Activation of extracellular signal‐regulated kinase is critical for the discriminative stimulus effects induced by U‐50,488H

Abstract

We previously demonstrated that the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H were associated with its aversive effects in rats. However, its molecular signaling mechanisms are not fully understood. The aim of this study was to investigate the intracellular signaling that plays a role in mediating the discriminative stimulus effect induced by U-50,488H. To better understand the involvement of molecular signaling mechanisms in the discriminative stimulus effects of U-50,488H, rats were subjected to a drug discrimination paradigm, and levels of immunoreactivity and mRNA expression were determined in these rats. Although U-50,488H-trained rats did not show changes in the mRNA expression of typical dopamine (DA) receptors, NMDA receptor subunits, or transcriptional activators, there were remarkable changes in the levels of immunoreactivity of several phosphorylated protein kinases. The levels of immunoreactivity of phosphorylated p38 MAPK and phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) were significantly increased in the nucleus accumbens and amygdala in lever-press, yoked and discrimination groups compared to a naive group. Furthermore, the level of phosphorylated cAMP response element-binding protein was also increased in both the discrimination and yoked groups. In contrast, the immunoreactivity of phosphorylated extracellular signaling-regulated kinase (ERK 1/2) was specifically increased in the discrimination group. These results suggest that the ERK signaling pathway in the nucleus accumbens and amygdala may be critical for the expression of the discriminative stimulus effects of U-50,488H.

Intra-amygdala inhibition of ERK1/2 potentiates the discriminative stimulus effects of alcohol

“…This is plausible given that the MAPK pathway is critically involved in learning and memory-associated plasticity processes [13, 17], and that the ERK pathway specifically in the amygdala has been shown to regulate memory consolidation [46] and the expression of drug-related cue learning [8, 9, 47]. Indeed, rats trained with the -opioid receptor agonist (U-50,488H) as a discriminative stimulus have greater pERK 1/2 levels in the central amygdala relative to drug-matched controls (i.e., nondiscrimination-trained) [48], suggestive of a learning-induced adaptation in pERK 1/2 . However, there is evidence to suggest that the ERK pathway is not involved in modulating alcohol-related associative learning (as measured by alcohol-induced conditioned place preference) [49].…”

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

“…KORs signal through both Gα and Gβγ subunits, and then activate a host of downstream signaling molecules, thereby activating g-protein gated inwardly rectifying potassium channels (GIRKs), reducing calcium currents, and decreasing cyclic AMP. KORs have been shown to activate both MEK/ERK (Belcheva et al 2005, Hahn et al 2010, Kivell et al 2014a, Li et al 2012, McLennan et al 2008, Potter et al 2011, Yoshizawa et al 2011) (although some groups do not see significant MEK/ERK activation following KOR activation, see (Asensio et al 2006)) and MAPK signaling cascades, and in particular, p38 (Bruchas et al 2006, Bruchas et al 2011, Hahn et al 2010, Yoshizawa et al 2011). This KOR interaction with p38 is thought to be mediated by arrestin signaling; co-expression with the dominant-mutant of β-arrestin prevents human KOR internalization in CHO cells (Li et al 1999).…”

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…CREB is activated by extracellular signal-regulated kinases (ERK1/2), and both KOPr and DAT proteins have been shown to signal via ERK1/2 pathways (Potter et al, 2011; Rothman, Dersch, Carroll, & Ananthan, 2002; Yoshizawa, Narita, Saeki, Narita, Isotani, Horiuchi et al, 2011). Activation of ERK1/2 leads to an increase in DAT function and cell surface expression (Bolan, Kivell, Jaligam, Oz, Jayanthi, Han et al, 2007; Moron, Zakharova, Ferrer, Merrill, Hope, Lafer et al, 2003), and ERK1/2 inhibitors (but not P38 MAPK inhibitors), cause a concentration and time dependent decrease in DA uptake, an effect shown to be due to decreased DAT cell-surface expression (Moron et al, 2003).…”