Table 2. Summary of Studies Examining the Role of GABA in the Extinction of Conditioned Fear.
| Study | Species | Drug | Time of administration | Route of administration | Proce- dure (task) | Findings | Role of GABA in extinction |
|---|---|---|---|---|---|---|---|
| Akirav (2007) | Rat | Muscimol | Post-extinction training | BLA | CTA | Intra-BLA muscimol disrupted extinction of CTA. The disruption persisted for at least 14 days. DCS reversed this effect. | Disrupts consolidation |
| Akirav et al (2006) | Rat | Muscimol | Pre and Post extinction training | IL, BLA | AFC | Pre-extinction training intra-IL infusion of muscimol facilitated extinction retention. Intra-BLA muscimol following short extinction facilitated extinction. | Facilitated acquisition |
| Berlau and McGaugh (2006) | Rat | Bicuculline | Post-extinction training | BLA | CFC | Bilateral intra-BLA bicuculline infusion enhanced extinction retention. | Disrupts consolidation |
| Muscimol, NE | Post-extinction training | DH | CFC | Muscimol had no effect on extinction, nor did it block the effects of NE (which enhanced extinction). | No effect | ||
| Bouton et al (1990) | Rat | MDZ, CDP | Pre-extinction training | Systemically | CFC | MDZ and CDP impaired long term expression of the extinction memory. However, pre-test CDP injection reinstated extinguished responding. | Disrupts acquisition through state dependency |
| Bustos et al (2009) | Rat | Midazolam (MDZ) | Post-extinction training | Systemic | CFC | MDZ disrupted extinction retention. | Disrupts consolidation |
| Chhatwal et al (2005) | Rat | H3-Flu | Variable times post-extinction training | BLA | LFC | The levels of gephyrin protein and mRNA were significantly increased 6 h following extinction training. Also, at both 2 and 6 h after extinction training there was increased binding of the benzodiazepine, H3-Flu to GABAA receptors. | Important for acquisition and/or expression |
| Cloutier et al (2006) | Male SD rats | Lindane | Pre-exposed to Lindane for 3 days or 5 days/week | Systemic | CFC | Pre-treatment with Lindane significantly impaired extinction, as freezing remained elevated in Lindane-treated rats relative to controls. | Disrupts acquisition |
| Corcoran and Maren (2001) | Male long-Evans rats | Muscimol | Pre-extinction-testing | DH | LFC | Muscimol-treated rats did not show renewal | Facilitated expression |
| Corcoran et al (2005) | Rats | Muscimol | Pre-extinction training and pre-extinction-testing | DH | AFC | Muscimol administered before extinction training, disrupted extinction retention. Muscimol infused before testing, abolished renewal. | Disrupts acquisition and facilitates expression. |
| Delamater and Treit (1988) | Male rats | CDP | Pre-extinction training | Systemic | CTA | CDP disrupted extinction of illness and shock-based taste aversions | Disrupts acquisition |
| Disorbo et al (2009) | Male SD rats | Muscimol | Pre- and post-extinction training | Systemic | CTA | Muscimol administered post, but not pre, produced a resistance to extinction across extinction-training sessions | Disrupts acquisition and consolidation |
| Dubrovina and Zinov'ev (2008) | Normal and stressed Male C57Bl/6J mice | Muscimol Bicuculline Baclofen Faclofen | Before fear acquisition | Systemic | Passive avoidance | Stressed rats exhibited impaired extinction compared to controls. Muscimol impaired extinction in control mice, but had no effect on stressed mice. Baclofen prolonged extinction in control mice, and facilitated it in stressed animals. Bicuculline had no effect. Faclofen delayed extinction in controls, and accelerated extinction in stressed mice. Interpretation of these results is difficult given that drugs were administered before conditioning. | Effects vary depending on emotional state of the animal |
| Goldman (1977) | Rat | CDP | Pre-extinction training | Systemic | AFC | CDP-treated animals failed to exhibit extinguished responding. | Disrupts acquisition |
| Gorman et al (1979) | Rat | Diazepam | Pre-extinction training | Systemic | IA | DZP produced a dose-dependent disruption in extinction retention | Disrupts acquisition |
| Graham (2006) | Rat | Bicuculline | Pre- and post-extinction training | Systemic | LFC | Administration of bicuculline facilitated extinction; however, the effects were unreliable. | Disrupts acquisition and consolidation |
| Harris and Westbrook (1998a) | Rat | FG7142 | Pre-extinction training and pre-re-extinction training | Systemic | CFC | FG7142 disrupted within-session extinction and extinction retention. The disruption was abolished when rats were tested in a different context | Facilitates acquisition and expression |
| Hart et al (2009) | Rat | MDZ (BZ/indirect agonist) | Pre-extinction training and pre-re-extinction training | Systemic and Intra BLA | CFC | MDZ disrupted within-session extinction and extinction retention, but had no effect on re-extinction memory. MDZ disrupted re-extinction when animals were extinguished under the influence of MDZ. | Disrupts acquisition of extinction, not re-extinction |
| Heldt and Ressler (2007) | c57BI/6J Mice | H3-Flu | Post-extinction training | BLA | AFC | Rats exhibited increased expression of GABAA receptor subunits within the amygdala—specifically α1 (LA), α2 (in the CE) and β2 (in the BLA). Rats also exhibited increased levels of gephyrin and GAD67 protein in the BLA. | Facilitates the acquisition and/or expression |
