To this the evidence of opposite effects of noradrenaline

To this, the evidence of opposite effects of noradrenaline and adrenaline on the striatal firing initiation (Fig. 6, Fig. 7) should not be ignored, because the striatum is related to controlling action timing by regulating the firing increase rate (Tanaka and Kunimatsu, 2011). Although the ligand supply source of adrenergic receptors in the striatum is still unknown, it is important to study the modulatory effects of noradrenaline and adrenaline on striatal firings, in order to understand the pathophysiology of PD related timing control deficiency. In summary, the activation of β-ARs accelerates striatal firing initiation and inhibits the firing increment, while the activation of α1-ARs delays striatal firing initiation and enhances the firing increment. These findings provide new insights into fundamental striatal mechanisms and pathomechanisms of striatum oriented disease.
Author contributions statement
Conflict of interest
Acknowledgments We are grateful to S. Kanda, Drs. K. Ooyo and Y. Yamaguchi for great technical assistance, and to D. A. Tyurmin for language assistance. This work was supported by MEXT/JSPS KAKENHI Grant Number 24700200, a grant for Specific Research from National Defense Medical College, Defense Medicine Propulsion Research of the Ministry of Defense, Japan, the Cooperative Research Project Program of RIEC, Tohoku University, the Research Foundation for Opto-Science and Technology, Hamamatsu, Japan and CREST, Japan Science and Technology Agency.
Introduction There are previous observations in the metabotropic glutamate (mGlu) receptor field that still remain unexplained after several years. One of these is the ability of L-2-amino-4-phosphonobutanoate (L-AP4) and l-serine-O-phosphate (L-SOP) to inhibit norepinephrine-stimulated polyphosphoinositide (PI) hydrolysis in 2461 tissue (Nicoletti et al., 1986). Norepinephrine-stimulated PI hydrolysis is mediated by the activation of α1-adrenergic receptors, which are coupled to Gq/11 and are largely expressed in the CNS (Johnson and Minneman, 1985, Minneman, 1988, Wilson and Minneman, 1989). L-AP4 and L-SOP are now considered as prototypical orthosteric agonists of group III mGlu receptors, displaying nanomolar affinity for mGlu8 receptors, low micromolar affinity for mGlu4 and mGlu6 receptors, and high micromolar affinity (>150/300 μM) for mGlu7 receptors (reviewed by Schoepp et al., 1999). The inhibitory action of L-SOP on norepinephrine-stimulated PI hydrolysis in rat hippocampal slices required concentrations ≥300 μM, whereas L-AP4 was tested exclusively at concentrations of 1 mM (Nicoletti et al., 1986). This raises the possibility that activation of mGlu7 receptors inhibits α1-adrenergic receptor signalling through a mechanism of receptor-receptor interaction, although high concentrations of L-AP4 and L-SOP may recruit additional targets, such as the Ca2+/Cl−-dependent glutamate transporter (Monaghan et al., 1983). The possibility that mGlu7 and α1-adrenergic receptors interact in brain tissue is particularly attractive because both receptors have been implicated in the pathophysiology of psychiatric disorders. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depression (O'Connor et al., 2010). In animal models, genetic deletion of mGlu7 receptors reduces anxiety-related and depressive-like behaviour in several tests, and causes changes that are consistent with an antidepressant phenotype (Cryan et al., 2003, Callaerts-Vegh et al., 2006). These receptors activate multiple transduction pathways, such as inhibition of adenylyl cyclase activity, and stimulation of ERK1/2 and the Jun kinase (JNK) pathways (Iacovelli et al., 2014). Drugs that enhance noradrenergic transmission (i.e., tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, and selective noradrenaline uptake inhibitors) are currently marketed for the treatment of anxious-depressive disorders, and activation of α1A-adrenergic receptors reduces anxiety-like behaviour and produces antidepressant-like effects in mice (Doze et al., 2011). The demonstration that mGlu7 receptors negatively modulate α1-adrenergic receptors may therefore provide new insights into the physiology of mGlu7 receptors and offer a new possible link between the monoaminergic and glutamatergic hypothesis of stress-related disorders.