Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads to alterations in MAPK signaling in NAc neurons, which facilitates changes in the glutamatergic system and thus behavioral changes. We have previously shown that following withdrawal from cocaine-induced behavioral sensitization (BS), an increase in glutamate receptor expression and elevated MAPK signaling was evident. Here, we set out to determine the time course and behavioral consequences of inhibition of extracellular signal-regulated kinase (ERK) or NMDA receptors following withdrawal from BS. We found that inhibiting ERK by microinjection of U0126 into the NAc at 1 or 6 days following withdrawal from BS did not affect the expression of BS when challenged with cocaine at 14 days. However, inhibition of ERK 1 day before the cocaine challenge abolished the expression of BS. We also inhibited NR2B-containing NMDA receptors in the NAc by microinjection of ifenprodil into the NAc following withdrawal from BS, which had no effect on the expression of BS. However, microinjection of ifenprodil to the NAc 1 day before challenge attenuated the expression of BS similar to ERK inhibition. These results suggest that following a prolonged period of withdrawal, NR2B-containing NMDA receptors and ERK activity play a critical role in the expression of cocaine behavioral sensitization.

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.

Use of biological toxins from different kinds is widely accepted in electrophysiological experiments. In particular, electrophysiological recordings from brain tissue slices are usually conducted with toxins to manipulate on different receptors or ion channels. Here we describe usage of toxins in electrophysiological experiments in acute brain slices.

In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditioned place preference (CPP) paradigm. We found that administration of Tempol during the conditioning session abolished the expression of cocaine-induced CPP. We also found that OS was significantly elevated following the establishment of CPP, and that cocaine-induced OS was significantly diminished by pretreatment with Tempol during conditioning. Furthermore, we found that repeated, but not single, administration of Tempol for seven days during withdrawal from CPP resulted in significant attenuation in the expression of CPP. Moreover, Tempol did not affect the expression of food reward. Taken together, these findings provide evidence for the involvement of Tempol in regulating cocaine rewarding properties without affecting natural rewards. Since Tempol was found to be effective in reducing OS and expression of CPP following withdrawal, it may be a potential treatment for cocaine addiction.