GABAB receptor ligands do not modify conditioned fear responses in BALB/c mice

Sweeney, Fabian F.; O’Leary, Olivia F.; Cryan, John F.

doi:10.1016/j.bbr.2013.07.035

Cited by 18 publications

(12 citation statements)

References 23 publications

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“…Interestingly, congruent with the lack of effect of BHF177 on FPS in rats in the present study, we previously reported that BHF177 had no specific effect on contextual and cued fear conditioning as assessed by freezing behavior in mice (Li et al, 2013). Recent studies also showed that GS39783 did not modify conditioned fear responses in mice (Sweeney et al, 2013). Taken together, these results indicate that the GABA B receptor PAMs, such as BHF177 and GS39783, may be effective in attenuating unconditioned anxiety, but not conditioned fear.…”

Section: Discussionmentioning

confidence: 99%

The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

Kaczanowska

Finn

et al. 2015

Neuropharmacology

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GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists.

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Section: Discussionmentioning

confidence: 99%

The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

Kaczanowska

Finn

et al. 2015

Neuropharmacology

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“…Notably, the reduction produced by GS39783, with minimal dose-related differences, was so large that alcohol intake dropped to values (approximately 0.8 g/kg) similar to those usually collected in untreated rats during the first hours of the dark phase. This leads us to hypothesize that the anxiolytic effects of GS39783 (Cryan et al, 2004; Mombereau et al, 2004; see, however, Paterson & Hanania, 2010; Sweeney et al, 2013) may have substituted for those of alcohol, resulting in the virtually complete abolishment of (a) the extra amount of alcohol (due to the late access to alcohol during the dark phase) and, likely, (b) the increased anxiety-like state produced by the time schedule of alcohol access.…”

Section: Discussionmentioning

confidence: 99%

“…GS39783 is an in vivo effective, positive allosteric modulator (PAM) of the GABA B receptor (GABA B PAM) (Urwyler et al, 2003). During recent years, several behavioral studies have depicted an interesting pharmacological profile for GS39783: its acute or repeated administration (a) exerted anxiolytic-like effects in some rat and mouse models of anxiety (Cryan et al, 2004; Mombereau et al, 2004; see, however, Paterson & Hanania, 2010; Sweeney, O’Leary, & Cryan, 2013), and (b) suppressed several alcohol-related behaviors, including alcohol drinking in sP rats exposed to the 2-bottle “alcohol vs. water” choice regimen with unlimited access (Orrù et al, 2005) and operant, oral alcohol self-administration in alcohol-preferring sP, Indiana P, and Alko Alcohol (AA) rats (Maccioni et al, 2007, 2008, 2010, 2012, 2015). Notably, with regard to the aims of the present study, a recent investigation (Linsenbardt & Boehm, 2014) found that acute treatment with GS39783 suppressed binge-like drinking in C57BL/6J mice exposed to the “Drinking-in-the-Dark” procedure (i.e., daily exposure to a single alcohol bottle in daily 2- or 4-h drinking sessions, occurring early in the dark phase [see Thiele & Navarro, 2014]).…”

Section: Introductionmentioning

confidence: 99%

Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Colombo

Lobina

Maccioni

et al. 2015

Alcohol

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Recent research found that exposure of selectively bred, Sardinian alcohol-preferring (sP) rats to multiple alcohol concentrations (10%, 20%, and 30%, v/v), under the 4-bottle “alcohol vs. water” choice regimen, in daily 1-h drinking sessions with an unpredictable time schedule, promoted high intakes of alcohol (≥2 g/kg) when the drinking session occurred over the final hours of the dark phase of the light/dark cycle. The present study was aimed at investigating whether these high intakes of alcohol (a) were associated with alterations in rats’ emotional state (Experiment 1) and (b) were pharmacologically manipulable (Experiment 2). In both experiments, over a period of 12 days, sP rats were initially exposed daily to a1-h drinking session performed during the 12-h duration of the dark phase; time of alcohol exposure was changed each day and was unpredictable to rats. The day after this 12-day drinking phase, rats were (a) exposed to the Social Interaction (SI) test at the 1st or 12th hour of the dark phase with no alcohol available (Experiment 1) or (b) treated acutely with the positive allosteric modulator of the GABAB receptor, GS39783 (0, 25, 50, and 100 mg/kg, intragastrically [i.g.]), and exposed to a drinking session at the 12th hour of the dark phase (Experiment 2). In Experiment 1, rats exposed to the SI test during the 12th hour spent approximately 35% less time in “social” behaviors than rats exposed to the SI test during the 1st hour. No difference in “social” behaviors was observed between alcohol-naive sP rats exposed to the SI test at the 1st and 12th hour. In Experiment 2, all doses of GS39783 selectively reduced alcohol intake. These results suggest that (a) expectation of alcohol availability likely exacerbated the anxiety-like state of sP rats and (b) the GABAB receptor is part of the neural substrate underlying these exceptionally high intakes of alcohol in sP rats.

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“…A contribution of GABA B receptors to extinction‐induced amygdala plasticity echoes the observation that extinction increases amygdala expression of the GABA B2 receptor subunit (Heaney et al ., ). It is also noteworthy, in light of behavioural studies, that systemic delivery of a GABA B receptor antagonist (baclofen) or gene deletion of the GABA B1 receptor subunit lead to impaired extinction, although other studies report no effect of other systemically delivered GABA B receptor antagonists (phaclofen or CGP52432) or positive allosteric modulators (GS39783) (Jacobson et al ., ; Heaney et al ., ; Sweeney et al ., ).…”

Section: Neurotransmitters and Neuromodulators In Mpfc–amygdala‐mediamentioning

confidence: 97%

Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

Bukalo

Pinard

Holmes

2014

British J Pharmacology

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The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)-amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC-amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC-amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC-amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC-amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders. LINKED ARTICLESThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-20 Abbreviations ACC, anterior cingulate cortex; BA, basal nucleus of the amygdala; BLA, basolateral amygdala; CBT, cognitive behavioural therapy; CCK, cholecystokinin; CeA, central nucleus of amygdala; CeL, lateral nucleus of the central amygdala; CeM, medial nucleus of the central amygdala; CITZ, capsular infralimbic subregion target zone; CRF, corticotropin-releasing factor; FAAH, fatty acid amide hydrolase; GluA1, AMPA receptor subunit 1; GluA2, AMPA receptor subunit 2; GluN2B, NMDA receptor subtype 2B; GluN2C/D, NMDA receptor subtype 2C/D; GRP, gastrin-releasing peptide; HDAC, histone deacetylase; HAT, histone acetyltransferase ICN, intercalated cell nuclei; IN, main intercalated nucleus; KOP, κ-opioid; LA, lateral amygdala; mGlu, metabotropic glutamate receptor; mImp, medial paracapsular intercalated nucleus; MOP, μ-opioid; mPFC, medial prefrontal cortex; NPS, neuropeptide S; NPY, neuropeptide Y; PD, panic disorder; PEPA, 2- [2,6-difluoro-4-[[2-[(phenylsulfonyl) Introduction Prevalence and treatment of anxiety disordersAnxiety disorders consti...

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GABAB receptor ligands do not modify conditioned fear responses in BALB/c mice

Cited by 18 publications

References 23 publications

The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

Anxiety-like behaviors at the end of the nocturnal period in sP rats with a “history” of unpredictable, limited access to alcohol

Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

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