Casein kinase 1 enables nucleus accumbens amphetamine‐induced locomotion by regulating AMPA receptor phosphorylation

Abstract

The closely related δ and ε isoforms of the serine/threonine protein kinase casein kinase 1 (Csnk1) have been implicated in the generation of psychostimulant-induced behaviors. Here we show that Csnk1δ/ε produces its effects on behavior by acting on the Darpp-32-PP1 signaling pathway to regulate AMPA receptor phosphorylation in the nucleus accumbens (NAcc). Inhibiting Csnk1δ/ε in the NAcc with the selective inhibitor PF-670462 blocks amphetamine induced locomotion and its ability to increase phosphorylation of Darpp-32 at S137 and T34, decrease PP1 activity and increase phosphorylation of the AMPA receptor subunit at S845. Consistent with these findings, preventing GluR1 phosphorylation with the alanine mutant GluR1(S845A) reduces glutamate-evoked currents in cultured medium spiny neurons and blocks the locomotor activity produced by NAcc amphetamine. Thus, Csnk1 enables the locomotor and likely the incentive motivational effects of amphetamine by regulating Darrp-32-PP1-GlurR1(S845) signaling in the NAcc. As such, Csnk1 may be a critical target for intervention in the treatment of drug use disorders.

Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

“…In contrast to the results observed with PF-4800567, we previously found that the CK-1 inhibitor PF-670462 decreased MA sensitivity (Bryant et al, 2009b;Li et al, 2011). PF-670462 was previously thought to be slightly more selective for Csnk1e over Csnk1d (Badura et al, 2007), but a recent study showed that PF-670462 was six-fold more selective for Csnk1d over Csnk1e and that PF-4800567 was 20-fold more selective for Csnk1e over Csnk1d (Walton et al, 2009).…”

“…Together, these results suggest that both Csnk1e and Csnk1d are important for sensitivity to drugs of abuse. However, because PF-670462 only exhibits six-fold selectivity for Csnk1d over Csnk1e (Walton et al, 2009;Meng et al, 2010), it is unclear if our previous results were mediated by Csnk1d or Csnk1e (Bryant et al, 2009b;Li et al, 2011).…”

“…This leads to the activation of DARPP-32 in part via CK-1 (Greengard, 2001) and we previously showed that coadministration of the Csnk1d-preferring compound PF-4076462 inhibited MA-induced DARPP-32 phosphorylation (Bryant et al, 2009b;Li et al, 2011). As such, how is it that two closely related isoforms might exert opposing effects on sensitivity to drugs of abuse?…”

“…Additionally, the CSNK1E SNP rs1534891 was associated with heroin addiction (Levran et al, 2008). Furthermore, coadministration of the casein kinase 1-d (Csnk1d)-preferring inhibitor PF-670462 with MA decreased locomotor activity and DARPP-32 phosphorylation in mice (Bryant et al, 2009b), and a similar result was observed following coadministration of PF-670462 with amphetamine in rats (Li et al, 2011). Conversely, Csnk1d overexpression in the forebrain resulted in baseline hyperactivity and an increased locomotor response to amphetamine (Zhou et al, 2010).…”

Relationship between a point mutation S97C in CK1δ protein and its affect on ATP-binding affinity

“…This mechanism is vital for centrosome translocation to the IS (Zyss et al, 2011). CK1δ was also shown to be involved in psychostimulant-induced behaviours by acting on the Darpp-32-PP1 signalling pathway to regulate AMPA receptor phosphorylation in the nucleus accumbens (Li et al, 2011).…”