Estrogen effects on cocaine-induced reinstatement of lever responding were examined in sham-operated, vehicle-treated (SH
+
VEH), ovariectomized (OVX
+
VEH), and OVX female Wistar rats with estrogen ...replacement (OVX
+
EB). The effect of long- (64
±
1.56 days) and short-term (9 days) EB treatment on reinstatement of cocaine-seeking behavior was compared in Experiment 1 and 2, respectively, in order to compare the effect of EB when it was present during the development vs. expression of reinstatement of cocaine-seeking behavior. Rats were trained to self-administer 0.4 mg/kg/inf cocaine. After the acquisition criteria were met, rats continued to respond for cocaine for 2 h/day for a 14-day maintenance period. Cocaine was then replaced with saline and the 21-day extinction period commenced. Subsequently, rats were tested for reinstatement of lever responding on the previously drug-paired lever after alternating daily injections of saline or cocaine. In both experiments, there were no differences between groups in self-administration behavior during training, maintenance, or extinction. In Experiment 1, SH
+
VEH and chronically treated OVX
+
EB rats had greater cocaine-induced reinstatement than OVX
+
VEH rats. In Experiment 2, short-term treated OVX
+
EB rats also showed enhanced cocaine-induced reinstatement compared to OVX
+
VEH rats. The results indicate that EB-mediated enhancement of cocaine-induced reinstatement is dependent on EB presence during the expression of reinstatement but not during the formation of stimulus–reward associations during the development of cocaine-reinforced behavior.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in ...cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor alpha (ERalpha) and beta (ERbeta) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERalpha/beta agonist estradiol benzoate (EB), the ERalpha-selective agonist, propyl-pyrazole-triol (PPT), the ERbeta-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX+DMSO controls. Selective activation of ERbeta with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERalpha with PPT did not affect cocaine-seeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERbeta.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chronic drug exposure induces alterations in gene expression profiles that are thought to underlie the development of drug addiction. The present study examined regulation of the Fos-family of ...transcription factors, specifically cFos, FosB, and DeltaFosB, in striatal subregions during and after chronic intravenous cocaine administration in self-administering and yoked rats. We found that cFos, FosB, and DeltaFosB exhibit regionally and temporally distinct expression patterns, with greater accumulation of DeltaFosB protein in the nucleus accumbens (NAc) shell and core after chronic cocaine administration, whereas DeltaFosB increases in the caudate-putamen (CPu) remained similar with either acute or chronic administration. In contrast, tolerance developed to cocaine-induced mRNA for DeltaFosB in all three striatal subregions with chronic administration. Tolerance also developed to FosB expression, most notably in the NAc shell and CPu. Interestingly, tolerance to cocaine-induced cFos induction was dependent on volitional control of cocaine intake in ventral but not dorsal striatal regions, whereas regulation of FosB and DeltaFosB was similar in cocaine self-administering and yoked animals. Thus, DeltaFosB-mediated neuroadaptations in the CPu may occur earlier than previously thought with the initiation of intravenous cocaine use and, together with greater accumulation of DeltaFosB in the NAc, could contribute to addiction-related increases in cocaine-seeking behavior. PUBLICATION ABSTRACT
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cocaine activates the mature hypothalamic–pituitary–adrenal (HPA) axis, increasing corticosterone concentrations in animals and humans and serotonin
2 receptors (5-HT
2) are involved in this effect. ...Although prenatal cocaine exposure is associated with altered responsiveness of the HPA axis to “stress” and serotonergic compounds postnatally, it is unknown whether cocaine directly activates the embryonic HPA axis or if 5-HT
2 receptors are involved. Domestic chicken eggs with viable embryos were exposed to either the 5-HT
2 receptor agonist dimethoxyiodophenylaminopropane (DOI: 0.4, 0.8, or 1.2 mg/kg egg) or saline on embryonic day 18 (E18). In a second study, the 5-HT
2 antagonist ritanserin (0.3 mg/kg egg, a dose found effective against other effects of DOI or cocaine) or vehicle was administered on E17, prior to treatment on E18 with either saline or cocaine (5 injections of 12 mg/kg egg, equivalent to a total dose of 3.5 mg/egg). Radioimmunoassay was used to measure serum corticosterone from blood samples taken approximately 1–2 h after drug injections. DOI significantly raised corticosterone in a dose-related fashion. Cocaine-induced corticosterone elevations were blocked by pretreatment with ritanserin, whereas ritanserin by itself did not affect corticosterone concentrations. These data indicate that 5-HT
2 receptors are involved in cocaine's effect on the HPA axis during late chicken embryogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We evaluated dementia and Alzheimer's disease (AD) risks after a cancer diagnosis in a population-based prospective cohort, the Adult Changes in Thought (ACT) study.
We followed community-dwelling ...people aged ≥65 years without dementia at study entry for incident dementia and AD from 1994-2015. We linked study data with cancer registry data and categorized cancer diagnoses as prevalent (diagnosed before ACT study enrollment) or incident (diagnosed during follow-up). We used Cox regression to estimate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia or AD risk comparing people with a cancer diagnosis to people without cancer. We conducted sensitivity analyses restricted to people surviving beyond age 80, and stratified by cancer stage, type, and whether the cancer was smoking-related.
