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



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.



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.



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.
Department of Pharmacology (Drs Carreno, Collins, Frazer, and Lodge), and Center for Biomedical Neuroscience (Drs Carreno, Frazer, and Lodge), University of Texas Health Science Center, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas (Drs Collins and Frazer).
Flavia R
FR
Carreno
Department of Pharmacology (Drs Carreno, Collins, Frazer, and Lodge), and Center for Biomedical Neuroscience (Drs Carreno, Frazer, and Lodge), University of Texas Health Science Center, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas (Drs Collins and Frazer).
Gregory T
GT
Collins
Department of Pharmacology (Drs Carreno, Collins, Frazer, and Lodge), and Center for Biomedical Neuroscience (Drs Carreno, Frazer, and Lodge), University of Texas Health Science Center, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas (Drs Collins and Frazer).
Alan
A
Frazer
Department of Pharmacology (Drs Carreno, Collins, Frazer, and Lodge), and Center for Biomedical Neuroscience (Drs Carreno, Frazer, and Lodge), University of Texas Health Science Center, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas (Drs Collins and Frazer).
Daniel J
DJ
Lodge
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology; D008012:Lidocaine; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012646:Self Administration; D019966:Substance-Related Disorders / Q000378:metabolism
D000928:Antidepressive Agents; C496250:Gabra5 protein, mouse; D007093:Imidazoles; C105490:L 655,708; D011963:Receptors, GABA-A; D007649:Ketamine; D008012:Lidocaine
708; L-655; abuse; antidepressant; α-5-containing GABAA receptors