Intra-amygdala ZIP injections impair the memory of learned active avoidance responses and attenuate conditioned taste-aversion acquisition in rats

Gámiz, Fernando; Gallo, M.

doi:10.1101/lm.2253311

Cited by 30 publications

(32 citation statements)

References 42 publications

(60 reference statements)

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“…Studies that have examined the application of post-training ZIP have found that it often produces amnesia (Pastalkova et al, 2006; Shema et al, 2007; Serrano et al, 2008; Kwapis et al, 2009; Gámiz and Gallo, 2011). However, Parsons and Davis (2011) suggested the effects of ZIP were dependent on the timing between training and administration.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PKC disrupts addiction-related memory

Howell

Monk

Carmack

et al. 2014

Front. Behav. Neurosci.

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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.

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Section: Discussionmentioning

confidence: 99%

Inhibition of PKC disrupts addiction-related memory

Howell

Monk

Carmack

et al. 2014

Front. Behav. Neurosci.

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“…ZIP is a myristoylated PKMζ pseudosubstrate inhibitory peptide that specifically mimics the autoregulatory domain of PKCζ, therefore blocks PKMζ. For this reason, ZIP infusions produce retrograde amnesia of several long-term memories (Shema et al , 2007; Serrano et al , 2008; Kwapis et al , 2009; Shema et al , 2009; Hardt et al , 2010; Madronal et al , 2010; Migues et al , 2010; Sacco & Sacchetti, 2010; von Kraus et al , 2010; Gamiz & Gallo, 2011; He et al , 2011; Shema et al , 2011; Crespo et al , 2012; Kwapis et al , 2012; Pauli et al , 2012). Hence, PKMζ is the first enzyme known to sustain memory by maintaining LTP in the brain.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Kinase Mζ (PKMζ) in the Mesolimbic System Alters Cocaine Sensitization in Rats

Vélez-Hernández

Vázquez-Torres

Velásquez-Martinez

et al. 2013

Journal of Drug and Alcohol Research

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Chronic cocaine use produces long-lasting changes in reward circuits that may underlie the transition from casual to compulsive patterns of drug use. Although strong neuroadaptations within the mesocorticolimbic system are known to occur, the specific role of these drug-induced plasticities on sensitization remains to be elucidated. Here we investigate whether PKMζ, a protein involved in maintaining long-term potentiation (LTP), plays a role in these cocaine-induced changes in synaptic strengthening. We performed whole-cell voltage clamp recordings of putative ventral tegmental area (VTA) dopamine (DA) cells 24 hours after five days of 15 mg/kg i.p. cocaine or isovolumetric saline injections. We observed that superfusion of 5µM ZIP (PKMζ inhibitory peptide) decreased AMPA currents and AMPA/NMDA ratios only in cocaine sensitized rats. In vivo ZIP microinfusions (10 nmol) into the VTA after cocaine sensitization decreased locomotor activity on a subsequent cocaine challenge only if given ZIP is given before the withdrawal period. On the other hand, ZIP microinfusions into the nucleus accumbens (NAc) core after a seven days withdrawal period disrupt the expression of locomotor sensitization. The present data provide a potentially relevant region, and time-specific PKMζ-dependent brain mechanism that enables sensitization. Our results support the vision that addiction involves a pathological learning process. They imply that if this synaptic strengthening is reversed, changes in the behavioral response may also be overturned.

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“…Overexpression of PKC isoform M zeta (PKMz) led to enhancement of long-term CTA memory, whereas inhibition of PKMz led to erasure or of long-term CTA memory (Edry et al, 2011;Shema et al, 2007Shema et al, , 2009Shema et al, , 2011. Further, the inhibition of PKMz in the amygdala also resulted in attenuated CTA memory (Gámiz and Gallo, 2011).…”

Section: Changes In Akt Following Cta Acquisition and Extinction Are mentioning

confidence: 99%

Memory of Conditioned Taste Aversion Is Erased by Inhibition of PI3K in the Insular Cortex

Slouzkey¹,

Rosenblum²,

Maroun³

2013

Neuropsychopharmacol

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The conditioned taste aversion (CTA) paradigm, in which association between a novel taste and visceral malaise is formed, gives a unique experimental setting to examine the mechanisms underlying memory acquisition and extinction processes. AKT is a main kinase of the phosphoinositide 3-kinase cascade (PI3K) and has been implicated in long-term memory. We have recently reported that blockade of PI3K in the basolateral amygdala (BLA) before retrieval of fear memory was associated with long-term reduction in fear responses, suggesting a possible role of PI3K inhibition in fear erasure. In this study, we aimed to elucidate whether PI3K has a similar role in the insular cortex (IC), which has a crucial role in CTA acquisition, consolidation, maintenance, and extinction. To that end, we (1) monitored AKT phosphorylation in the IC following CTA acquisition and extinction and (2) inhibited PI3K by local microinjection of the PI3K inhibitor LY294002 at different stages of CTA acquisition and extinction. Our results show that while AKT phosphorylation is increased following CTA learning, it is decreased following CTA extinction. Inhibition of AKT phosphorylation in the IC before or after the first CTA retrieval test resulted in reduction in the aversion index. This reduction in aversion is due to the erasure of the original CTA trace memory, as re-application of the unconditioned stimulus (lithium chloride) did not induce the recovery of aversion in LY294002-treated animals. Our present data add new evidence to suggest that PI3K is engaged in consolidation of aversive memories, as its inhibition is associated with erasure of CTA memory.

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Intra-amygdala ZIP injections impair the memory of learned active avoidance responses and attenuate conditioned taste-aversion acquisition in rats

Cited by 30 publications

References 42 publications

Inhibition of PKC disrupts addiction-related memory

Inhibition of PKC disrupts addiction-related memory

Inhibition of Protein Kinase Mζ (PKMζ) in the Mesolimbic System Alters Cocaine Sensitization in Rats

Memory of Conditioned Taste Aversion Is Erased by Inhibition of PI3K in the Insular Cortex

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