Neuron
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Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. ⋯ Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
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T-type calcium channels are essential contributors to the transmission of nociceptive signals in the primary afferent pain pathway. Here, we show that T-type calcium channels are ubiquitinated by WWP1, a plasma-membrane-associated ubiquitin ligase that binds to the intracellular domain III-IV linker region of the Cav3.2 T-type channel and modifies specific lysine residues in this region. ⋯ In vivo knockdown of USP5 or uncoupling USP5 from native Cav3.2 channels via intrathecal delivery of Tat peptides mediates analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity. Altogether, our experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling.