Environmental cues associated with drug use are potent mediators of relapse in drug addiction [1]. Little is known about molecular mechanisms underlying these associations. In a recent issue of Neuropsychopharmacology, McGrath et al. [2] proposed a role for the enzyme protein kinase M zeta (PKMζ) in the nucleus accumbens (NAc) in cocaine self-administration and reinstatement.

PKMζ has been implicated in molecular mechanisms that maintain memory and long-term potentiation (LTP). PKMζ is a member of the atypical protein kinase C (PKC) subfamily and is transcribed from an internal start site within the Prkcz gene, which also encodes protein kinase C zeta (PKCζ). PKMζ possesses two key properties of a memory maintenance molecule: It is produced during LTP by de novo protein synthesis and is autonomously active without the requirement of second messenger stimulation. However, its role in memory maintenance is controversial. To inhibit PKMζ, early studies used the PKC inhibitor chelerythrine, a psuedosubstrate PKCζ inhibitory peptide (ZIP) or a dominant negative mutant of PKMζ to reverse LTP maintenance and disrupt long-term memory. These findings were later challenged by studies showing intact LTP and long-term memory in PKMζ knockout mice [3, 4]. Moreover, ZIP was effective in disrupting memory and LTP in PKMζ knockout mice, and current evidence indicates that ZIP and chelerythrine are not selective PKMζ inhibitors. Although a recent study using antisense oligonucleotides suggested that LTP and memory in PKMζ knockout mice are mediated by compensatory upregulation of another atypical PKC, PKCι/λ [5], such a mechanism does not explain intact LTP in adult mice with conditional deletion of hippocampal PKMζ [4].

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