age, when absence epilepsy worsens in WAG/Rij rats, the plasma concentration of 3α,5α‐TH PROG remained high whereas that of 3α,5α‐TH DOC had increased, the cerebrocortical levels of both 3α,5α‐TH PROG and 3α,5α‐TH DOC had increased, and the thalamic concentrations of these metabolites had decreased. At 6 months of age the expression of the α4and δ subunits of the GABAAreceptor in relay nuclei was increased. Finally, chronic stress induced by social isolation elicited a reduction in the amount of 3α,5α‐TH PROG in the thalamus of 2‐month‐old WAG/Rij rats that was associated with a reduction in the number and overall duration of SWDs at 6 months of age. Absence epilepsy in the WAG/Rij rat is thus associated with changes in the abundance of neuroactive steroids and in the expression of specific GABAAreceptor subunits in the thalamus, a brain area key to the pathophysiology of this condition.