Chronic Cocaine Administration Research Articles

Acute and chronic cocaine differentially alter the subcellular distribution of AMPA GluR1 subunits in region-specific neurons within the mouse ventral tegmental area

Cocaine administration increases AMPA GluR1 expression and receptor-mediated activation of the ventral tegmental area (VTA). Functionality is determined, however, by surface availability of these receptors in transmitter- and VTA-region-specific neurons, which may also be affected by cocaine. To test this hypothesis, we used electron microscopic immunolabeling of AMPA GluR1 subunits and tyrosine hydroxylase (TH), the enzyme needed for dopamine synthesis, in the cortical-associated parabrachial (PB) and in the limbic-associated paranigral (PN) VTA of adult male C57BL/6 mice receiving either a single injection (acute) or repeated escalating-doses for 14 days (chronic) of cocaine. Acute cocaine resulted in opposing VTA-region-specific changes in TH-containing dopaminergic dendrites. TH-labeled dendrites within the PB VTA showed increased cytoplasmic GluR1 immunogold particle density consistent with decreased AMPA receptor-mediated glutamatergic transmission. Conversely, TH-labeled dendrites within the PN VTA showed greater surface expression of GluR1 with increases in both synaptic and plasmalemmal GluR1 immunogold density after a single injection of cocaine. These changes diminished in both VTA subregions after chronic cocaine administration. In contrast, non-TH-containing, presumably GABAergic dendrites showed VTA-region-specific changes only after repeated cocaine administration such that synaptic GluR1 decreased in the PB, but increased in the PN VTA. Taken together, these findings provide ultrastructural evidence suggesting that chronic cocaine not only reverses the respective depression and facilitation of mesocortical (PB) and mesolimbic (PN) dopaminergic neurons elicited by acute cocaine, but also differentially affects synaptic availability of these receptors in non-dopaminergic neurons of each region. These adaptations may contribute to increased cocaine seeking/relapse and decreased reward that is reported with chronic cocaine use.

Locomotor responding in adolescent CD-1 mice following acute and chronic cocaine administration is unaffected by low dose perinatal bisphenol A exposure

Locomotor responding in adolescent CD-1 mice following acute and chronic cocaine administration is unaffected by low dose perinatal bisphenol A exposure

Acute withdrawal from chronic escalating-dose binge cocaine administration alters kappa opioid receptor stimulation of [ 35S] guanosine 5′-O-[gamma-thio]triphosphate acid binding in the rat ventral tegmental area

There is evidence that the kappa opioid system plays an important role in cocaine addiction and that chronic cocaine administration and withdrawal from chronic cocaine alter kappa opioid receptor (KOPr) density. The present study employed in situ [ 35S]guanosine 5′-O-[gamma-thio]triphosphate acid (GTPγS) binding autoradiography to measure KOPr-stimulated activation of G-protein in the caudate putamen, nucleus accumbens core and shell, lateral hypothalamus, basolateral amygdala, substantia nigra compacta, substantia nigra reticulata and ventral tegmental area (VTA), in response to chronic cocaine administration or acute and chronic withdrawal from chronic cocaine. Male Fischer rats were injected i.p. with saline or cocaine three times daily at 1 h intervals in an escalating-dose paradigm for 14 days (from 3×15 mg/kg/injection on days 1–3 up to 3×30 mg/kg/injection on days 10–14). Identically treated separate groups were withdrawn from cocaine or saline for 24 h or 14 days. No significant change in KOPr agonist U-69593-stimulated [ 35S]GTPγS was found in the seven regions studied 30 min or 14 days after chronic 14 days escalating-dose binge cocaine administration. However there was an increase in KOPr -stimulated [ 35S]GTPγS binding in the VTA ( P<0.01) of rats withdrawn for 24 h from chronic cocaine. Our results show a cocaine withdrawal induced increase of KOPr signaling in the VTA, and suggest that the KOPr may play a role in acute withdrawal from cocaine.

