Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • To examine whether the interaction between mGlu and adrenerg

    2024-03-19

    To examine whether the interaction between mGlu7 and α1-adrenergic receptors could be confirmed at a behavioural level, we performed the FST in mice. This test has value in predicting the antidepressant-like effect of drugs or environmental manipulations (Krishnan and Nestler, 2008, Krishnan and Nestler, 2010). The choice of the FST was motivated by the evidence that both α1-adrenergic and mGlu7 receptors have been linked to stress-related disorders including major depression. A large body of evidence suggests that activation of α1-adrenergic receptors by selective pharmacological agents or genetic manipulation produces antidepressant-like effects (Doze et al., 2009, Wakabayashi et al., 2011, Cunha et al., 2013) and mediates the beneficial effect of the antidepressant, desipramine, on cognitive dysfunction caused by chronic stress (Bondi et al., 2010). In contrast, chronic stress impairs mechanisms of α1-adrenergic receptor-dependent synaptic plasticity in the dorsal raphe nucleus (Haj-Dahmane and Shen, 2014), and pharmacological blockade of α1-adrenergic receptors induces depressive-like behaviour (Stone and Quartermain, 1999). The role played by mGlu7 receptors in depressive-like behaviour is more controversial. Mice with genetic deletion of mGlu7 receptors show an anxiolytic and antidepressant-like phenotype (Callaerts-Vegh et al., 2006, Cryan et al., 2003, Stachowicz et al., 2008, Peterlik et al., 2016), and treatment with the selective mGlu7 receptor antagonist, XAP044, reduces anxiety- and depressive-like behaviour in mice (Gee et al., 2014). In apparent NS 1619 to these findings, systemic administration of the mGlu7 receptor agonist, AMN082, produces anxyolitic and antidepressant-like effects that are abrogated by the mGlu7 receptor antagonist, MMPIP, and are not visible in mGlu7−/− mice (Palucha et al., 2007, Pałucha-Poniewiera et al., 2010, Pałucha-Poniewiera and Pilc, 2013). Ligand bias may contribute to explain these contrasting findings. Unraveling the precise mechanism by which mGlu7 receptors regulate mood is important because genetic variants of GRM7 (the gene encoding for mGlu7 receptors) are associated with major depressive disorder (Saus et al., 2010, Shyn et al., 2011, Li et al., 2016) and the response to antidepressant medication (Fabbri et al., 2013). We have found that central administration of the group III mGlu receptor agonist L-SOP was inactive on its own, but attenuated the antidepressant-like effect of the selective α1-adrenergic receptor agonist PE in the forced swim test. We cannot exclude that changes in locomotor activity might have influenced our data with PE and L-SOP in the forced swim test. However, there is large body of evidence demonstrating an anti-depressant effect of α1-adrenergic receptor activation by PE injected i.c.v. with doses and time schedules comparable to the present study using the forced swim test as well as other tests for depressive-like behaviour like the tail suspension test (Kitada et al., 1983, Cunha et al., 2013). Thus, our data strongly suggest that L-SOP is able to attenuate the antidepressant-like effect of PE in mice. Although the action of L-SOP might involve other group III mGlu receptor subtypes, this finding can be interpreted as a behavioural counterpart of in vitro data suggesting that mGlu7 receptors negatively modulate the function of α1-adrenergic receptors, although we cannot exclude that the action of L-SOP recruits other group III mGlu receptors in in vivo experiments. We extended the study to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which has an established role in the stress response and in the pathophysiology of mood disorders (reviewed by Brown et al., 1999, Nestler, 2014). We were surprised to find that L-SOP mimicked the action of PE in enhancing corticosterone secretion, but, interestingly, corticosterone secretion in response to combined administration of L-SOP and PE was much lower than that observed in response to either drug administered alone (although the reduction was statistically significant only with respect to L-SOP-treated mice). Activation of the HPA axis in response to central administration of PE was expected on the basis of previous findings (Bugajski et al., 1994, Bugajski et al., 1995, Feldman et al., 2000). Furthermore, the effect of L-SOP alone is in line with the evidence that the mGlu7 receptor agonist, AMN082, enhances corticosterone secretion (Mitsukawa et al., 2005), and that mGlu7−/− mice are more sensitive to glucocorticoid-mediated inhibition of the HPA axis (Mitsukawa et al., 2006). The lower corticosterone secretion in response to the combination of PE and L-SOP further supports the interaction between mGlu7 receptors and α1-adrenergic receptors in the CNS and raises the possibility that the interaction might be bidirectional. This interesting hypothesis warrants further investigation.