Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects
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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.
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The antidepressant-like effects of the α5 negative allosteric modulator L-655,708 are blocked with an intrahippocampal infusion of lidocaine.
“Furthermore, the antidepressant-like effects of the α5 negative allosteric modulator L-655,708 are blocked with an intrahippocampal infusion of lidocaine [140].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [140]
Effects of negative allosteric modulators of α5GABAARs are observed both 1 hour and 24 hours following administration.
“Although it is not entirely clear how positive and negative modulation of the same receptor subtype could have antidepressant-like effects, it should be noted that the effects of the negative allosteric modulators are observed both 1 hour and 24 hours following administration.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [140]
Administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA receptors promotes coherent network activity via disinhibition of excitatory neurotransmission and exerts rapid antidepressant actions in several animal tests.
“Further supporting this hypothesis, administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA 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–”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [48]
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- Authors
- Carreno, F. R., Collins, G. T., Frazer, A., & Lodge, D. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Carreno, Flavia R.
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-01-25
- Volume
- 20
- Issue
- 6
- Pages
- 504-509
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC5458335
- OpenAlex
- W2601083671
- Cited by
- 31
- References
- 30
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 9
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000559)
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (5r01mh090067-10)
- National Institute of Mental Health (R01: MH090067, R01MH082933)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- alpha5 GABA-A receptor, hippocampal activation, antidepressant-like effects, ketamine, negative allosteric modulators, prepulse inhibition, psychotomimetic effects, forced swim test, off-target effects
- MeSH terms
- Animals, Antidepressive Agents, Depressive Disorder, Hippocampus, Imidazoles, Ketamine, Lidocaine, Receptors, GABA-A, Self Administration, Reflex, Startle, Rats, Sprague-Dawley, Substance-Related Disorders, Prepulse Inhibition
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