The effects of intra-cerebral drug infusions on animals' unconditioned fear reactions: A systematic review

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: 4.03). 08/2008; 32(6):1399-1419. DOI: 10.1016/j.pnpbp.2008.03.020

ABSTRACT 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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    • "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. "
    Pharmacology, 03/2012; , ISBN: 978-953-51-0222-9
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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. "
    The Amygdala - A Discrete Multitasking Manager, Edited by Barbara Ferry, 01/2012; InTech.
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    • "It is believed that many brain regions are involved in the modulation of anxiety (McNaughton and Corr, 2004). Among all these studied areas, amygdala has received special attention for its key role in the regulation and expression of fear and anxiety in many animal species like rodents and human (Davis and Whalen, 2001; Engin and Treit, 2008; Millan, 2003; Perez de la Mora et al., 2008). The basolateral complex of the amygdala is the main gate receiving sensory information from the environment via cortical and thalamic neurons (McDonald et al., 1996; Romanski and LeDoux, 1992). "
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    ABSTRACT: Cholinergic system stimulation in some parts of the brain may affect anxiety-related behaviors. This system has many interactions with dopaminergic neurotransmission in the brain. We have studied the effect of cholinergic system activation in the basolateral amygdala on anxiety-related behaviors in adult male wistar rats using the acetylcholinesterase inhibitor physostigmine. Furthermore, the possible involvement of dopamine D(1) and D(2) receptors of basolateral amygdala in physostigmine induced effects has been evaluated. The elevated plus-maze task was used to assess anxiety parameters and all drugs were delivered into basolateral amygdala via bilaterally implanted chronic cannulas. Physostigmine (20 μg/rat) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), revealing an anxiolytic-like effect. However, muscarinic receptor antagonist scopolamine (8 μg/rat) decreased %OAT indicating anxiogenic-like effect. A sub-effective dose of scopolamine (2 μg/rat) plus physostigmine decreased %OAT and %OAE in comparison to saline plus physostigmine (20 μg/rat). Muscarinic receptor agonist pilocarpine (5 μg/rat), dopamine D(1) receptor antagonist SCH23390 (1 μg/rat) and dopamine D(2) receptor antagonist sulpiride (5 μg/rat) significantly increased %OAT which may show anxiolytic-like effects of drugs. Sulpiride (5 μg/rat) also increased %OAE parameter. Pre-treatment with SCH23390 (0.5 and 1 μg/rat) or sulpiride (5 μg/rat) blocked anxiolytic-like effect of physostigmine (20 μg/rat). All drugs were devoid of any significant effect on locomotor activity. It is concluded that intra-basolateral amygdala administration of physostigmine has anxiolytic-like effects which may be via muscarinic mechanisms. Furthermore, dopaminergic system activation probably via dopamine D(1) and D(2) receptors is necessary for mediating anxiolytic-like effects of physostigmine.
    European journal of pharmacology 12/2011; 672(1-3):106-12. DOI:10.1016/j.ejphar.2011.09.168 · 2.68 Impact Factor
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