# Selective negative allosteric modulators of alpha 5-GABAA receptors: novel psychotherapeutic drugs

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2020 · —

## Abstract

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid, with both
having exposure to stressors a contributing factor to their development. They share similarities in treatment with
selective serotonin reuptake inhibitors (SSRIs) being the most common pharmacological treatment for both, even
though their efficacy is modest. There is a serious unmet need for better treatments for these disorders. The now
replicated finding that the NMDA receptor antagonist ketamine has both rapid and sustained efficacy in patients
with treatment resistant depression (TRD) has had tremendous impact. It may also have rapid efficacy in patients
with chronic PTSD. Because of ketamine's adverse effect profile, it would be useful to identify drugs that mimic
ketamine's beneficial clinical effects without producing its adverse effects. We recently demonstrated, in rodents,
that the ventral hippocampus (vHipp) is a critical target for the antidepressant (AD)-like response to ketamine.
By contrast, direct effects of ketamine on non-hippocampal pathways are likely involved in some of its adverse
effects. Consequently, we have begun to study effects of drugs targeting the Hipp because of the distinct
localization there of the subtypes of receptors on which they act. The α5-subunit of the Gamma Aminobutyric
Acid receptor, subtype A (GABAA) has a preferential hippocampal localization and selective negative allosteric
modulators (NAMs) of the α5-GABAA receptor have been developed. Their effect on glutamatergic output
neurons in the hippocampus would be expected to be similar to that of ketamine. We recently reported that one
such drug, L-655,708, replicated the sustained AD-like effect of ketamine but had neither reinforcing-,
psychotomimetic- nor anxiogenic-like effects.
To extend these observations, we will examine the effects of L-655,708 on stress-induced behaviors thought to
mimic symptoms consistent with either MDD or PTSD. The stress procedure will be the administration of
inescapable shock (IS) to rats on two consecutive days. Control rats will receive escapable shock (ES). Stress-
induced behavioral deficits will be measured using the following parameters: 1) forced swim test; 2) shock probe
defensive burying; 3) female urine sniffing test (FUST), and 4) the attentional set-shifting test (AST). These four
procedures evaluate specific behavioral deficits seen in these disorders, e.g., the FUST for anhedonia or the
AST for cognitive impairment. The effect of L-655,708 on these behaviors will be evaluated when it is given either
prior to ES or IS (i.e., prophylaxis) or after ES or IS (i.e., treatment). A chemogenetic (DREADD) approach will
be used to evaluate if activation of pathway from the vHipp –medial prefrontal cortex (mPFC) and a circuit from
the vHipp – nucleus accumbens (NAc), either directly or via its projection to the mPFC are necessary for the
effects of L-655,708 on the FST and FUST respectively. Our overriding hypotheses...

## Key facts

- **NIH application ID:** 9894634
- **Project number:** 5I01BX000559-09
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** ALAN FRAZER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-01-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894634

## Citation

> US National Institutes of Health, RePORTER application 9894634, Selective negative allosteric modulators of alpha 5-GABAA receptors: novel psychotherapeutic drugs (5I01BX000559-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894634. Licensed CC0.

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