27 This receptor downregulation is most probably related to the stress-mediated rise in noradrenaline tree concentrations. Regulation of noradrenaline release is impaired soon after the onset of the stress period, as revealed by reduced expression of the α2A-AR in the LC.28 During a stress period lasting several weeks, adrenergic regulation changes, Inhibitors,research,lifescience,medical giving an initially high level and then finally a low level of noradrenaline. This is the case in the prefrontal cortex, a brain area important for the regulation of mood and behavior.29 Following a chronic stress period, noradrenaline concentrations
are obviously low throughout the whole brain, probably due to a gradually acquired deficit in transmitter synthesis, transport, and/or release from the noradrenergic neurons.30 Interestingly, Inhibitors,research,lifescience,medical studies on postmortem material from brains of
depressed human patients also revealed the upregulation of oc2-ARs in several brain regions.31-33 These data therefore support the “noradrenaline deficit hypothesis,” which assumes there is a reduced noradrenaline concentration in the brains of depressed patients.34 Antidepressants that interact with α2-ARs such as mirtazapinc probably counteract this deficit.35 β-ARs also Inhibitors,research,lifescience,medical change during stress GPCR P-adrenoceptors (β-ARs) increase cAMP synthesis.36 They are present in neurons and glial cells.37 When stimulated by agonists (adrenaline or noradrenaline), β-ARs are rapidly internalized Inhibitors,research,lifescience,medical into the cells. Therefore, high levels of endogenous agonists
quickly reduce numbers of β-AR molecules in the plasma membrane of target cells, inducing desensitization.11-38 β-ARs are first internalized into the cell; they undergo intracellular sequestration with subsequent reinsertion into the plasma membrane, thereby restoring the normal receptor pattern in the membrane. β-AR dysfunction is thought to play a role in psychiatric disorders, and β-AR blockers have been used to treat depression and anxiety.39 The number of β-ARs in the temporal and frontal cortex of suicide victims has been found to be significantly lower than in matched controls.40,41 However, the psychotropic role of β-AR Levetiracetam downregulation Inhibitors,research,lifescience,medical is still under discussion since the antidepressant desmethylimipramine also downregulates brain β-ARs.42 On the other hand, the treatment of rats with the selective serotonin reuptake inhibitors (SSRIs) citalopram and fluoxetine increased prAR radioligand binding in the frontal cortex and striatum.43 Stress downregulates β-ARs in the brain.44 Our data from the tree shrew chronic stress model reveal that (i) the effects are dependent on the duration of a stressful event; (ii) β1 – and β2-ARs are differentially regulated; and (iii) the effects differ in different brain regions.45 Some of the stress-induced click here changes are only transient, since normal receptor numbers are restored through the reinsertion of intracellular sequestered receptor molecules into the plasma membrane.