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Pregnanolone Hemisuccinate Inhibits NMDA Receptors with Selectivity for the NR1A/2A Subtype

Glutamate receptors play a major role in relapse of cocaine addiction. Effective treatments for prevention of relapse are still lacking. Previously, our laboratory has shown that pregnanolone hemisuccinate (3α5βHS or PAHS), the synthetic analogue of pregnanolone sulfate, inhibits reinstatement of cocaine seeking behavior in rats. In order to determine the mechanism of action of 3α5βHS, recombinant NMDA, AMPA and GABAA receptors were expressed in Xenopus laevis oocytes and two electrode voltage‐clamp recordings were performed. We observed that 3α5βHS inhibits all four subtypes of the NMDA receptor with similar efficacies (about −20%). However, the potency at the NR1A/2A subunit combination is 10 to 30 fold higher as compared with the NR1A/2B, 2C, and 2D subtypes. The EC50 for NR1A/2A is 0.32μM, whereas the EC50's for the NR1A/2B, 2C, and 2D subtypes are 4.3μM, 12.3μM and 9.8μM, respectively. Four subtypes of the GABA‐A receptor (α1β2γ2s, α2β2γ2s, α3β2γ2s, and α5β2γ2s) are inhibited by 3α5βHS with potencies ranging from 6–9μM and maximum efficacy of −18%. The AMPA receptor subtype GluR1 is slightly inhibited by 3α5βHS, however, 3α5βHS has no effect on GluR3 and the heteromeric GluR1/R2 receptor. The use of a multifunction compound acting on multiple receptor subtypes such as 3α5βHS may be effective in the treatment of cocaine seeking.