Inhibition of striatal‐enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption

Abstract

The STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) inhibits the activity of the tyrosine kinase Fyn and dephosphorylates the GluN2B subunit of the NMDA receptor, whereas PKA phosphorylation of STEP61 inhibits the activity of the phosphatase (Goebel-Goody et al. 2012). Previously, we found that ethanol activates Fyn in the dorsomedial striatum (DMS) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (Wang et al. 2010). Here, we tested the hypothesis that inhibition of STEP61 by ethanol is upstream of Fyn/GluN2B. We show that exposure of mice to ethanol increased STEP61 phosphorylation in the DMS, which was maintained after withdrawal and was not observed in other striatal regions. Specific knockdown of STEP61 in the DMS of mice enhanced ethanol-mediated Fyn activation and GluN2B phosphorylation, and increased ethanol intake without altering the level of water, saccharine, quinine consumption or spontaneous locomotor activity. Together, our data suggest that blockade of STEP61 activity in response to ethanol is sufficient for the activation of the Fyn/GluN2B pathway in the DMS. Being upstream of Fyn and GluN2B, inactive STEP61 in the DMS primes the induction of ethanol intake.

Molecular mechanisms underlying alcohol-drinking behaviours

“…Indeed, excessive alcohol intake (20%IA2BC model) increases the interaction between FYN and PTPα, which in turn contributes to the sustained activation of the kinase 30 . Interestingly, alcohol-induced inhibition of STEP, as well as activation of FYN and PTPα, can be detected in the DMS but not in other striatal regions (that is, the dorsolateral striatum (DLS) and the NAc) 24, 29, 30, 32 , demonstrating that the molecular changes induced by alcohol intake are highly selective.…”

“…1), and the inhibition of A2ARs reduces alcohol consumption in rats in a moderate alcohol consumption model (10%OSA paradigm) 22, 23 . Alcohol-induced activation of PKA leads to the phosphorylation of numerous PKA substrates, including the FYN kinase inhibitor, striatum-enriched protein-tyrosine phosphatase (STEP; also known as PTPN5) 24 and RAS-specific guanine nucleotide-releasing factor 1 (RAS-GRF1) 25 . The consequences of these phosphorylation events are outlined below.…”

“…In mice, excessive alcohol consumption (for example, repeated cycles of binge drinking and alcohol withdrawal in the intermittent access to 20% alcohol in a two-bottle choice (20%IA2BC) paradigm; Box 1) results in PKA-mediated phosphorylation of STEP (and thus inhibition of the phosphatase) in the dorsomedial striatum (DMS) 24 . As alcohol inhibits STEP activity, a robust and sustained activation of FYN is detected in the DMS of rodents consuming high levels of alcohol (20%IA2BC paradigm) 24, 29, 30 . In fact, the requirement of PKA for alcohol-mediated activation of FYN was first reported in hippocampal slices 31 .…”

“…Similarly, the inhibition of CaMKII or AMPARs in the CeA reduces moderate alcohol intake 35 . Conversely, the global or DMS-specific knockdown of STEP increases alcohol intake in mice in moderate and excessive alcohol consumption models (10%CA2BC, 20%IA2BC and ESC-CA2BC paradigms 24, 41 ; Box 1). …”

Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders

“…Although the answer to this question has not yet been fully investigated, it is likely that there is a differential regulation of STEP posttranslational modifications, depending on different brain regions. For example, phosphorylation of STEP 61 after alcohol consumption was described in the dorsomedial striatum but not in the nearby dorsolateral striatum or the nucleus accumbens (Darcq et al, 2014), while dephosphorylation of STEP 61 was reported within the hippocampus after alcohol consumption (Hicklin et al, 2011). The differential regulation of STEP is an open area of research in the biology of STEP and should provide additional insights into mechanisms by which disruption of STEP activity may give rise to one distinct disorder compared to another.…”