Cocaine-induced changes in affective state modulate the light-enhanced startle response

In order to evaluate the influence of changes in affective state on light-enhanced startle, the effects of positive affect, induced by acute cocaine administration, and the effect of negative affect, induced by spontaneous cocaine withdrawal-induced anxiety, were studied. Acute cocaine administration decreased LES, whereas withdrawal from chronic cocaine administration exacerbated LES 24 h after withdrawal, an effect indicative of increased anxiety. This exacerbated LES was reduced, but not back to normal, 4 days after withdrawal. The finding that both cocaine-induced positive and negative affect can be detected in LES, suggests that this may be a valuable tool in studying affect regulation in rodents.

Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity

Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor DeltaFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.

The emerging role of integrins in neuropsychiatric disorders

Disrupted physical and functional associations between neurons are thought to govern the abnormal patterns of neural signaling that underlie neuropsychiatric disorders. As membrane signaling proteins that bridge extracellular interactions and intracellular signaling, integrins have been well studied for their role in cell migration, cell adhesion, and metastasis, but have been relatively underexplored for their contribution to mental illness and pharmacotherapy. Integrins are obligate α- and β-heterodimers that display molecular heterogeneity, as well as developmental and regional regulation (Denda and Reichardt, 2007). Early in development, integrin signaling supports developmental events such as neuronal migration and synaptic differentiation. Integrins also contribute to the plasticity of mature synapses. In turn, both integrin expression and signaling are sensitive to drug and pathophysiological manipulation of synapses. For example, integrin subunit expression is differentially altered by acute and chronic cocaine administration (Wiggins et al, 2009). Such alterations are likely to be functionally important, as integrin expression can influence neuronal recovery after injury, a capacity that depends on the interaction of integrins with growth factor receptors and cytokines. Several integrins have been associated with neuropsychiatric disorders, raising the possibility that they represent important new targets for medication development. Recently, we provided evidence that integrins containing the β3-subunit (ITGB3) influence the serotonin system through, in part, a direct interaction with the serotonin transporter (SERT, SLC6A4) (Carneiro et al, 2008, AM Carneiro and RD Blakely, unpublished results). These findings provide a physical basis for multiple studies that have reported associations of both ITGB3 and SLC6A4 (and gene × gene interactions) with autism risk. The SERT/β3 complex may provide an important framework for SERT regulation that likely relies on the clustering of integrins and integrin-associated proteins. Thus, targetting this complex may prove fruitful in rectifying altered serotonergic signaling in multiple neuropsychiatric disorders. In addition, integrin-αVβ3 modulates glutamatergic signaling in the CNS. Activation of αVβ3 by ligand binding leads to selective activation of MAPK-linked signaling pathways (Watson et al, 2007), as well as plasma membrane trafficking of AMPA-type glutamate receptors (Cingolani et al, 2008). These changes alter synaptic scaling, leading to alterations in the long-term potentiation of neuronal signaling. Further studies will no doubt seek to extend these findings to determine their relationship to behaviors such as learning and memory. Nonselective peptide ligands and novel subunit-specific ligands are used to pursue the role of integrins in neuronal function. Integrin-β3 ligands are based on the Arg-Gly-Asp sequence present in the binding domain of extracellular matrix proteins. Cyclic Arg-Gly-Asp peptides show nanomolar αVβ3 affinities, whereas isoxazoline compounds (currently under clinical trials) show femtomolar affinities (Miller et al, 2000). Although these compounds were initially developed for in vivo mapping of malignant tumors and cancer treatment, they also provide exciting leads for reagents that can target αVβ3-specific pathways in neurons. Furthermore, they provide a platform for developing blood–brain barrier penetrant ligands that can probe in vivo contributions of integrin signaling to behavior and possibly novel treatments for devastating brain disorders.

