Local Changes in Neurosteroid Levels in the Substantia Nigra Reticulata and the Ventral Tegmental Area Alter Chronic Ethanol Withdrawal Severity in Male Withdrawal Seizure‐Prone Mice

Background Allopregnanolone ( ALLO ) is a potent positive modulator of γ‐aminobutyric acid A receptors ( GABA A R s) that affects ethanol ( E t OH ) withdrawal. Finasteride ( FIN ), a 5α‐reductase inhibitor that blocks the formation of ALLO and other GABA ergic neurosteroids, alters E t OH sensitivity. Recently, we found that Withdrawal Seizure‐Prone mice from the first genetic replicate ( WSP ‐1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during E t OH withdrawal and that intrahippocampal FIN significantly increased E t OH withdrawal severity. The purpose of this study was to determine whether neurosteroid manipulations in the substantia nigra reticulata ( SNR ) and ventral tegmental area ( VTA ) produced effects during E t OH withdrawal comparable to those seen with intrahippocampal ALLO and FIN . Methods Male WSP ‐1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at 2 weeks prior to E t OH vapor or air exposure for 72 hours. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100, or 400 ng/side) at a time corresponding to peak withdrawal in the air‐ and E t OH ‐exposed mice. Separate studies examined the effect of 4 FIN infusions (0 or 10 μg/side/d) during the development of physical dependence on the expression of E t OH withdrawal. Results ALLO infusion exerted a potent anticonvulsant effect in E t OH ‐naïve mice, but a diminished anticonvulsant effect during E t OH withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in EtOH‐naïve mice, whereas infusion into the VTA increased E t OH withdrawal duration. Conclusions Activation of local GABA A R s in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during E t OH withdrawal. Thus, E t OH withdrawal reduced sensitivity of GABA A R s to GABA ergic neurosteroids in 2 neuroanatomical substrates within the basal ganglia in WSP ‐1 male mice.