Serotonergic mechanisms in anxiety

Eison, Arlene S.; Eison, Michael S.

doi:10.1016/0278-5846(94)90023-x

Cited by 73 publications

(45 citation statements)

References 50 publications

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“…In vitro, OFQ/N has been shown to inhibit serotonin release from cortical serotonergic nerve terminals (Siniscalchi et al, 1999). The dorsal raphe nucleus is the main cell body region of the serotonergic neuronal system in the CNS, and neuronal hyperactivity in this area has been associated with increased anxiety (Eison and Eison, 1994;Coplan et al, 1995). Furthermore, there is substantial preclinical evidence showing the anxiolytic actions of agents that either decrease presynaptic release of serotonin (Sánchez, 1993;Menard and Treit, 1999) or block postsynaptic serotonin receptors within this neuronal system (Griebel, 1995;Menard and Treit, 1999).…”

Section: Discussionmentioning

confidence: 99%

The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

Varty¹,

Lu²,

Morgan³

et al. 2008

J Pharmacol Exp Ther

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Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC 50 ϭ 12 nM) that binds with high affinity (K i ϭ 0.3 nM) and functional selectivity (Ͼ50-fold over the -, -, and ␦-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.The nociceptin opioid receptor (NOP) was identified using a human cDNA library on the basis of close homology with the -, -, and ␦-opioid receptors (Bunzow et al., 1994;Mollereau et al., 1994). Subsequently, the endogenous ligand for the NOP receptor, orphanin FQ/nociceptin (OFQ/N), was identified from brain extracts and found to bind with high affinity to the NOP site, but not to -, -, or ␦-opioid receptors (Meunier et al., 1995;Reinscheid et al., 1995). Immunohistochemical studies demonstrated that the mRNA for OFQ/N and its precursor prepronociceptin, as well as immunoreactivity for the NOP receptor, are localized to corticolimbic regions of the central nervous system (CNS). These regions include the amygdaloid complex, septohippocampal regions, periaqueductal gray, locus coeruleus, and dorsal raphe nucleus (Darland et al., 1998). In vitro electrophysiological studies using brain slices have shown that OFQ/N has potent Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 99%

The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

Varty¹,

Lu²,

Morgan³

et al. 2008

J Pharmacol Exp Ther

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“…Ritanserin, a 5-HT 2A /5-HT 2C receptor antagonist, reduced risk assessment in the cat odor situation but was without effect on other Anxiety/Defense Test Battery measures. It has been reported to be clinically effective against some (Eison and Eison, 1994) but not all (Den Boer et al, 1995) types of anxiety. Specificity of this profile of effects was further emphasized by findings that drugs such as the 5-HT 3 receptor antagonists MDL 72222 and ondansetron were without effect in these models (Shepherd et al, 1993).…”

Section: The Anxiety/defense Test Batterymentioning

confidence: 99%

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Blanchard

Griebel

Blanchard

2003

European Journal of Pharmacology

258

159

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The Mouse Defense Test Battery was developed from tests of defensive behaviors in rats, reflecting earlier studies of both acute and chronic responses of laboratory and wild rodents to threatening stimuli and situations. It measures flight, freezing, defensive threat and attack, and risk assessment in response to an unconditioned predator stimulus, as well as pretest activity and postthreat (conditioned) defensiveness to the test context. Factor analyses of these indicate four factors relating to cognitive and emotional aspects of defense, flight, and defensiveness to the test context. In the Mouse Defense Test Battery, GABA A -benzodiazepine anxiolytics produce consistent reductions in defensive threat/attack and risk assessment, while panicolytic and panicogenic drugs selectively reduce and enhance, respectively, flight. Effects of GABA A -benzodiazepine, serotonin, and neuropeptide ligands in the Mouse Defense Test Battery are reviewed. This review suggests that the Mouse Defense Test Battery is a sensitive and appropriate tool for preclinical evaluation of drugs potentially effective against defense-related disorders such as anxiety and panic. D

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“…Serotonergic neurons play a role in reconfiguring neural circuitry in the sensory and motor systems and are associated with anxiety and defensive behaviors (Eison and Eison, 1994;Meneses, 1999). Recently, it has been shown that 5-HT 2A receptors alone mediate fear and anxiety states (Castilho and Brandao, 2001;Weisstaub et al, 2006) and that activation of 5-HT 2A receptors improves learning and working memory (Williams et al, 2002;Harvey, 2003;Harvey et al, 2004;Romano et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Serotonergic Modulation of Plasticity of the Auditory Cortex Elicited by Fear Conditioning

Suga²

2007

J. Neurosci.

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In the awake big brown bat, 30 min auditory fear conditioning elicits conditioned heart rate decrease and long-term best frequency (BF) shifts of cortical auditory neurons toward the frequency of the conditioned tone; 15 min conditioning elicits subthreshold cortical BF shifts that can be augmented by acetylcholine. The fear conditioning causes stress and an increase in the cortical serotonin (5-HT) level. Serotonergic neurons in the raphe nuclei associated with stress and fear project to the cerebral cortex and cholinergic basal forebrain. Recently, it has been shown that 5-HT 2A receptors are mostly expressed on pyramidal neurons and their activation improves learning and memory. We applied 5-HT, an agonist (␣-methyl-5-HT), or an antagonist (ritanserin) of 5-HT 2A receptors to the primary auditory cortex and discovered the following drug effects: (1) 5-HT had no effect on the conditioned heart rate change, although it reduced the auditory responses; (2) 4 mM 5-HT augmented the subthreshold BF shifts, whereas 20 mM 5-HT did not; (3) 20 mM 5-HT reduced the long-term BF shifts and changed them into short-term; (4) ␣-methyl-5-HT increased the auditory responses and augmented the subthreshold BF shifts as well as the long-term BF shifts; (5) in contrast, ritanserin reduced the auditory responses and reversed the direction of the BF shifts. Our data indicate that the BF shift can be modulated by serotonergic neurons that augment or reduce the BF shift or even reverse the direction of the BF shift. Therefore, not only the cholinergic system, but also the serotonergic system, plays an important role in cortical plasticity according to behavioral demands.

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Serotonergic mechanisms in anxiety

Cited by 73 publications

References 50 publications

The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Serotonergic Modulation of Plasticity of the Auditory Cortex Elicited by Fear Conditioning

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