Arousal-Mediated Sleep Disturbance Persists During Cocaine Abstinence in Male Mice.
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ABSTRACT:
SUBMITTER: Bjorness TE
PROVIDER: S-EPMC9260276 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Former sleep studies among non-treatment seeking chronic cocaine users had captured polysomnographic changes for as long as three weeks of abstinence.20 cocaine dependent participants, randomized to placebo in an ongoing clinical trial, received 12 days of inpatient substance abuse treatment followed by 6 weeks of outpatient cognitive behavioral therapy. Polysomnographic recording was performed on consecutive nights during the 1st and 2nd inpatient and 3rd and 6th outpatient weeks. Number of days abstinent was determined from thrice weekly urine toxicology and self-report. Polysomnographic sleep was compared between study week 1 and 2, using paired t-tests. Trajectory of total sleep time (TST) was modeled both as a linear and a quadratic function of days abstinent.Despite reporting an improvement in overall sleep quality, polysomnographic sleep worsened from week 1 to 2. Among all participants, TST and stage 2 sleep time decreased, while REM sleep latency increased. Among participants who began the study with a positive urine test, there was also a decrease in REM and a trend for decreased slow wave sleep. TST compared to number of days abstinent (up to 54 days) was best fit with a quadratic model (p=0.002), suggesting the possibility of an improvement in total sleep time with extended abstinence.This is the first polysomnographic characterization of sleep in a large sample of cocaine users in treatment. Present findings confirm earlier results of poor and deteriorating sleep early in abstinence, and raise the possibility of improvement after an extended abstinence.
| S-EPMC4396819 | biostudies-literature
Project description:During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population.
| S-EPMC5806585 | biostudies-literature
Project description:Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them.
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Project description:10X single nucleus RNAseq of hyprcretin neurons from lateral hypothalamus in young and aged mice
2021-05-01 | GSE160581 | GEO
Project description:BackgroundSleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction.MethodsMice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice.ResultsFragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice.ConclusionsSF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target.
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Project description:Distinct subsets of nucleus accumbens (NAc) neurons differentially encode goal-directed behaviors for natural vs. drug rewards [R. M. Carelli et al. (2000)The Journal of Neuroscience, 20, 4255-4266], and the encoding of cocaine-seeking is altered following cocaine abstinence [J. A. Hollander & R. M. Carelli (2007) The Journal of Neuroscience, 27, 3535-3539]. Here, electrophysiological recording procedures were used to determine if the selective encoding of natural vs. cocaine reward by NAc neurons is: (i) maintained when the natural reinforcer is a highly palatable sweet tastant and (ii) altered by cocaine abstinence. Rats (n = 14) were trained on a multiple schedule of sucrose reinforcement and cocaine self-administration (2-3 weeks) and NAc activity was recorded during the task before and after 30 days of cocaine abstinence. Of 130 cells recorded before abstinence, 82 (63%) displayed patterned discharges (increases or decreases in firing rate, termed phasic activity) relative to operant responding for sucrose or cocaine. As in previous reports, the majority of those cells displayed nonoverlapping patterns of activity during responding for sucrose vs. cocaine. Specifically, only 17 (21%) showed similar patterns of activity (i.e. overlapping activity) across the two reinforcer conditions. After abstinence, this pattern was largely maintained, 23 of 70 phasic cells (33%) were overlapping. However, cocaine abstinence altered the overall percentage of selectively active neurons across reinforcer conditions. Specifically, significantly more neurons became selectively activated during cocaine-directed behaviors than during sucrose-directed behaviors. The results indicate that, although the selective encoding of cocaine and natural rewards is maintained even with a highly palatable substance, 30 days of cocaine abstinence dynamically alters the overall population encoding of natural and drug rewards by NAc neurons.
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Project description:Childhood maltreatment is associated with increased severity of substance use disorder and frequency of relapse to drug use following abstinence. However, the molecular and neurobiological substrates engaged during early traumatic events and mediating the relapse risk are poorly understood. Here, we show that the exposure to an adverse/hostile social experience in juvenile mice (social stressed mice, SS) influences the propensity to reinstate cocaine seeking after withdrawal periods. This effect is associated with an increased blood coagulation and a pauperization of brain vasculature. Moreover, a treatment with an anticoagulant agent during withdrawal abolishes the susceptibility to reinstate cocaine seeking in SS mice. These findings for the first time propose a molecular mechanism contributing to the increased susceptibility to relapse into cocaine abuse observed in individuals who had experienced childhood maltreatment. To analyze global gene expression differences between mice experiencing an hostile/adverse social environment during the third postnatal week and juvenile social isolated (SI) mice during cocaine abstinence. Peripheral Blood Mononuclear Cells were measured with Agilent mouse gene expression microarray during cocaine abstince after undergoing cocaine-seeking behavior studies by conditioned place preference test, extinction and withdrawal. Blood was collected 24 hours after the extinction test and genome-wide
2015-11-15 | GSE69019 | GEO
Project description:How does mitosis influence the critical process of endocytosis? Some experiments lead to the conclusion that endocytosis arrests completely during mitosis, whereas others indicate that endocytosis persists. We have resolved this apparent discrepancy by showing how conditions of the experiment influence its outcome. The dynamics of clathrin-coated pit formation and the uptake of transferrin are maintained in naturally dividing cells but are nearly absent in mitotic cells arrested chemically by treatment with nocodazole, S-Trityl-L-cysteine, or RO-3306. Moreover, sequentially incubating cells at 4°C and then shifting them to 37°C or to serum starvation artificially increases the amount of transferrin receptor at the surface of naturally dividing cells, leading to the incorrect conclusion that endocytosis has ceased during mitosis. Thus, our data show that endocytosis is unaffected during all stages of natural cell division.
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Project description:Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of Kcnq2/3 genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.
| S-EPMC9107327 | biostudies-literature
Project description:Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.
| S-EPMC7585028 | biostudies-literature