Stressful situations can result in relapse in dependent or abstinent causing reinstatement of drug-seeking. In fact, it has been suggested that activation of the brain stress system results in glucocorticoid release that affects the dopaminergic pathways. Also, the noradrenergic system innervates the extrahypothalamic BSS from the nucleus of tractus solitarius (NTS), resulting in a feedforward loop between the corticotropin-releasing factor (CRF) and noradrenaline (NA) crucial in drug addiction and relapses. Glucocorticoids interact with two receptors: mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) which bind to a GRE site located in tyrosine hydroxylase (TH), resulting in the upregulation of TH synthesis and, finally, increasing dopamine (DA) release in the nucleus accumbens. TH upregulation depends on the phosphorylation of serine 31 and/or serine 40. Previous research has shown that protein kinase C (PKC) activates extracellular signal-regulated kinase (ERK) pathway and in turn phosphorylates serine 31 in the NTS. Besides, cAMP response element binding protein (CREB) is regulated by PKA and PKC. The results shown after pretreating morphine-withdrawn rats with mifepristone and spironolactone (GR and MR antagonists, respectively) suggest that glucocorticoids have a prominent role in addiction because GR would activate ERK and CREB in the NTS, phosphorylating serine 31 and activating TH and indeed noradrenergic release in the paraventricular nucleus (PVN).
Part of the book: Opioids