| Hobin et al (2006) | Rat | Muscimol (full agonist) | Pre-extinction testing | Ventral hippocampus | CFC | Muscimol disrupted context-specific fear memory retrieval. Specifically, animals exhibited extinguished responding regardless of the test context. Therefore, animals did not exhibit renewal. | Facilitates expression |
| Ishitobi et al (2009) | Rat | MDZ and Propofol | During conditioning (between CS and US onset) | Systemic | CTA | MDZ and propofol disrupted retention and enhanced extinction of CTA. Results are difficult to interpret since drugs were administered during conditioning, and not extinction-training. | Facilitates acquisition |
| Jacobson et al (2006) | Mice | GABA-B(1a) −/− and GABA-B(1b) −/− mice. | Pre-training | CTA | GABA-B(1b) KO mice failed to acquire CTA. In contrast GABA-B(1a) KO mice, failed to extinguish the aversion. | Facilitates acquisition and expression | |
| Kamano (1972) | Rats | CDP Amobarbital | Pre extinction training | Systemic | IA | Both CDP and Amobarbital disrupted extinction retention. | Disrupts acquisition |
| Kim and Richardson (2007) | Rat (PND 16 and 23) | FG7142 | Pre extinction testing | Systemic | AFC | Pre-testing FG7142 produced a context-specific deficit in the expression of extinction learning in PND23 rats, but not PND-18 rats. | Facilitates expression in older animals |
| Kim and Richardson (2009) | Rat | FG7142 | Pre-extinction testing | Systemic | AFC | Higher freezing was shown in the FG7142 rats compared to vehicle rats, regardless of whether the test context was similar or different to the extinction-training context. | Facilitates expression |
| Lin, Mao, Chen, and Gean (2008) | Rat | WIN55212-2 Bicuculline | Pre-conditioning (once per day for 7 days) and pre-extinction training | Systemic and IL | LFC | In control rat slices of the IL, WIN application reduced GABAergic inhibitory transmission. Extinction was intact among these rats. In contrast, WIN pre-treated rats showed persistent GABAergic inhibitory transmission in response to WIN application. These rats also displayed a resistance to the extinction-enhancing effects of pre-extinction training WIN administration. Furthermore, administration of bicuculline into the IL produced an extinction-like reduction in startle in both control and WIN-treated animals. | Disrupts acquisition |
| Marsciano et al (2002) | Mice | CB1−/− mice and control CB1+/+ mice | Pre-training | LA | AFC | In control CB+/+ mice, but not CB−/− mice, long-term depression (LTD) was induced successfully in LA slices. This was associated with a suppression of GABAA receptor-mediated inhibitory post-synaptic currents. | Disrupts acquisition and/or consolidation |
| McGaugh et al (1990) | Male CD1 mice | Picrotoxin | Post-extinction-training | Systemic | AFC | Picrotoxin facilitated extinction | Disrupts consolidation |
| Nomura and Matsuki (2008) | Male SD rats | Ethanol | Post-extinction | Systemic | CFC | Ethanol had no effect on the retention of extinction. | Not involved in extinction |
| Pereira et al (1989) | Female Wistar rats | Diazepam | Pre-extinction-training | Systemic | Shuttle avoidance | DZP disrupted extinction retention, regardless of whether extinction training occurred 2 or 24 h after conditioning. | Disrupts acquisition |
| Shumyatsky et al (2002) | Mice | Genetically modified mice with a GRPR KO | Pre-extinction training | CFC and AFC | GRPR KO's exhibited greater freezing compared to wild-type controls. Both groups showed reduced freezing over subsequent brief-CS re-exposure sessions. | Facilitates acquisition and/or expression | |
| Taub et al (1977) | Male SD rats | CDP | Pre-extinction training | Systemic | IA | Animals treated with CDP before extinction training disrupted extinction retention. | Disrupts acquisition |
| Yee et al (2004) | Alpha-5(H105R) mutant mice | Genetically modified mice, expressing fewer α5 subunit-containing GABA receptors in the hippocampus | Knock-in-pre-training. | Hippocampus | AFC | During extinction testing, female but not male, mutant mice exhibited greater levels of freezing indicating impaired extinction. However, across additional testing sessions, both male and female mice displayed a resistance to extinction. | Facilitates acquisition and/or expression |
Abbreviations: AFC, auditory fear conditioning; BLA, basolateral amygdala; BZ, Benzodiazepine; CB1+/+, wild-type mouse; CB1−/−, CB1 receptor-deficient mouse; CDP, chlordiazepoxide; CD1, cluster of differentiation 1 a family of glycoproteins; CFC, contextual fear conditioning; CS, conditioned stimulus; CTA, conditioned taste aversion; C57Bl/6J, CE, mouse strain; DH, dorsal hippocampus; DCS, d-cycloserine; DZP, diazepam; GABA, gamma-amino butyric acid; GABA-B(1a), subunit 1a of the GABA-B receptor; GABA-B(1b), subunit 1b of the GABA-6B receptor; GAD67, glutamic acid decarboxylase 67; GRP, gastrin-releasing peptide; GRPR, gastrin-releasing peptide receptor; H3-Flu, H3-flunitrazepam; IA, inhibitory avoidance; IL, Infralimbic cortex; KO, knockout; LA, lateral amygdala; LFC, light fear conditioning; MDZ, midazolam; mRNA, messenger ribonucleic acid; NE, norepinephrine; PND, post-natal day; SD, Sprague–Dawley rat strain; US, unconditioned stimulus; WIN 55,212-2, 3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl](1-naphthalenyl)methanone.