Glycogen synthase kinase 3β in the nucleus accumbens core mediates cocaine‐induced behavioral sensitization

Glycogen synthase kinase 3beta (GSK-3beta) is a ubiquitous serine/threonine protein kinase involved in a number of signaling pathways. Previous studies have demonstrated a role for GSK-3beta in the synaptic plasticity underlying dopamine-associated behaviors and diseases. Drug sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. However, the role of GSK-3beta in cocaine-induced behavior sensitization has not been examined. The present study investigated the effects of chronic cocaine exposure on GSK-3beta activity in the nucleus accumbens (NAc) and determined whether changes in GSK-3beta activity in the NAc are associated with cocaine-induced locomotor sensitization. We also explored whether blockade of GSK-3beta activity in the NAc inhibits the initiation and expression of cocaine-induced locomotor sensitization in rats using systemic or brain region-specific administration of the GSK-3beta inhibitors lithium chloride (LiCl) and SB216763. GSK-3beta activity in the NAc core, but not NAc shell, increased after chronic cocaine (10 mg/kg, i.p.) administration. The initiation and expression of cocaine-induced locomotor sensitization was attenuated by systemic administration of LiCl (100 mg/kg, i.p.) or direct infusion of SB216763 (1 ng/side) into the NAc core, but not NAc shell. Collectively, these results indicate that GSK-3beta activity in the NAc core, but not NAc shell, mediates the initiation and expression of cocaine-induced locomotor sensitization, suggesting that GSK-3beta may be a potential target for the treatment of cocaine addiction.

INFLUENCES ON COCAINE TOLERANCE ASSESSED UNDER A MULTIPLE CONJUNCTIVE SCHEDULE OF REINFORCEMENT

Under multiple schedules of reinforcement, previous research has generally observed tolerance to the rate-decreasing effects of cocaine that has been dependent on schedule-parameter size in the context of fixed-ratio (FR) schedules, but not under the context of fixed-interval (FI) schedules of reinforcement. The current experiment examined the effects of cocaine on key-pecking responses of White Carneau pigeons maintained under a three-component multiple conjunctive FI (10 s, 30 s, & 120 s) FR (5 responses) schedule of food presentation. Dose-effect curves representing the effects of presession cocaine on responding were assessed in the context of (1) acute administration of cocaine (2) chronic administration of cocaine and (3) daily administration of saline. Chronic administration of cocaine generally resulted in tolerance to the response-rate decreasing effects of cocaine, and that tolerance was generally independent of relative FI value, as measured by changes in ED50 values. Daily administration of saline decreased ED50 values to those observed when cocaine was administered acutely. The results show that adding a FR requirement to FI schedules is not sufficient to produce schedule-parameter-specific tolerance. Tolerance to cocaine was generally independent of FI-parameter under the present conjunctive schedules, indicating that a ratio requirement, per se, is not sufficient for tolerance to be dependent on FI parameter.

Synergistic Interactions between Histone Deacetylase Inhibitors and Drugs of Abuse

Synergistic Interactions between Histone Deacetylase Inhibitors and Drugs of Abuse

The brain-specific Neural Zinc Finger transcription factor 2b (NZF-2b/7ZFMyt1) causes suppression of cocaine-induced locomotor activity

Chronic cocaine induces high expression of the brain-specific Neural-Zinc-Finger transcription factor-2b (NZF-2b/7ZFMyt1), particularly in the mesolimbic dopaminergic pathway, resulting in a 11-fold increase in NZF-2b/7ZFMyt1 expression in the Nucleus Accumbens (NAc). Overexpression of this gene in the NAc with a NZF-2b/7ZFMyt1-expressing lentivirus resulted in >55% decrease in locomotor activity upon chronic cocaine administration, compared to control animals. In contrast knocking-down the gene in the NAc with lentiviruses expressing shRNAs against NZF-2b/7ZFMyt1 induced strong hyperlocomotor activity upon cocaine. Strong inhibition of BDNF is observed upon NZF-2b/7ZFMyt1 expression, concomitant with strong induction of transcription factors REST1 (RE silencing transcription factor-1) and NAC1, probably leading to regulation of gene expression by interaction with histone deacetylases. These changes lead to decreased responsiveness of the animal to the locomotor-activating effects of cocaine, indicating that NZF-2b/7ZFMyt1 expression plays an important role in phenotypic changes induced by the drug.

Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models.

