Howell Kristin K, Monk Bradley R, Carmack Stephanie A, Mrowczynski Oliver D, Clark Robert E, Anagnostaras Stephan G
Molecular Cognition Laboratory, Department of Psychology, University of California San Diego, La Jolla, CA, USA.
Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Front Behav Neurosci. 2014 Mar 7;8:70. doi: 10.3389/fnbeh.2014.00070. eCollection 2014.
The atypical PKC isoforms, PKMζ and PKCλ have been proposed as integral substrates of long-term memory (LTM). Inhibition of these isoforms has recently been demonstrated to be sufficient for impairing the expression and maintenance of long-term potentiation. Additionally, the pseudosubstrate inhibitor, zeta inhibitory peptide (ZIP), which effectively blocks PKMζ and PKCλ, has previously been shown to disrupt associative memory; very little is known about its effects on pathological nonassociative forms of memory related to addiction. The neural and molecular substrates of memory and addiction have recently been argued to overlap. Here, we used ZIP to disrupt PKMζ and PKCλ activity to examine their role in cocaine sensitization, a nonassociative, addiction-related memory argued to underlie the transition from casual to pathological drug use. We examined the effects of both continuous and acute administration of ZIP. Even a single application of ZIP blocked the development of sensitization; sustained inhibition using osmotic pumps produced an almost complete blockade of sensitization. Further, a single application of ZIP was shown to reduce membrane-bound AMPAR expression. These results demonstrate a novel, critical role for the atypical PKC isoforms in nonassociative memory and cocaine addiction.
非典型蛋白激酶C亚型PKMζ和PKCλ被认为是长期记忆（LTM）的重要底物。最近已证明抑制这些亚型足以损害长期增强的表达和维持。此外，伪底物抑制剂ζ抑制肽（ZIP）可有效阻断PKMζ和PKCλ，此前已表明它会破坏联想记忆；关于其对与成瘾相关的病理性非联想记忆形式的影响知之甚少。最近有人认为记忆和成瘾的神经及分子底物存在重叠。在此，我们使用ZIP破坏PKMζ和PKCλ的活性，以研究它们在可卡因敏化中的作用，可卡因敏化是一种与成瘾相关的非联想记忆，被认为是从偶尔使用药物转变为病理性药物使用的基础。我们研究了连续和急性给予ZIP的效果。即使单次应用ZIP也能阻断敏化的发展；使用渗透泵持续抑制几乎完全阻断了敏化。此外，单次应用ZIP可降低膜结合型AMPA受体的表达。这些结果证明了非典型蛋白激酶C亚型在非联想记忆和可卡因成瘾中具有新的关键作用。
