Abstract: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 perfor… Show more
“…We note that Volk et al had reported ZIP induces decreases in both tetanized and untetanized pathways in slices ( Volk et al, 2013 ). These results conflict with evidence from a large number of studies showing exclusive actions of ZIP in tetanized or facilitated pathways and not in baseline pathways, including seven studies in brain slices of fEPSPs ( Ling et al, 2002 ; Serrano et al, 2005 ; Sajikumar et al, 2005 ; Navakkode et al, 2010 ; Lin et al, 2012 ; Panaccione et al, 2013 ; Chen et al, 2015 ), four studies of EPSCs ( Li et al, 2010 ; Yao et al, 2013 ; Velez-Hernandez et al, 2013 ; Li et al, 2014 ), two studies in model systems ( Cai et al, 2011 ; Balaban et al, 2015 ), and four studies in vivo of fEPSPs ( Pastalkova et al, 2006 ; Madronal et al, 2010 ; Dong et al, 2015 ) and evoked responses ( Cooke and Bear, 2010 ), as well as evidence of stable basal properties of hippocampal neurons following ZIP injections recorded in vivo ( Barry et al, 2012 ). DOI: http://dx.doi.org/10.7554/eLife.14846.004 10.7554/eLife.14846.005 Figure 1—figure supplement 2.…”
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI:
http://dx.doi.org/10.7554/eLife.14846.001
“…We note that Volk et al had reported ZIP induces decreases in both tetanized and untetanized pathways in slices ( Volk et al, 2013 ). These results conflict with evidence from a large number of studies showing exclusive actions of ZIP in tetanized or facilitated pathways and not in baseline pathways, including seven studies in brain slices of fEPSPs ( Ling et al, 2002 ; Serrano et al, 2005 ; Sajikumar et al, 2005 ; Navakkode et al, 2010 ; Lin et al, 2012 ; Panaccione et al, 2013 ; Chen et al, 2015 ), four studies of EPSCs ( Li et al, 2010 ; Yao et al, 2013 ; Velez-Hernandez et al, 2013 ; Li et al, 2014 ), two studies in model systems ( Cai et al, 2011 ; Balaban et al, 2015 ), and four studies in vivo of fEPSPs ( Pastalkova et al, 2006 ; Madronal et al, 2010 ; Dong et al, 2015 ) and evoked responses ( Cooke and Bear, 2010 ), as well as evidence of stable basal properties of hippocampal neurons following ZIP injections recorded in vivo ( Barry et al, 2012 ). DOI: http://dx.doi.org/10.7554/eLife.14846.004 10.7554/eLife.14846.005 Figure 1—figure supplement 2.…”
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI:
http://dx.doi.org/10.7554/eLife.14846.001
“…ζ -pseudosubstrate inhibitory peptide (ZIP), a selective inhibitor of PKM ζ , can reverse LTP maintenance and block L-LTP induction [ 14 , 15 ]. Furthermore, ZIP can also reverse a variety of memory types, such as spatial information, fear, addiction, and conditioned taste aversion (CTA) memory [ 15 – 19 ]. Several studies have reported that PKM ζ -related pain memory can be erased in the spinal cord and the brain [ 9 , 20 , 21 ].…”
The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ (PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζ in the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ (p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.
“…Long-term changes in the VTA are induced by a single and multiple cocaine injections [40,41]. In addition, LTP, as the persistent increase in AMPA/NMDA ratio on VTA DA cells, is critical for the maintenance of cocaine sensitization [63]. These changes in synaptic plasticity in the VTA have been implicated in the development of drug addiction and cocaine sensitization [5,54,64,65].…”
The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs’ amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs’ function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.
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