Activation of D₂-like receptors in rat ventral tegmental area inhibits cocaine-reinstated drug-seeking behavior

Relapse is a hallmark of cocaine addiction. Cocaine‐induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre‐clinical evidence indicates that relapse to cocaine‐seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D₂‐like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D₂‐like receptors in the ventral tegmental area can inhibit cocaine‐induced reinstatement of extinguished cocaine‐seeking behavior. Rats were trained to self‐administer i.v. cocaine (0.25 mg/infusion) under a modified fixed‐ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine‐seeking behavior. The effect of quinpirole, a selective D₂‐like receptor agonist microinjected into the ventral tegmental area, on cocaine‐induced reinstatement was then assessed. Quinpirole (0–3.2 μg/side) dose‐dependently decreased cocaine‐induced reinstatement and such effects were reversed by the selective D₂‐like receptor antagonist eticlopride when co‐microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D₂‐like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre‐frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine‐induced reinstatement. The role of potential changes in D₂‐like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.     

Putative γ-aminobutyric acid neurons in the ventral tegmental area have a similar pattern of plasticity as dopamine neurons during appetitive and aversive learning

Dopamine influences affective, motor and cognitive processing, and multiple forms of learning and memory. This multifaceted functionality, which operates across long temporal windows, is broader than the narrow and temporally constrained role often ascribed to dopamine neurons as reward prediction error detectors. Given the modulatory nature of dopamine neurotransmission, that dopamine release is activated by both aversive and appetitive stimuli, and that dopamine receptors are often localized extrasynaptically, a role for dopamine in transmitting precise error signals has been questioned. Here we recorded from ventral tegmental area (VTA) neurons, while exposing rats to novel stimuli that were predictive of an appetitive or aversive outcome in the same behavioral session. The VTA contains dopamine and -aminobutyric acid (GABA) neurons that project to striatal and cortical regions and are strongly implicated in learning and affective processing. The response of VTA neurons, regardless of whether they had putative dopamine or GABA waveforms, transformed flexibly as animals learned to associate novel stimuli from different sensory modalities to appetitive or aversive outcomes. Learning the appetitive association led to larger excitatory VTA responses, whereas acquiring the aversive association led to a biphasic response of brief excitation followed by sustained inhibition. These responses shifted rapidly as outcome contingencies changed. These data suggest that VTA neurons interface sensory information with representational memory of aversive and appetitive events. This pattern of plasticity was not selective for putative dopamine neurons and generalized to other cells, suggesting that the temporally precise information transfer from the VTA may be mediated by faster acting GABA neurons.     

The effect of behavior therapy on caudate N-acetyl-l-aspartic acid in adults with obsessive–compulsive disorder

Previous studies suggest that baseline differences in neuronal markers between patients with obsessive–compulsive disorder (OCD) and healthy controls no longer exist following successful pharmacotherapy. The current study used proton magnetic resonance spectroscopy (MRS) to investigate differences in absolute concentrations of neurochemicals (i.e., N-acetyl-l-aspartic; NAA) in the head of the caudate nucleus (HOC) and orbital frontal white matter (OFWM) between 15 adults with OCD and a sex- and age-matched control group, as well as the effects of behavior therapy on these chemicals. Behavior therapy was associated with a significant increase in left HOC NAA. When the analyses were restricted to only pairings with complete data (OCD patient, control, post-treatment), the levels of left HOC NAA were significantly lower in patients compared to controls, and increased significantly with treatment. Exploratory analyses suggested that levels of NAA and Cr (creatine) in the right OFWM may be significantly lower in the OCD group than the control group. The results raise the possibility that successful behavioral treatment may be associated with increases in markers of neuronal viability, although other associations found in the literature were not replicated.     

Dissociation in response to methylphenidate on response variability in a group of medication naïve children with ADHD

Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to dopamine signaling is suggested in ADHD that may be ameliorated by methylphenidate (MPH). This study investigated the effects of MPH administration on the variability in RT and error performance on a sustained attention task of a group of 31 medication naïve children with ADHD, compared with 22 non-ADHD, non-medicated, control children. All children performed the fixed-sequence sustained attention to response task (SART) at two time-points: at baseline and after six weeks. The children with ADHD were tested when medication naive at baseline and after six weeks of treatment with MPH and whilst on medication. The medication naïve children with ADHD performed the SART with greater errors of commission and omission when compared with the control group. They demonstrated greater standard deviation of RT and fast moment-to-moment variability. They did not differ significantly from the control group in terms of slow variability in RT. MPH administration resulted in reduced and normalised levels of commission errors and fast, moment-to-moment variability in RT. MPH did not affect the rate of omission errors, standard deviation of RT or slow frequency variability in RT. MPH administration may have a specific effect on those performance components that reflect sustained attention and top–down control rather than arousal.     

Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome?

Objective

Cognitive behavior therapy (CBT) leads to a significant reduction in fatigue severity and impairment in patients with chronic fatigue syndrome (CFS). The purpose of the present study was to determine whether the effect of CBT for CFS on fatigue and impairment is mediated by a decrease in avoidance behavior and focusing on fatigue.

Methods

For this purpose, we reanalyzed a randomized controlled trial which was previously conducted to test the efficacy of CBT for CFS. Two hundred nineteen patients completed assessment prior and subsequent to treatment or a control group period.

Results

Mediation analysis revealed that a decrease in focusing on fatigue mediated the effect of CBT for CFS on fatigue and impairment. Avoidance of activity and avoidance of aversive stimuli were not significantly changed by treatment and were therefore excluded from mediation analysis.

Conclusion

A decrease in the focus on fatigue seems to contribute to the treatment effect of CBT for CFS.     

Effects of apomorphine and β-carbolines on firing rate of neurons in the ventral pallidum in the rats

The ventral pallidum (VP) is a critical element of the mesocorticolimbic system that is inter-connected with motor and limbic structures and may be considered as an interface between motivational and effector neural signals. Dopamine is important in behavioral output of the VP, and dysfunctioning its dopamine quantity leads to various neuropsychiatric disorders. Understanding neural substrate underlying this phenomenon has become an important affair in recent years. In this study, neuronal activities were recorded from the VP in presence or absence of the mixed dopamine D1/D2 receptor agonist, apomorphine, and/or β-carbolines, using an extracellular single-unit recording technique. We reported that subcutaneous administration of apomorphine (0.5 mg/kg) decreased neural activity in the VP. In addition, neither harmine (7.8 mg/kg; i.p.) nor harmane (4 mg/kg; i.p.) and norharmane (2.5 mg/kg; i.p.) had any effect on neural firing in the VP. Finally, pretreatment with β-carbolines prevented the apomorphine-induced inhibition on VP firing rate. Thus, according to the results of aforementioned study and our results in the present study, we can conclude that presumably most responses in the VP are D2 dopamine dependent. Although the β-carbolines were unable to alter neural activity in the VP, interestingly, pretreatment with β-carbolines protect decreasing in firing rate of neurons in the VP followed by apomorphine administration. This protective effect could be explained by interaction between β-carbolines and dopaminergic mechanisms.     

The effect of high-fat diet on rat’s mood,feeding behavior and response to stress

An association between obesity and depression has been indicated in studies addressing common physical (metabolic) and psychological (anxiety, low self-esteem) outcomes. Of consideration in both obesity and depression are chronic mild stressors to which individuals are exposed to on a daily basis. However, the response to stress is remarkably variable depending on numerous factors, such as the physical health and the mental state at the time of exposure. Here a chronic mild stress (CMS) protocol was used to assess the effect of high-fat diet (HFD)-induced obesity on response to stress in a rat model. In addition to the development of metabolic complications, such as glucose intolerance, diet-induced obesity caused behavioral alterations. Specifically, animals fed on HFD displayed depressive- and anxious-like behaviors that were only present in the normal diet (ND) group upon exposure to CMS. Of notice, these mood impairments were not further aggravated when the HFD animals were exposed to CMS, which suggest a ceiling effect. Moreover, although there was a sudden drop of food consumption in the first 3 weeks of the CMS protocol in both ND and HFD groups, only the CMS-HFD displayed an overall noticeable decrease in total food intake during the 6 weeks of the CMS protocol. Altogether, the study suggests that HFD impacts on the response to CMS, which should be considered when addressing the consequences of obesity in behavior.     

