Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects

Background: Selective augmentation of hippocampal activity in ways similar to that caused by ketamine may have therapeutic advantages over ketamine, which has psychotomimetic and reinforcing effects likely due to effects outside the hippocampus (i.e., off-target effects). Methods: Here we evaluated the antidepressant-like response to a negative allosteric modulator of α5 subunit- containing gamma aminobutyric acid subtype A receptors, L-655,708, as these receptors are expressed to a much greater extent in the hippocampus than in other brain areas. Results: Systemic administration of L-655,708 produced a sustained antidepressant-like effect in the forced swim test that was comparable with that of ketamine and was blocked by hippocampal inactivation with lidocaine. However, in contrast to ketamine, L-655,708 did not affect prepulse inhibition of startle, nor did it maintain responding in rats trained to self-administer i.v. ketamine. Conclusion: Taken together, these findings suggest that activation of the hippocampus by L-655,708 produces an antidepressant-like effect in the absence of any psychotomimetic or abuse-related effects.