Among 4,357 people, 756 (17.4%) had prevalent cancer; 583 (13.4%) developed incident cancer, 1,091 (25.0%) developed dementia, and 877 (20.1%) developed AD over a median 6.4 years (34,482 total person-years) of follow-up. Among complete cases (no missing covariates) with at least one follow-up assessment, adjusted HRs for dementia following prevalent and incident cancer diagnoses were 0.92 (95%CI: 0.76, 1.11) and 0.87 (95%CI: 0.64, 1.04), compared to no cancer history. HRs for AD were 0.95 (95%CI: 0.77, 1.17) for prevalent cancer and 0.73 (95%CI: 0.55, 0.96) for incident cancer. In sensitivity analyses, prevalent late-stage cancers were associated with reduced risks of dementia (HR = 0.51, 95%CI: 0.30, 0.89) and AD (HR = 0.50, 95%CI: 0.27, 0.94). When limited to people who survived beyond age 80, incident cancers were still associated with reduced AD risk (HR = 0.69, 95%CI: 0.51, 0.92).
Our results do not support an inverse association between prevalent cancer diagnoses, which were primarily early-stage, less aggressive cancers, and risk of dementia or AD. A reduced risk of AD following an incident cancer diagnosis is biologically plausible but may reflect selective mortality.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To determine whether higher cumulative proton pump inhibitor (PPI) exposure is associated with greater dementia risk.
Design
Prospective population‐based cohort study.
Setting
Kaiser ...Permanente Washington, an integrated healthcare delivery system in Seattle, Washington.
Participants
Individuals aged 65 and older without dementia at study entry (N = 3,484).
Measurements
Participants were screened for dementia every 2 years, and those who screened positive underwent extensive evaluation. Dementia outcomes were determined using standard diagnostic criteria. Time‐varying PPI exposure was determined from computerized pharmacy data and consisted of total standardized daily doses (TSDDs) dispensed to an individual in the prior 10 years. We also assessed duration of use. Multivariable Cox regression was used to estimate the association between PPI exposure and time to dementia or Alzheimer's disease (AD).
Results
Over a mean follow‐up of 7.5 years, 827 participants (23.7%) developed dementia (670 with possible or probable AD). PPI exposure was not associated with risk of dementia (P = .66) or AD (P = .77). For dementia, the risk for specific levels of cumulative exposure compared to no use was: 365 TSDDs (HR 0.87, 95% CI 0.65–1.18), 1,095 TSDDs (HR 0.99, CI 0.75–1.30) and 1,825 TSDDs (HR 1.13, CI 0.82–1.56). These TSDD levels represent approximately 1, 3 and 5 years of daily use respectively. Duration of PPI use was not associated with dementia outcomes either.
Conclusion
Proton pump inhibitor use was not associated with dementia risk, even for people with high cumulative exposure. Although there are other safety concerns with long‐term PPI use, results from our study do not support that these medications should be avoided out of concern about dementia risk.
See related Editorial by Yu‐Xiao Yang.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
It is well established that individual medications that affect the central nervous system (CNS) increase falls risk in older adults. However, less is known about risks associated ...with taking multiple CNS-active medications.
Methods
Employing a new user design, we used data from the Adult Changes in Thought study, a prospective cohort of community-dwelling people aged 65 and older without dementia. We created a time-varying composite measure of CNS-active medication exposure from electronic pharmacy fill data and categorized into mutually exclusive categories: current (within prior 30 days), recent (31–90 days), past (91–365 days), or nonuse (no exposure in prior year). We calculated standardized daily dose and identified new initiation. Cox proportional hazards models examined the associations between exposures and the outcome of fall-related injury identified from health plan electronic databases.
Results
Two thousand five hundred ninety-five people had 624 fall-related injuries over 15,531 person-years of follow-up. Relative to nonuse, fall-related injury risk was significantly greater for current use of CNS-active medication (hazard ratio HR = 1.95; 95% CI = 1.57–2.42), but not for recent or past use. Among current users, increased risk was noted with all doses. Risk was increased for new initiation compared with no current use (HR = 2.81; 95% CI = 2.09–3.78). Post hoc analyses revealed that risk was especially elevated with new initiation of opioids.
Conclusions
We found that current use, especially new initiation, of CNS-active medications was associated with fall-related injury in community-dwelling older adults. Increased risk was noted with all dose categories. Risk was particularly increased with new initiation of opioids.
Background Serum levels of vascular cell adhesion molecule-1 (VCAM-1) are reflective of endothelial activation. Although VCAM-1 has been implicated in the pathogenesis of heart failure with preserved ...ejection fraction (HFpEF), the prospective association of VCAM-1 with development of clinically overt heart failure (HF) across ejection fraction categories is unclear. Methods and Results In MESA (the Multi-Ethnic Study of Atherosclerosis), we evaluated the association of VCAM-1 at examination 2 (2002-2004) with incident HF (HFpEF and HF with reduced ejection fraction) after adjustment for cardiovascular risk factors. Incident HF was independently adjudicated as first hospitalization for symptomatic HF. Among 2297 participants (mean age, 63 years; women, 53%), those with higher VCAM-1 were more likely to be White race, had higher blood pressure, and had lower kidney function. Over a median of 14.4 years, there were 102 HF events (HFpEF=65; HF with reduced ejection fraction=37). After covariate adjustment, each doubling of VCAM-1 was associated with incident HF (hazard ratio HR, 1.94; 95% CI, 1.17-3.23;
=0.01). This association appeared stronger among current/former smokers compared with never smokers. On evaluation of HF subtypes, VCAM-1 was associated with incident HFpEF (HR, 1.97; 95% CI, 1.04-3.72;
=0.04) but not with incident HF with reduced ejection fraction, although risk estimates were consistent (HR, 1.82; 95% CI, 0.79-4.21;
=0.16). Conclusions In a multiethnic cohort, VCAM-1 was significantly associated with incident HF over long-term follow-up. These findings suggest a potential role for endothelial activation in driving clinical HF, and specifically HFpEF. Therapies that decrease endothelial activation may prevent the progression from cardiovascular risk factors to clinical HF.
Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported ...that azacitidine (Aza C) was active in patients with high-risk MDS.
A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C.
Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C.
Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.
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