Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala

Abstract

Recent advances suggest that acetaldehyde mediates some of the neurobiological properties of ethanol. In a recent study, we have shown that ethanol elicits the phosphorylation of extracellular signal-regulated kinase (pERK) in the nucleus accumbens and extended amygdala, via a dopamine D(1) receptor-mediated mechanism. The aim of this study was to determine whether acetaldehyde and ethanol-derived acetaldehyde elicit the activation of ERK in the nucleus accumbens and extended amygdala. The effects of acetaldehyde (10 and 20 mg/kg) and ethanol (1 g/kg), administered to rats intragastrically, were assessed by pERK peroxidase immunohistochemistry. To establish the role of ethanol-derived acetaldehyde, the alcohol dehydrogenase inhibitor, 4-methylpyrazole (90 mg/kg), and the acetaldehyde-sequestering agent, D-penicillamine (50 mg/kg), were administered before ethanol. Acetaldehyde increased pERK immunoreactivity in the nucleus accumbens and extended amygdala. Inhibition of ethanol metabolism and sequestration of newly synthesized acetaldehyde completely prevented ERK activation by ethanol. In addition, to establish the role of D(1) receptors stimulation in acetaldehyde-elicited ERK phosphorylation, we studied the effect of the D(1) receptor antagonist, SCH 39166. Pretreatment with the D(1) receptor antagonist (50 μg/kg) fully prevented acetaldehyde-elicited ERK activation. Overall, these results indicate that ethanol activates ERK by means of its metabolic conversion into acetaldehyde and strengthen the view that acetaldehyde is a centrally acting compound with a pharmacological profile similar to ethanol.

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

“…In CPP experiments the inhibition of ADH1 (Peana et al, 2008) or catalase (Font et al, 2008) as well as the reduction of acetaldehyde bioavailability, by the use of sequestering agents, impairs the acquisition of ethanol-elicited CPP (Peana et al, 2008, 2009; Ledesma et al, 2013). Furthermore, acetaldehyde itself elicits the acquisition of CPP (Spina et al, 2010) through the activation of extracellular signal regulated kinase pathway via a DA D 1 receptor-mediated mechanism (Ibba et al, 2009; Spina et al, 2010; Vinci et al, 2010). In operant experiments, acetaldehyde was reported to be orally self-administered and, similarly to ethanol, its oral self-administration was reported to be prevented by L-cysteine (Peana et al, 2010a), an agent that acts either as radical scavenger or as precursor of cysteine and that is also able to sequestrate acetaldehyde either peripherally or centrally.…”

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…The acute EtOH-induced c-fos induction in the medial Amy was inhibited by the MEK inhibitor, U0126 238 . Similarly, acute acetaldehyde (ACD), the first and main metabolite of EtOH, enhanced pERK in the NAc, CeA and BNST through activation of D1-R and opioid receptors 239,240 . Behaviorally, the low dose of acute EtOH (1mg/kg) is associated an anxiolytic response accompanied by the rapid increase of spine density in the CeA and medial Amy (MeA) through the BDNF-mediated TrkB phosphorylation and pERK/pElk-1/pCREB and Arc induction 241 .…”

Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol

“…Indeed, also this line of investigation has generated a significant body of data that also converged toward the characterization of ACD as a neurochemical agent able to elicit locomotor activity (Correa et al, 2009b) and anxiolytic effects (Correa et al, 2008), to sustain drug discrimination (York, 1981; Redila et al, 2000, 2002; Quertemont and Grant, 2002), to affect cognition (Sershen et al, 2009), and to elicit motivational effects (York, 1981; Peana et al, 2008a, 2009, 2010b; Spina et al, 2010). Interestingly, the behavioral evidence for the characterization of ACD as a drug with motivational properties was gathered, from conditioned place preference (CPP) and self-administration studies, in parallel with electrophysiological, biochemical and immunohistochemical studies pointing also to the critical role of dopamine (DA) (Foddai et al, 2004; Melis et al, 2007; Enrico et al, 2009; Spina et al, 2010; Vinci et al, 2010; Sirca et al, 2011) and opioid (Pastor et al, 2004; Sánchez-Catalán et al, 2009; Peana et al, 2011) transmission as well as to the involvement of Extracellular signal Regulated Kinase (ERK) (Spina et al, 2010; Vinci et al, 2010) at the basis of ACD's motivational properties. The present review aims to recapitulate this evidence in support of the tenet of ACD as a molecule able to exert motivational effects in rodents (for a recent comprehensive review see Correa et al, 2012).…”