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

Abstract

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.

Mechanisms of ketamine action as an antidepressant

“…In rats, ketamine administration at sub-anesthetic doses results in a significant increase in extracellular glutamate levels 35 and an increase in glutamate cycling 44 in the prefrontal cortex. Further supporting this hypothesis, administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABA A receptors, which are selectively expressed in the forebrain, including prefrontal cortex and hippocampus, promote coherent network activity via disinhibition of excitatory neurotransmission 45 and exert rapid antidepressant actions in several animal tests 46–48 . Notably, ketamine 13 , similar to negative allosteric modulators of alpha5-containing GABA A receptors 47 , enhance gamma band electroencephalography power, which is hypothesized to be directly related to cortical disinhibition 49–52 , further supporting the role of cortical disinhibition in the rapid antidepressant actions of these drugs.…”

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…Furthermore, MRK‐016 produced ketamine‐like rapid‐acting antidepressant actions, through AMPAR‐dependent increase coherent neuronal activity . Furthermore, L‐655,708 and another GABA B receptor, MAM RY‐080, had antidepressant‐like effects in rodents . However, unlike ( R )‐ketamine, MRK‐016 did not produce an antidepressant effect 7 days after a single dose in a CSDS model although MRK‐016 elicited rapid‐acting antidepressant effects in the same model.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Specifically, administration of GABA-NAMs that are selective for receptors containing alpha5 subunits, such as L-655,781 or MRK-016, reversed social interaction and sucrose preference deficits following several chronic stress paradigms 24 h after administration in rats [162]. The effects of a single injection were long-lasting since decreases in behavioral despair in the forced-swim test and restoration of sucrose preference deficits could be seen up to 7 days post-treatment [163]. In mice, MRK-016 administration rapidly reversed chronic restraint stress-induced decreases in female urine sniffing preference (a measure of hedonic behavior in male mice) and it decreased immobility time in the 24-h forced-swim test [164].…”

“…More recently, the alpha5-selective GABA-NAM, RY-080, was shown to reduce behavioral despair in the acute forced-swim paradigm [165]. Importantly, in contrast to ketamine, alpha5-selective GABA-NAMs lack the sensory dissociation and abuse liability at antidepressant-relevant doses in animal models [163, 164] and in humans [166]. Rodent expression of the alpha5 subunit is largely limited to the hippocampus and PFC [167], with humans also showing preferential expression in these regions [168].…”