Engin E, Treit D. The effects of intra-cerebral drug infusions on animals' unconditioned fear reactions: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry 32: 1399-1419

Department of Psychology and division of Neuroscience, University of Alberta, P449 Biological Sciences Building, Edmonton, Canada AB T6G 2E9
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 3.69). 08/2008; 32(6):1399-1419. DOI: 10.1016/j.pnpbp.2008.03.020


Intra-cerebral (i.c.) microinfusion of selective receptor agonists and antagonists into behaving animals can provide both neuroanatomical and neurochemical insights into the neural mechanisms of anxiety. However, there have been no systematic reviews of the results of this experimental approach that include both a range of unconditioned anxiety reactions and a sufficiently broad theoretical context. Here we focus on amino acid, monoamine, cholinergic and peptidergic receptor ligands microinfused into neural structures previously implicated in anxiety, and subsequent behavioral effects in animal models of unconditioned anxiety or fear. GABAA receptor agonists and glutamate receptor antagonists produced the most robust anxiolytic-like behavioral effects, in the majority of neural substrates and animal models. In contrast, ligands of the other receptor systems had more selective, site-specific anti-anxiety effects. For example, 5-HT1A receptor agonists produced anxiolytic-like effects in the raphe nuclei, but inconsistent effects in the amygdala, septum, and hippocampus. Conversely, 5-HT3 receptor antagonists produced anxiolytic-like effects in the amygdala but not in the raphe nuclei. Nicotinic receptor agonists produced anxiolytic-like effects in the raphe and anxiogenic effects in the septum and hippocampus. Unexpectedly, physostigmine, a general cholinergic agonist, produced anxiolytic-like effects in the hippocampus. Neuropeptide receptors, although they are popular targets for the development of selective anxiolytic agents, had the least reliable effects across different animal models and brain structures, perhaps due in part to the fact that selective receptor ligands are relatively scarce. While some inconsistencies in the microinfusion data can easily be attributed to pharmacological variables such as dose or ligand selectivity, in other instances pharmacological explanations are more difficult to invoke: e.g., even the same dose of a known anxiolytic compound (midazolam) with a known mechanism of action (the benzodiazepine–GABAA receptor complex), can selectively affect different fear reactions depending upon the different subregions of the nucleus into which it is infused (CeA versus BLA). These particular functional dissociations are important and may depend on the ability of a GABAA receptor agonist to interact with distinct isoforms and combinations of GABAA receptor subunits (e.g., α1-6, β1-3, ϒ1-2, δ), many of which are unevenly distributed throughout the brain. Although this molecular hypothesis awaits thorough evaluation, the microinfusion data overall give some support for a model of “anxiety” that is functionally segregated along different levels of a neural hierarchy, analogous in some ways to the organization of sensorimotor systems.

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    • "A broad range of neurotransmitters released into the PAG have been shown to play important roles in the mediation of defensive behaviors. For instance, it has been shown that serotonin, gamma-aminobutyric acid (GABA), glutamate and neuropeptides such as opioid and corticotropin-releasing factor (CRF) receptor agonists and antagonists change defensive behavior when injected into this midbrain structure (5,6). "
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    ABSTRACT: The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of N(ω)-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.
    Full-text · Article · Mar 2012 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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    • "Anxiety results from an imbalance between GABAergic and glutamatergic systems, either from overactive glutamatergic neurotransmission or inadequate GABAergic activity in hypothalamus, periaqueductal gray, hippocampus and prefrontal cortex (Engin and Treit, 2008). It is hypothesised that the antagonism of mGlu 1 receptors is capable of augmenting the GABAergic response, whilst concomitantly decreasing the NMDA receptor-mediated glutamatergic response in key brain regions involved in anxiety. "

    Full-text · Chapter · Mar 2012
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    • "State fear within animal models is most often studied by measures of freezing and fear-potentiated startle, both acquired via classical conditioning of rodents [1] [8]. State anxiety, on the other hand, is most often studied using apparatus such as an open field, elevated plus maze, or light-dark box, which all take advantage of the rodent's preference for familiar, dark, and/or enclosed areas [1] [9]. Notably, these paradigms do not rely on the processes underlying classical conditioning, although McNaughton and Corr [2] caution against defining fear verses anxiety as conditioned versus unconditioned responses. "

    Full-text · Chapter · Jan 2012
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