Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608)

Spooren, Will; Schoeffter, Philippe; Gasparini, F.; Kühn, Rainer; Gentsch, C.

doi:10.1016/s0014-2999(01)01562-x

Cited by 137 publications

(92 citation statements)

References 18 publications

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“…LY354740 has evidenced activity in a number of rodent stress and anxiety models, including fear-potentiated startle, elevated plus maze, lactate-induced panic, and stress-induced hyperthermia (Walker et al, 2002;Tizzano et al, 2002;Monn et al, 1997;Shekhar and Keim, 2000;Spooren et al, 2002). Importantly, the effects of LY354740 occur at doses that are not associated with psychomotor impairment, which is common with benzodiazepine pharmacology (Helton et al, 1998;Tizzano et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Dunayevich

Erickson

Levine

et al. 2007

Neuropsychopharmacol

171

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Section: Introductionmentioning

confidence: 99%

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Dunayevich

Erickson

Levine

et al. 2007

Neuropsychopharmacol

171

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“…In addition, the effects of LY354740 on the visual pathways could also affect the EPM behavior, given the importance of visual cues in this test. However, LY354740 is active in several other anxiety tests that are not dependent on visual cues, for example, stress-induced hyperthermia (Spooren et al, 2002) and conflict drinking test (Klodzinska et al, 1999). Moreover, LY354740 administered locally to the hippocampus or amygdala produces anxiolytic-like behaviors (Tatarczynska et al, 2001;Walker et al, 2002), suggesting that the activation of visual regions by systemic LY354740 is most likely unrelated to its anxiolytic actions.…”

Section: Central C-fos After Anxiolytic Ly354740mentioning

confidence: 99%

“…It activates human cloned mGlu2 and mGlu3 receptors in non-neuronal cells with EC 50 values of 5 and 24 nM, respectively, while EC 50 values for other mGlu receptors were 36 mM (mGlu8) or higher (EC 50 4100 mM for mGlu1, 5, 4, 7) (reviewed by Schoepp et al, 1999b). LY354740 produces anxiolytic-like effects in several animal models of anxiety, including fear-potentiated startle (Helton et al, 1998), elevated plus maze (EPM) (Monn et al, 1997;Helton et al, 1998;Ferris et al, 2001), conflict drinking test (Klodzinska et al, 1999), and stress-induced hyperthermia (Spooren et al, 2002). LY354740 is also active in an animal model of panic disorder (Shekhar and Keim, 2000).…”

Section: Introductionmentioning

confidence: 99%

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

Lindén

Greene

Bergeron

et al. 2003

Neuropsychopharmacol

101

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LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety, including the elevated plus maze (EPM) test. Here, we studied neuronal activation in mouse brain after EPM exposure in saline-and LY354740-treated mice using c-Fos immunoreactivity as a marker. The effect of LY354740 on c-Fos expression was also studied in cage control (no EPM) mice. Pretreatment with LY354740 (20 mg/kg, s.c.) produced robust anxiolytic behavior on the EPM. LY354740 administration decreased EPM-induced increases in c-Fos expression in the CA3 of the hippocampus, while having no significant effects on basal c-Fos expression in the hippocampus. LY354740 administration significantly increased c-Fos expression in specific limbic regions, including the lateral division of the central nucleus of the amygdala (CeL), lateral parabrachial nucleus, locus coeruleus, and Edinger-Westphal nucleus, whether or not animals were exposed to the EPM. Moreover, LY354740 administration per se significantly increased c-Fos expression in regions processing sensory information, including the paraventricular and lateral geniculate nucleus of the thalamus as well as the nucleus of the optic tract and superior colliculus. In particular, the suppression of fear-evoked neuronal activity in the hippocampus and drug-induced increases in neuronal activation in the CeL have been previously linked to the anxiolytic effects of clinically effective drugs such as benzodiazepines, and thus may contribute to anxiolytic actions of LY354740 in animal models and human anxiety patients.

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“…Stress-induced hyperthermia was also demonstrated to retain its magnitude of effect after repeated trials in mice, rendering the method acceptable for testing in chronic situations (Nordquist et al 2007). Humans also respond to stress with hyperthermia, for instance, to a stressor in the form of university exams (Briese 1995;Marazziti et al 1992 Spooren et al 2002), and mGlu 5 receptor antagonists (Nordquist et al 2007;Rorick-Kehn et al 2005;Spooren et al 2002) have been demonstrated to reduce the magnitude of stress-induced hyperthermia in mice. Given the relative simplicity of the model and the solid evidence from mouse studies that modulation of metabotropic glutamate receptors play a key role in stress-induced hyperthermia, this method would be a candidate to further investigate the role of metabotropic glutamate receptors in anxiety in humans.…”

Section: Translational Research With Mglur Binding: Development Of a mentioning

confidence: 99%

“…For instance, stress-induced hyperthermia involves a body temperature increase of 0.5°C-0.8°C, an increase which can also fairly easily be caused by other mild hyperthermic processes such as exercise. This increase can be detected in humans (Marazziti et al 1992), and pharmacological changes in stress-induced hyperthermia can be detected under strictly controlled conditions in animals (Bouwknecht et al 2007;Spooren et al 2002), however, it remains to be seen if pharmacological interventions will cause alterations in stress-induced hyperthermia with a small enough variability to be statistically reliably detected. Similar warnings may apply to fearpotentiated startle, which produces relatively small effects in humans.…”

Section: Effect Size and Translational Medicinementioning

confidence: 99%

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Nordquist

Steckler²,

Wettstein

et al. 2008

Psychopharmacology

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Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

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Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608)

Cited by 137 publications

References 18 publications

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

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