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

ArticleinProgress in Neuro-Psychopharmacology and Biological Psychiatry 32(6):1399-1419 · August 2008with8 Reads
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.
    • "It has also been demonstrated that: (i) KD may increase extracellular adenosine level (Masino et al., 2012; Lutas and Yellen, 2013); (ii) inhibition of adenosine receptors (A 1 R and A 2A R) by means of caffeine promotes anxious behavior (Klein et al., 1991); (iii) A 1 R-or A 2A R-knockout mice showed anxiogenic-like behaviors (Ledent et al., 1997; Johansson et al., 2001); and (iv) modulation of adenosine receptor activity might be an effective treatment strategy for patients with anxiety disorders (Kovács and Dobolyi, 2013). In addition, as KD may evoke decreased extracellular glutamate level (Lutas and Yellen, 2013) and NMDA receptor antagonists may have anxiolytic effects (Guimarães et al., 1991; Engin and Treit, 2008) KD may exert its alleviating effect on anxiety level via glutamatergic system. Thus, theoretically, as ketone supplementation may generate similar changes in brain neurotransmitter systems as KD by means of ketosis (Figures 1–3), chronic and sub-chronic ketone supplementation-provoked anxiolytic effects may be evoked by means of glutamatergic and/or GABAergic as well as adenosinergic system in SPD and WAG/Rij rats. "
    [Show abstract] [Hide abstract] ABSTRACT: Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ~10 g/kg/day, LKE), high dose ketone ester (HKE; ~25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (βHB-S; ~25 g/kg/day, KS) and βHB-S + medium chain triglyceride (MCT; ~25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood βHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood βHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.
    Full-text · Article · Dec 2016
    • "The results of this work showed that the bilateral microinfusion of OT into the CeA decrease the total time that rats spend burying the electrified probe used in the Shock-Probe Burying test, which is considered the most sensitive measure of anxiety in this unconditioned paradigm [56]. OT effects were dose-dependent, and could be blocked by the simultaneous infusion of OTA, an OTR antagonist at doses that fail to affect by itself burying behavior. "
    [Show abstract] [Hide abstract] ABSTRACT: Dopamine D2 receptor (D2R)-Oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. In this work the hypothesis is tested using cotransfected HEK293 cells whether allosteric reciprocal D2R-OTR interactions can enhance signaling of D2R-OTR heterocomplexes along the CREB, MAPK and PLC pathways and whether the anxiolytic effects of OT may involve facilitatory D2R-OTR interactions within the central amygdaloid nucleus (CeA). Oxytocin enhanced the D2-like agonist quinpirole induced inhibition of the AC-PKA-pCREB signaling cascade and increased its signaling over the RAS-MAPK-pELK pathway. Quinpirole enhanced the oxytocin induced increases in the activity of the PLCbeta-IP3-calcineurin and RAS-MAPK-pELK cascades. Bilateral infusion of oxytocin (0.9-150 ng/side) into the CeA of the rat elicited anxiolytic effects in the Shock-Probe Burying test, an unconditioned model of fear/anxiety. This action was not observed when oxytocin (25ng/side) was simultaneously co-infused with raclopride (neither 250 nor 500 ng/side), a D2/D3 antagonist, into the CeA. Based on the current findings, the blockade of the anxiolytic effects of oxytocin by the simultaneous intra-CeA administration of raclopride can be explained by a lack of facilitatory protomer interactions in D2R-OTR heterocomplexes. Dysfunction and/or disruption of such interactions in the central amygdala may lead to anxiety development. Restoration of such interactions may represent a new strategy for development of novel anxiolytic drugs.
    Full-text · Article · Jul 2016
    • "ECs control both excitatory and inhibitory neurotransmission (Azad et al., 2003; Kreitzer and Regehr, 2001; Ohno-Shosaku et al., 2001) and were shown to affect anxiety by modulating GABAergic and glutamatergic functions (Haller et al., 2007; Rubio et al., 2008). CB1 and 5HT 3 receptors are co-expressed by GABAergic interneurons in the BLA, hippocampus and cortex (Hermann et al., 2002; Morales and Wang, 2002; Morales et al., 2004 ), brain structures involved in the control of anxiety (Davidson, 2002; Engin and Treit, 2008 ). It has been suggested that 5HT 3 neurotransmission is one of the important mechanisms through which cannabinoids affect anxiety (Freund and Hajos, 2003 ): postsynaptic 5HT 3 receptors mediate the serotonergic inputs received from the raphe nuclei, whereas presynaptic 5HT 3 and CB1 control GABAergic output to postsynaptic principal cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Both the serotonergic and the endocannabinoid system play a major role in mediating fear and anxiety. In the basolateral amygdala (BLA) it has been shown that the cannabinoid receptor 1 (CB1) is highly co-expressed with 5-HT3 receptors on GABAergic interneurons suggesting that 5-HT3 receptor activity modulates CB1-mediated effects on inhibitory synaptic transmission. In the present study, we investigated the possible interaction of CB1 and 5-HT3-mediated neuronal processes in the BLA using electrophysiological and behavioural approaches. Whole-cell patch-clamp recordings were performed in coronal brain slices of mice. Electric stimuli were delivered to the lateral amygdala to evoke GABAA receptor-mediated inhibitory postsynaptic currents (GABAA-eIPSCs) in the BLA. The induction of LTDi, a CB1-mediated depression of inhibitory synaptic transmission, was neither affected by the 5-HT3 antagonists ondansetron (OND; 20µM) and tropisetron (Trop; 50nM) nor by the 5-HT3 agonists SR57227A (10µM). In auditory fear conditioning tests, mice treated with SR57227A (3.0mg/kg i.p.) showed sustained freezing, whereas treatment with Trop (1.0mg/kg i.p.) decreased the expression of conditioned fear. These effects were overruled by the CB1 antagonist rimonabant (RIM; 3.0mg/kg), which caused increased freezing with or without co-treatment with Trop. In summary, these experiments do not support a functional interaction between CB1 and 5-HT3 receptors at the level of GABA neurotransmission in the BLA nor in terms of fear regulation.
    Full-text · Article · Jun 2013
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