Drug-addicted individuals show high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human drug users. This article reviews this literature, with a particular focus on the effects of chronic cocaine administration, which have been most thoroughly characterized. The potential mechanisms of these effects are described in terms of drug-induced neural alterations in ventral striatal and prefrontal cortical brain systems. Some implications of this research for pharmacological treatment of drug-induced increases in impulsive choice are discussed, along with suggestions for future research in this area.

MicroRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

MicroRNAs play key regulatory roles in cellular processes including neurogenesis, synapse development and plasticity in the brain. Psychostimulants induces strong neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. MicroRNA profiling for identifying miRNAs regulating cocaine-induced, plasticity-related genes revealed significant regulation of a set of miRNAs upon cocaine administration, especially let-7d, miR-181a and the brain-specific miR-124. These miRNAs target many genes involved in cocaine addiction. Precursor and mature miRNA quantification by qRT-PCR showed that miR-124 and let-7d are significantly downregulated, whereas miR-181a is induced in the mesolimbic dopaminergic system under chronic cocaine administration. Results were confirmed by in situ hybridization, Northern blots, FISH analysis and RNase protection assay. Using lentiviral-mediated miRNA expression, we show a significant downregulation of BDNF and D3R both at mRNA and protein levels by miR-124 and let-7d, respectively. Our data suggest that miR-124, let-7d and miR-181a may be involved in a complex feedback loop with cocaine-responsive plasticity genes, highlighting the possibility that some miRNAs are key regulators of the reward circuit and may be implicated in addiction.

Upregulation of acid-sensing ion channel 1 protein expression by chronic administration of cocaine in the mouse striatum in vivo

Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by a drop in extracellular pH. They are enriched in the mammalian brain with a high synaptic density. Accumulating evidence suggests that ASIC1 contributes to synaptic activity related to learning/memory and fear conditioning, and also plays critical roles in neurodegenerative diseases. In this study, we explored the effect of the psychostimulant, cocaine, on protein expression of ASICs in the mouse forebrain in vivo. We found that chronic systemic injection of cocaine (20 mg/kg, once daily for 5 consecutive days; 14 days of withdrawal) increased ASIC1, but not ASIC2, protein levels in the striatum, including the dorsal (caudate putamen) and the ventral (nucleus accumbens) striatum. No significant changes in ASIC1 or 2 protein levels in the median prefrontal cortex and the hippocampus were observed following the chronic cocaine administration. These data demonstrate that chronic cocaine exposure can upregulate ASIC expression in the striatum in a subunit-selective manner.

Genome-wide Analysis of Chromatin Regulation by Cocaine Reveals a Role for Sirtuins

Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of DeltaFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine-including a new role for sirtuins (Sirt1 and Sirt2)-which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.

Cocaine withdrawal enhances long-term potentiation in rat hippocampus via changing the activity of corticotropin-releasing factor receptor subtype 2

The neural plasticity mechanisms that underlie learning and memory may also be engaged when drug addiction occurs. It was reported that long-lasting neuroadaptations induced by cocaine use and withdrawal require the participation of hippocampus. However, the role of corticotrophin-releasing factor receptors in this process remains unclear. In the present study, the effects of chronic cocaine treatment (a 14-day cocaine administration, 20 mg/kg i.p., daily) and short-term cocaine withdrawal (a 3-day cocaine extinction following a 14-day cocaine administration) on long-term potentiation (LTP), one prominent cellular mechanism for learning and memory, were assessed in the CA1 region of the rat hippocampal slices. We found that cocaine withdrawal, but not the chronic cocaine administration itself, significantly enhanced the magnitude of LTP in hippocampal slices, as compared with that in saline controls. Selective blockade of corticotrophin-releasing factor receptor subtype 1 (CRF 1) with the specific antagonist NBI 27914 (100 nM in vitro) attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal rats, and intriguingly, also from saline control rats, while specific blockade of corticotrophin-releasing factor receptor subtype 2 (CRF 2) with astressin2-B (100 nM in vitro) selectively attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal rats. Our data suggest that short-term cocaine withdrawal treatment may cause synaptic plasticity in hippocampus partially via changing the activity of CRF 2 in the hippocampus.

