Plasticity of glutamatergic synapses is a fundamental mechanism through which experience changes neural function to impact future behavior. In animal models of addiction, glutamatergic signaling in the nucleus accumbens (NAc) exerts powerful control over drugseeking behavior. However, little is known about whether, how or when experience with drugs may trigger synaptic plasticity in this key nucleus. Using whole-cell synaptic physiology in NAc brain slices, we demonstrate that a progression of bidirectional changes in glutamatergic synaptic strength occurs after repeated in vivo exposure to cocaine. During a protracted drug-free period, NAc neurons from cocaine-experienced mice develop a robust potentiation of AMPAR-mediated synaptic transmission. However, a single re-exposure to cocaine during extended withdrawal becomes a potent stimulus for synaptic depression, abruptly reversing the initial potentiation. These enduring modifications in AMPAR-mediated responses and plasticity may provide a neural substrate for disrupted processing of drugrelated stimuli in drug-experienced individuals.

The inbred mouse C57BL/6J is the reference strain for genome sequence and for most behavioral and physiological phenotypes. However the International Knockout Mouse Consortium uses an embryonic stem cell line derived from a related C57BL/6N substrain. We found that C57BL/6N has lower acute and sensitized response to cocaine and methamphetamine. We mapped a single causative locus and identified a non-synonymous mutation of serine to phenylalanine (S968F) in Cytoplasmic FMR interacting protein 2 (Cyfip2) as the causative variant. The S968F mutation destabilizes CYFIP2 and deletion of the C57BL/6N mutant allele leads to acute and sensitized cocaine response phenotypes. We propose CYFIP2 is a key regulator of cocaine response in mammals and present a framework to utilize mouse substrains to discover novel genes and alleles regulating behavior.

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. The Sig-1R is an intracellular chaperone that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanism linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating some aspects of neurological and psychiatric diseases.