aPKC-Mediated Persistent Increase in AMPA/NMDA Ratio in the VTA Participates in the Neuroadaptive Signal Necessary to Induce NAc Synaptic Plasticity After Cocaine Administration

Abstract

Chronic cocaine exposure produces enduring neuroadaptations in the brain’s reward system. Persistence of early cocaine evoked neuroadaptations in the ventral tegmental area (VTA) are necessary for later synaptic alterations in the nucleus accumbens (NAc), suggesting a temporal sequence of neuroplastic changes between these two areas. However, the molecular nature of the signal that mediates this sequential event is unknown. Here we used the behavioral sensitization model and the aPKC inhibitor of late-phase LTP maintenance, ZIP, to investigate if a persistent increase in AMPA/NMDA ratio plays a role in the molecular mechanism that allows VTA neuroadaptations to induce changes in the NAc. Results showed that intra-VTA ZIP microinfusion successfully blocked cocaine evoked synaptic enhancement in the VTA and the expected AMPA/NMDA ratio decrease in the NAc following cocaine sensitization. ZIP microinfusions also blocked the expected AMPA/NMDA ratio increase in the NAc following cocaine withdrawal. These results suggest that a persistent increase in AMPA/NMDA ratio, mediated by aPKC’s, could be the molecular signal that enables the VTA to elicit synaptic alterations in the NAc following cocaine administration.

Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity

“…Elevated levels of ΔFosB have been previously observed in the NAc of adult mice after prolonged HFD consumption [ 12 , 19 ] and in the NAc of ΔFosB-overexpressing adult mice that fed HFD when they were young [ 41 ]. ΔFosB, a sustained molecular switch that accumulates within a subset of neurons of the nucleus accumbens during addiction, likely contributes to the long-term neural and behavioral plasticity that underlies addiction [ 42 ], and can be related to the LTP-like AMPA/NMDA ratio increase occurring in the NAc during seeking behavior following cocaine withdrawal [ 43 ].…”

Reversing Cocaine-Induced Plasticity with Zeta Inhibitory Peptide

“…This peptide has been used extensively in memory studies to support a role for PKM in maintaining memories via long-term potentiation (Hrabetova and Sacktor, 1996;Past-alkova et al, 2006;Sacktor, 2011;Zhang et al, 2016). Additionally, ZIP has also been shown to disrupt cocaine-conditioned reward in the nucleus accumbens (NAc) (Li et al, 2011;Shabashov et al, 2012), cocaine-induced synaptic potentiation in the ventral tegmental area (VTA) (Ho et al, 2012;Vaquer-Alicea et al, 2018), and cocaine sensitization when injected into the ventricle (Howell et al, 2014). However, recent studies using mice deficient in PKM show that these isoforms are not necessary for synaptic plasticity or memory (Lee et al, 2013;Volk et al, 2013).…”