Cocaine challenge enhances release of neuroprotective amino acid taurine in the striatum of chronic cocaine treated rats: A microdialysis study

Drug addiction is a serious public health problem. There is increasing evidence on the involvement of augmented glutamatergic transmission in cocaine-induced addiction and neurotoxicity. We investigated effects of acute or chronic cocaine administration and cocaine challenge following chronic cocaine exposure on the release of excitotoxic glutamate and neuroprotective taurine in the rat striatum by microdialysis. Cocaine challenge, following withdrawal after repeated cocaine exposure markedly increased the release of glutamate, which may cause neurotoxicity. Simultaneously, cocaine challenge after withdrawal also significantly increased the release of taurine, which counteracts glutamate-mediated excitotoxicity and possibly cell death. Thus, the mammalian brain has an endogenous self-protective mechanism against cocaine-mediated neurotoxicity and potentially addiction.

Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats

Event Abstract Back to Event Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats Cecilia Juliana Alves1, 2, A. Magalhaes1, L. De-Sousa1, 2, M. A. Tavares1, 3, P. R. Monteiro1, 4 and Teresa Summavielle1, 4* 1 Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Portugal 2 Instituto de Ciencias Biomedicas de Abel Salazar, Portugal 3 University of Porto, Faculty of Medicine, Portugal 4 Escola Superior de Tecnologia da Saúde do Porto do IPP, Portugal This study aimed to evaluate the long-term effects of chronic cocaine exposure during adolescence in the aggressive behaviour of young adult male rats through the social threat provided by the resident-intruder paradigm. The neurochemical and stress-hormone response to the social threat were also evaluated. To achieve this objective it was developed an animal model of chronic cocaine administration during adolescence in Wistar rats. Adolescent males were submitted to a chronic “binge” pattern of cocaine-hydrochloride administration (3x15 mg/kg/day at hourly intervals; intraperitoneal), from postnatal day (PND) 35 to PND 50. Controls were given a 0.9% NaCl solution following the same experimental protocol. Ten days after the last administration of cocaine, rats were tested using the resident-intruder paradigm. Offensive, defensive and social behaviour were registered during 10 min. At the end of the test the substantia nigra and the ventral tegmental area (SN-VTA), the dorsal raphe nucleus, the amygdala, the hippocampus, the prefrontal cortex and the hypothalamus were collected for neurochemical determination. Plasma was also collected for corticosterone levels determination. Cocaine-treated male rats presented no differences in frequency, duration or latency of the offensive behaviours, however, these animals displayed increased duration of the anogenital sniffing behaviour, and increased latency and lower frequency of flight behaviour. Neurochemical data indicated that after the behavioural test cocaine-treated rats displayed lower levels of DOPAC in the hippocampus and lower 5-HT turnover rate in the SN-VTA. The corticosterone response to the resident- intruder paradigm did not differ between cocaine-treated and control animals. The results seem to indicate that although cocaine treatment during adolescence did not affected the aggressive behaviour of young adult rats; it affected social investigation that was increased by pre-exposure to cocaine. Consistently, the observed alterations in the dopaminergic and serotonergic systems were not associated with aggressive behaviour, but may have been relevant to the increased social investigation observed in cocaine-treated rats in response to the challenge provided by the test.Alves CJ was granted by FCT (SFRH/BD/17195/2004) Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neuronal Communication Citation: Juliana Alves C, Magalhaes A, De-Sousa L, Tavares MA, Monteiro PR and Summavielle T (2009). Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.139 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Aug 2009; Published Online: 11 Aug 2009. * Correspondence: Teresa Summavielle, Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal, tsummavi@ibmc.up.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Google Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Google Scholar Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle PubMed Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

ΔFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine

The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor ΔFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC ΔFosB through viral-mediated gene transfer mimics these behavioural changes: ΔFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing ΔFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing ΔFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC ΔFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine's many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction.

Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats. To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied. Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration. Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.

Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine

Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, and by predicting the down-regulation of glutamate transporters, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis.