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.

Summary The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an inter-organelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K+ current in the nucleus accumbens (NAc) that results in neuronal hypoactivity, and thereby enhances behavioral cocaine response. Combining ex vivo and in vitro studies, we demonstrated that this neuroadaptation is caused by a persistent protein-protein association between Sig-1Rs and Kv1.2 channels, a phenomenon that is associated to a redistribution of both proteins from intracellular compartments to the plasma membrane. In conclusion, the dynamic Sig-1R - Kv1.2 complex represents a novel mechanism that shapes neuronal and behavioral response to cocaine. Functional consequences of Sig-1R binding to K+ channels may have implications for other chronic diseases where maladaptive intrinsic plasticity and Sig-1Rs are engaged.

The transcription factor ΔFosB and the brain-enriched protein kinase CaMKIIα (calcium/calmodulin-dependent protein kinase II) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, where the two proteins mediate sensitized drug responses. Although ΔFosB and CaMKIIα both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27, and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D1-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of ΔFosB are both CaMKII-dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB and CaMKII engage in a cell type- and brain region-specific positive feed-forward loop as a key mechanism for regulating the brain’s reward circuitry in response to chronic cocaine.

The principal components of neuronal excitability include synaptic and intrinsic membrane parameters. While recent studies indicate that cocaine exposure can induce widespread changes in synaptic function in the neural circuits for reward, intrinsic firing properties have received much less attention. Using whole cell recording in ex vivo brain slices from cocaine-treated mice, we studied the intrinsic firing characteristics of medium-spiny projection neurons of the nucleus accumbens—a key node in the circuit that controls reward-directed behavior. Our data demonstrate that repeated in vivo cocaine (5 × 15 mg/kg i.p. once daily, 5 days) induces opposite changes in neurons of the two main subdivisions of the accumbens, the shell and the core. While shell neurons exhibit an initial depression in firing capacity (1-3 days abstinence) that persists for at least two weeks, core neurons exhibit increased firing capacity during early abstinence (1-3 days) that declines to basal levels within two weeks. Shared adaptations between addictive drugs may mediate core processes of addiction. We find that amphetamine exposure (5 × 5 mg/kg i.p. once daily, 5 days) that induced a similar degree of locomotor sensitization as cocaine also induced an indistinguishable pattern of NAc intrinsic plasticity. Finally, we provided evidence that opposite regulation of A-type potassium current is an important factor in this bidirectional intrinsic plasticity for both cocaine and amphetamine. We propose that a persistent disparity in core/shell excitability might be an important mediator of the changes in reward circuit activity that drive drug-seeking behavior in animal models of addiction.

Background Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. Methods To identify the METH-induced epigenetic underpinnings of these adaptations in the brain, we injected increasing METH doses to rats for two weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation using chromatin immunoprecipitation (ChIP) and qPCR. We also measured METH-induced changes in DNA methylation and hydroxylation by using methylated (Me) and hydroxymethylated (hMe) DNA precipitation (DIP) and qPCR. Results Chronic METH decreased transcript and protein expression of GluA1 and GluA2 AMPAR and GluN1 NMDAR subunits. These changes were associated with decreased electrophysiological glutamatergic responses in striatal neurons. ChIP-PCR revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. METH also increased protein levels of histone deacetylases (HDAC1, HDAC2 and SIRT2), protein repressors (REST and CoREST), and of the methylated DNA binding protein, MeCP2. Moreover, METH exposure increased CoREST, MeCP2, and HDAC2, but not SIRT1 or SIRT2, enrichment onto GluA1 and GluA2 gene sequences. Furthermore, METH caused interactions of CoREST and MeCP2 with HDAC2 and of REST with HDAC1. Surprisingly, MeDIP and hMeDIP-PCR revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Furthermore, the HDAC inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and NMDAR subunits. Finally, valproic acid also attenuated METH-induced decreased H4K16Ac recruitment on AMPAR gene sequences. Conclusions These observations suggest that histone H4 hypoacetylation might be the main determinant of METH-induced decreased striatal glutamate receptor expression.

Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype.