Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity.

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.

The Cocaine and Oxycodone Biobanks, Two Repositories from Genetically Diverse and Behaviorally Characterized Rats for the Study of Addiction.

The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.

Microliter ultrafast centrifuge platform for size-based particle and cell separation and extraction using novel omnidirectional spiral surface acoustic waves.

Asymmetric surface acoustic waves have been shown useful in separating particles and cells in many microfluidics designs, mostly notably sessile microdroplets. However, no one has successfully extracted target particles or cells for later use from such samples. We present a novel omnidirectional spiral surface acoustic wave (OSSAW) design that exploits a new cut of lithium niobate, 152 Y-rotated, to rapidly rotate a microliter sessile drop to ∼10 g, producing efficient multi-size particle separation. We further extract the separated particles for the first time, demonstrating the ability to target specific particles, for example, platelets from mouse blood for further integrated point-of-care diagnostics. Within ∼5 s of surface acoustic wave actuation, particles with diameter of 5 µm and 1 µm can be separated into two portions with a purity of 83% and 97%, respectively. Red blood cells and platelets within mouse blood are further demonstrated to be separated with a purity of 93% and 84%, respectively. These advancements potentially provide an effective platform for whole blood separation and point-of-care diagnostics without need for micro or nanoscale fluidic enclosures.

Correction to: Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking.

The author reports that data for electrophysiology findings reported in Figs. 4 and 5 for control group and Meth Rst group have been published previously (Galinato MH et al., J Neurosci. 2018 Feb 21; 38(8):2029-2042.

Helium-Induced Changes in Circulating Caveolin in Mice Suggest a Novel Mechanism of Cardiac Protection.

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.

Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking is Associated with Distinct Neuroadaptations in the Dentate Gyrus.

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats, and neuronal excitability was evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males was associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII, and choline acetyltransferase in the DG. Enhanced excitability in females was associated with an increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs was associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins, and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors.

Hippocampal neural progenitor cells play a distinct role in fear memory retrieval in male and female CIE rats.

Adult male and female GFAP-TK transgenic rats experienced six weeks of chronic intermittent ethanol vapor inhalation (CIE). During the last week of CIE, a subset of male and female TK rats were fed with Valcyte to ablate neural progenitor cells (NPCs). Seventy-two hours after CIE cessation, all CIE and age-matched ethanol naïve controls experienced auditory trace fear conditioning (TFC). Twenty-four hours later all animals were tested for cue-mediated retrieval in the fear context. Adult male CIE rats showed a significant burst in NPCs paralleled by reduction in fear retrieval compared to naïve controls and Valcyte treated CIE rats. Adult female CIE rats did not show a burst in NPCs and showed similar fear retrieval compared to naïve controls and Valcyte treated CIE rats, indicating that CIE-mediated impairment in fear memory and its regulation by NPCs was sex dependent. Valcyte significantly reduced Ki-67 and NeuroD labeled cells in the dentate gyrus (DG) in both sexes, demonstrating a role for NPCs in reduced fear retrieval in males. Valcyte prevented adaptations in GluN2A receptor expression and synaptoporin density in the DG in males, indicating that NPCs contributed to alterations in plasticity-related proteins and mossy fiber projections that were associated with reduced fear retrieval. These data suggest that DG NPCs born during withdrawal and early abstinence from CIE are aberrant, and could play a role in weakening long-term memory consolidation dependent on the hippocampus.

Ethanol Reinforcement Elicits Novel Response Inhibition Behavior in a Rat Model of Ethanol Dependence.

Lower impulse control is a known risk factor for drug abuse vulnerability. Chronic experience with illicit drugs is suggested to enhance impulsivity and thereby perpetuate addiction. However, the nature of this relationship (directionality, causality) with regard to alcohol use disorder is unclear. The present study tested the hypothesis that higher impulsivity is observed during chronic intermittent ethanol vapor inhalation (CIE; a model of ethanol dependence) and subsequent abstinence from CIE in adult Wistar rats. Impulsivity was tested using a differential reinforcement of low rates 15 s (DRL15) schedule using either nondrug reward (palatable modified sucrose pellets) or sweetened ethanol. A decrease in the efficiency of earning reinforcers (expressed as % reinforcers/responses) is indicative of a decrease in response inhibition or an increase in impulsivity. The efficiency of reinforcement and amount of reinforcers earned were unaltered in CIE and control animals when the reinforcer was sucrose. When the reinforcer was sweetened ethanol, the efficiency of reinforcement increased in CIE rats compared with controls only during protracted abstinence. Responding for sweetened ethanol under a progressive-ratio schedule was more rapid in CIE rats during protracted abstinence. Contrary to the initial hypothesis, impulsivity did not increase in rats with a history of CIE; instead, it decreased when ethanol was used as the reinforcer. Furthermore, although the efficiency of ethanol reinforcement did not differ between CIE and control animals during CIE, CIE rats escalated the amount of sweetened ethanol consumed, suggesting that behavioral adaptations that are induced by CIE in rats that are tested under a DRL15 schedule appear to be targeted toward the maximization of ethanol intake and thus may contribute to escalation and relapse.

Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking.

Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naïve (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABAA subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression of GluNs and decreases in GABAA subunits that may contribute to the altered synaptic connectivity-neuronal circuitry-and activity in the hippocampus, and enhance propensity for relapse.

Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory.

Abstinence from methamphetamine addiction enhances proliferation and differentiation of neural progenitors and increases adult neurogenesis in the dentate gyrus (DG). We hypothesized that neurogenesis during abstinence contributes to context-driven drug-seeking behaviors. To test this hypothesis, the pharmacogenetic rat model (GFAP-TK rats) was used to conditionally and specifically ablate neurogenesis in the DG. Male GFAP-TK rats were trained to self-administer methamphetamine or sucrose and were administered the antiviral drug valganciclovir (Valcyte) to produce apoptosis of actively dividing GFAP type 1 stem-like cells to inhibit neurogenesis during abstinence. Hippocampus tissue was stained for Ki-67, NeuroD, and DCX to measure levels of neural progenitors and immature neurons, and was stained for synaptoporin to determine alterations in mossy fiber tracts. DG-enriched tissue punches were probed for CaMKII to measure alterations in plasticity-related proteins. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naive (controls) and methamphetamine experienced animals (+/-Valcyte). Spontaneous EPSCs and intrinsic excitability were recorded from granule cell neurons (GCNs). Reinstatement of methamphetamine seeking enhanced autophosphorylation of CaMKII, reduced mossy fiber density, and induced hyperexcitability of GCNs. Inhibition of neurogenesis during abstinence prevented context-driven methamphetamine seeking, and these effects correlated with reduced autophosphorylation of CaMKII, increased mossy fiber density, and reduced the excitability of GCNs. Context-driven sucrose seeking was unaffected. Together, the loss-of-neurogenesis data demonstrate that neurogenesis during abstinence assists with methamphetamine context-driven memory in rats, and that neurogenesis during abstinence is essential for the expression of synaptic proteins and plasticity promoting context-driven drug memory.SIGNIFICANCE STATEMENT Our work uncovers a mechanistic relationship between neurogenesis in the dentate gyrus and drug seeking. We report that the suppression of excessive neurogenesis during abstinence from methamphetamine addiction by a confirmed phamacogenetic approach blocked context-driven methamphetamine reinstatement and prevented maladaptive changes in expression and activation of synaptic proteins and basal synaptic function associated with learning and memory in the dentate gyrus. Our study is the first to demonstrate an interesting and dysfunctional role of adult hippocampal neurogenesis during abstinence to drug-seeking behavior in animals self-administering escalating amounts of methamphetamine. Together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.

Platelet Endothelial Cell Adhesion Molecule-1 and Oligodendrogenesis: Significance in Alcohol Use Disorders.

Alcoholism is a chronic relapsing disorder with few therapeutic strategies that address the core pathophysiology. Brain tissue loss and oxidative damage are key components of alcoholism, such that reversal of these phenomena may help break the addictive cycle in alcohol use disorder (AUD). The current review focuses on platelet endothelial cell adhesion molecule 1 (PECAM-1), a key modulator of the cerebral endothelial integrity and neuroinflammation, and a targetable transmembrane protein whose interaction within AUD has not been well explored. The current review will elaborate on the function of PECAM-1 in physiology and pathology and infer its contribution in AUD neuropathology. Recent research reveals that oligodendrocytes, whose primary function is myelination of neurons in the brain, are a key component in new learning and adaptation to environmental challenges. The current review briefly introduces the role of oligodendrocytes in healthy physiology and neuropathology. Importantly, we will highlight the recent evidence of dysregulation of oligodendrocytes in the context of AUD and then discuss their potential interaction with PECAM-1 on the cerebral endothelium.

Hyper-oligodendrogenesis at the vascular niche and reduced blood-brain barrier integrity in the prefrontal cortex during protracted abstinence.

Alcoholism is a relapsing disorder with limited treatment options, in part due to our limited understanding of the disease etiology. We have recently shown that increased ethanol-seeking in a behavioral model of relapse in a rat model of alcoholism was associated with increased oligodendrogenesis which was positively correlated with platelet/endothelial cell adhesion molecule (PECAM-1) expression in the medial prefrontal cortex (mPFC). The current study investigated whether newly born oligodendrocytes form close physical associations with endothelial cells expressing PECAM-1 and whether these changes were accompanied by altered blood-brain barrier (BBB) integrity. Colableling and confocal analysis demonstrate that newly born oligodendroglia were always located in close physical proximity to PECAM-1 in the mPFC of rats that were ethanol dependent and demonstrated high propensity for relapse. Notably, the endothelial proximity of new oligodendrocytes was associated with reduced expression of endothelial barrier antigen (SMI-71), a marker for BBB integrity. Furthermore, voluntary wheel running during abstinence enhanced SMI-71 expression in endothelial cells, indicating protection against abstinence-induced reduction in BBB integrity. Taken together, these results suggest that ethanol experience and abstinence disrupts homeostasis in the oligo-vascular niche in the mPFC. Reversing these mechanisms may hold the key to reducing propensity for relapse in individuals with moderate to severe alcohol use disorder.

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors.

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.

Dietary restriction reduces hippocampal neurogenesis and granule cell neuron density without affecting the density of mossy fibers.

The hippocampal formation undergoes significant morphological and functional changes after prolonged caloric and dietary restriction (DR). In this study we tested whether prolonged DR results in deleterious alterations in hippocampal neurogenesis, density of granule cell neurons and mossy fibers, all of which support plasticity in the dentate gyrus. Young adult animals either experienced free access to food (control condition), or every-other-day feeding regimen (DR condition) for 3months. The number of Ki-67 cells and 28-day old 5-bromo-2'-deoxyuridine (BrdU) cells were quantified in the dorsal and ventral dentate gyrus to determine the effect of DR on cellular proliferation and survival of neural progenitor cells in the anatomically defined regions of the dentate gyrus. The density of granule cell neurons and synaptoporin were also quantified to determine the effect of DR on granule cell neurons and mossy fiber projections in the dentate gyrus. Our results show that DR increases cellular proliferation and concurrently reduces survival of newly born neurons in the ventral dentate gyrus without effecting the number of cells in the dorsal dentate gyrus. DR reduced density of granule cell neurons in the dorsal dentate gyrus. These alterations in the number of granule cell neurons did not affect mossy fiber density in DR animals, which was visualized as no differences in synaptoporin expression. Our findings demonstrate that granule cell neurons in the dentate gyrus are vulnerable to chronic DR and that the reorganization of granule cells in the dentate gyrus subregions is not producing concomitant alterations in dentate gyrus neuronal circuitry with this type of DR.

Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function.

Role of striatal dopamine D1 receptors (D1Rs) in methamphetamine (Meth) taking and seeking is recognized from contingent Meth self-administration studies. For example, Meth increases levels of D1Rs in the dorsal striatum in animal models of Meth addiction, and blockade of striatal D1Rs decreased responding for Meth and reduced Meth priming-induced drug seeking. However, the mechanism underlying enhanced expression of striatal D1Rs in animals self-administering Meth is unknown and is hypothesized to involve maladaptive intracellular signal transduction mechanism via hyperphosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). D1Rs are predominantly localized to detergent-resistant membrane/lipid raft fractions (MLR fraction), and in vitro studies indicate that D1R signaling and recycling is regulated by the MLR-resident protein caveolin-1 (Cav-1), in an endocytotic-dependent manner. Notably, expression of Cav-1 is inversely regulated by ERK1/2 activation, suggesting a signaling interplay among D1Rs, ERK1/2 and Cav-1. We therefore evaluated the effects of extended access Meth self-administration on expression of striatal D1Rs, activated ERK1/2 and Cav-1. We first report that Cav-1 is heavily expressed in neurons located in the dorsal striatum. We also report that extended access Meth produces compulsive-like unregulated intake of the drug, and these behavioral outcomes are associated with enhanced expression of D1Rs, increased activity of ERK1/2, and reduced Cav-1 expression in the dorsal striatum. These data suggest a possible cellular mechanism that involves Cav-1 regulation of D1R expression in response to escalated Meth intake, and how this response of altered D1Rs and enhanced ERK1/2 activation to Meth self-administration contributes to contingent-related processes such as addiction.

Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling.

Effects of withdrawal from ethanol drinking in chronic intermittent ethanol vapor (CIE)-exposed dependent rats and air-exposed nondependent rats on proliferation and survival of progenitor cells in the hippocampus and the medial prefrontal cortex (mPFC) were investigated. Rats were injected with 5'-Bromo 2-deoxyuridine 72 h post-CIE to measure proliferation (2 h-old cells) and survival (29-day-old cells) of progenitors born during a time-point previously reported to elicit a proliferative burst in the hippocampus. Hippocampal and mPFC brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B receptor (TrkB) expression were measured 3 h or 21d post-CIE to evaluate neurotrophic signaling during a time point preceding the proliferative burst and survival of newly born progenitors. CIE rats demonstrated elevated drinking compared to nondependent rats and CIE rats maintained elevated drinking following protracted abstinence. Withdrawal from CIE increased BDNF levels in the hippocampus and mPFC, and subsequently increased proliferation in the hippocampus and mPFC compared to nondependent rats and controls. Protracted abstinence from CIE reduced BDNF expression to control levels, and subsequently reduced neurogenesis compared to controls and nondependent rats in the hippocampus. In the mPFC, protracted abstinence reduced BDNF expression to control levels, whereas increased oligodendrogenesis in dependent rats compared to nondependent rats and controls. These results suggest a novel relationship between BDNF and progenitors in the hippocampus and mPFC, in which increased ethanol drinking may alter hippocampal and cortical function in alcohol dependent subjects by altering the cellular composition of newly born progenitors in the hippocampus and mPFC.

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons.

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug-cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6 h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for 3 weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also suggest that wheel running may be preventing certain allostatic changes in the brain reward and stress systems contributing to the negative reinforcement and perpetuation of the addiction cycle.

Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction-Like Behavior.

The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction.

Role of NG2 expressing cells in addiction: a new approach for an old problem.

Neuron-glial antigen 2 (NG2) is a proteoglycan expressed predominantly in oligodendrocyte progenitor cells (OPCs). NG2-expressing OPCs (NG2-OPCs) are self-renewing cells that are widely distributed in the gray and white matter areas of the central nervous system. NG2-OPCs can mature into premyelinating oligodendrocytes and myelinating oligodendroglia which serve as the primary source of myelin in the brain. This review characterizes NG2-OPCs in brain structure and function, conceptualizes the role of NG2-OPCs in brain regions associated with negative reinforcement and relapse to drug seeking and discusses how NG2-OPCs are regulated by neuromodulators linked to motivational withdrawal. We hope to provide the readers with an overview of the role of NG2-OPCs in brain structure and function in the context of negative affect state in substance abuse disorders and to integrate our current understanding of the physiological significance of the NG2-OPCs in the adult brain.