A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.

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