Saïd Kourrich

Dynamic Interaction between Sigma-1 Receptor and Kv1.2 Shapes Neuronal and Behavioral Responses to Cocaine

The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an interorganelle 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 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.

Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell

The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which 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 feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine.

Similar Neurons, Opposite Adaptations: Psychostimulant Experience Differentially Alters Firing Properties in Accumbens Core versus Shell

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 d) 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 d abstinence) that persists for at least 2 weeks, core neurons exhibit increased firing capacity during early abstinence (1–3 d) that declines to basal levels within 2 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 d) 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.

Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms.

BACKGROUND Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. METHODS To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we injected increasing METH doses to rats for 2 weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation. We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation. RESULTS Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase chain reaction revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2, onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor 1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced decrease H4K16Ac recruitment on AMPAR gene sequences. CONCLUSIONS These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression.

C57BL/6N Mutation in Cytoplasmic FMRP interacting protein 2 Regulates Cocaine Response

Not All Mice Are Equal Different laboratories often use different strains of inbred animals, but one cannot make behavioral comparisons and assume that their reaction to interventions will necessarily be similar. Kumar et al. (p. 1508) have detected differences in cocaine response between the widely used C57BL/6N and C57BL/6J mouse strains and used quantitative trait locus analysis to identify a mutation in an inducible gene, Cyfip, that interacts with the Fragile X protein (FMRP) to regulate sensitivity and sensitization to cocaine through regulation of neuronal connectivity. Acute locomotor responses to cocaine differ significantly in the most widely used inbred strains of laboratory mice. 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 a lower acute and sensitized response to cocaine and methamphetamine. We mapped a single causative locus and identified a nonsynonymous mutation of serine to phenylalanine (S968F) in Cytoplasmic FMRP 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 that CYFIP2 is a key regulator of cocaine response in mammals and present a framework to use mouse substrains to identify previously unknown genes and alleles regulating behavior.

Intrinsic plasticity: an emerging player in addiction

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.

Gβ5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling

The type 5 G protein β subunit (Gβ5) can form complexes with members of the regulator of G protein signaling 7 (RGS7) family, but its relevance to neuronal G protein signaling is unclear. We found that mouse RGS7-Gβ5 complexes bound to G protein–gated potassium channels and facilitated their functional coupling to GABAB receptors in neurons. Our findings identify a compartmentalization mechanism that is critical for ensuring high temporal resolution of neuronal G protein signaling.

Apamin improves reference memory but not procedural memory in rats by blocking small conductance Ca2+-activated K+ channels in an olfactory discrimination task

Apamin blocks SK channels responsible for long-lasting hyperpolarization following the action potential. Using an olfactory associative task, the effect of an intracerebroventricular 0.3 ng apamin injection was tested on learning and memory. Apamin did not modify the learning of the procedure side of the task or the learning of the odor-reward association. To test reference memory specifically, the rats were trained on a new odor-association problem using the same procedure (acquisition session), and they were tested for retention 24 h later. Apamin injected before or after the acquisition session improved retention of the valence of a new odor pair. Apamin injected before the retention session did not affect the retrieval of the new valence. Thus, the results indicate that the blockage of apamin-sensitive SK channels facilitate consolidation on new-odor-reward association.

Differential behavioral and neurochemical effects of cocaine after early exposure to methylphenidate in an animal model of attention deficit hyperactivity disorder.

We used a putative animal model of attention deficit hyperactivity disorder (ADHD), the SHR rat, to examine the effects of repeated exposure to methylphenidate (MPH; Ritalin) during the pubertal period on cocaine-induced conditioned place preference and dopamine (DA) levels in the nucleus accumbens (NAc) in adulthood. Our results indicate that early exposure to methylphenidate diminishes sensitivity to the incentive properties of cocaine in adulthood, but it does so without altering the response of the mesolimbic dopamine system.

A new class of scorpion toxin binding sites related to an A-type K+ channel: pharmacological characterization and localization in rat brain.

A new scorpion toxin (3751.8 Da) was isolated from the Buthus martensi venom, sequenced and chemically synthesized (sBmTX3). The A‐type current of striatum neurons in culture completely disappeared when 1 μM sBmTX3 was applied (K d=54 nM), whereas the sustained K+ current was unaffected. 125I‐sBmTX3 specifically bound to rat brain synaptosomes (maximum binding=14 fmol mg−1 of protein, K d=0.21 nM). A panel of toxins yet described as specific ligands for K+ channels were unable to compete with 125I‐sBmTX3. A high density of 125I‐sBmTX3 binding sites was found in the striatum, hippocampus, superior colliculus, and cerebellum in the adult rat brain.