The effect of instructional use of an iPad® on challenging behavior and academic engagement for two students with autism

iPads^® are increasingly used in the education of children with autism spectrum disorder. However, few empirical studies have examined the effects of iPads^® on student behaviors. The purpose of this study was to compare academic instruction delivered with an iPad^® to instruction delivered through traditional materials for two students with autism spectrum disorder who engaged in escape-maintained challenging behavior. An ABAB reversal design was utilized in which academic instruction with an iPad^® and academic instruction with traditional materials were compared. Both participants demonstrated lower levels of challenging behavior and higher levels of academic engagement in the iPad^® condition and higher levels of challenging behavior with lower levels of academic engagement during the traditional materials condition. These results suggest that the use of an iPad^® as a means of instructional delivery may reduce escape-maintained behavior for some children with autism. Suggestions for future research directions are discussed.     

Sleep duration and risk of stroke: a dose–response meta-analysis of prospective cohort studies

ObjectivesSuboptimal sleep duration has been considered to increase the risk of stroke incidence. Thus we aimed to conduct a dose–response meta-analysis to examine the association between sleep duration and stroke incidence.MethodsWe searched PubMed, Web of science and the Cochrane Library to identify all prospective studies evaluating the association of sleep duration and nonfatal and/or fatal stroke incidence. Then, restricted cubic spline functions and piecewise linear functions were used to evaluate the nonlinear and linear dose–response association between them.ResultsWe included a total of 16 prospective studies enrolling 528,653 participants with 12,193 stroke events. Nonlinear dose–response meta-analysis showed a J-shaped association between sleep duration and total stroke with the lowest risk observed with sleeping for 7 h. Considering people sleeping for 7 h as reference, long sleepers had a higher predicted risk of total stroke than short sleepers [the pooled risk ratios (95% confidence intervals): 4 h: 1.17 (0.99–1.38); 5 h: 1.17 (1.00–1.37); 6 h: 1.10 (1.00–1.21); 8 h: 1.17 (1.07–1.28); 9 h: 1.45 (1.23–1.70); 10 h: 1.64 (1.4–1.92); p_nonlinearity<0.001]. Short sleep durations were only significantly associated with nonfatal stroke and with total stroke in the subgroups of structured interview and non-Asian countries. Additionally, we found a slightly decreased risk of ischemic stroke among short sleepers. For piecewise linear trends, compared to 7 h, every 1-h increment of sleep duration led to an increase of 13% [the pooled risk ratios (95% confidence intervals): 1.13 (1.07–1.20); p < 0.001] in risk of total stroke.ConclusionBoth in nonlinear and piecewise linear dose–response meta-analyses, long sleep duration significantly increased the risk of stroke incidence.     

Synergistic effect of α-dihydroergocryptine and L-dopa or dopamine on dopaminergic neurons in primary culture

Summary. There is an ongoing controversy about potential toxicity of L-3,4-dihydroxyphenylalanine (L-dopa) to dopaminergic neurons in Parkinson’s disease (PD). Neuroimaging data suggest that L-dopa accelerates the loss of dopamine nerve terminals, especially at higher doses. The disputed aspect of toxicity and the frequently observed motor complications accompanying L-dopa therapy have led to an increased use of dopamine agonists during the past two decades. Reports describing their neuroprotective potential to dopaminergic neurons have attracted much attention. Here, we describe the novel finding that the combination of a dopamine (DA) agonist, α-dihydroergocryptine (DHEC), with L-dopa or DA exerts a synergistic stimulatory effect on dopaminergic neurons in primary culture, while each substance alone had no or less effect. DA receptor stimulation plays a decisive role. The synergistic effect suggests that a combinatory therapy can be beneficial to slow the degeneration of dopaminergic neurons. First and second authors contributed equally to the publication     

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson’s disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were significantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no significant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s12264-014-1512-6 and is accessible for authorized users.     

Association of napping and all-cause mortality and incident cardiovascular diseases: a dose–response meta analysis of cohort studies

BackgroundNapping is a habit prevalent worldwide and occurs from an early age. However, the association between napping and the risk of incident cardiovascular disease (CVD) and all-cause mortality remains unclear.MethodsWe conducted a systematic search of Medline, Embase, and Cochrane databases from inception to December 2019 for cohort studies investigating the association between napping and the risk of incident CVD and/or all-cause mortality. Overall estimates were calculated using random-effect models with inverse variance weighting. Dose–response meta-analysis was performed using restricted cubic spline models.ResultsA total of 313,651 participants (57.8% female, 38.9% took naps) from 20 cohort studies were included in the analysis. All-cause mortality was associated with napping overall (HR 1.19, 95% CI 1.12–1.26). Pooled analysis detected no association between daytime nap and incident CVD. However, in subgroup analysis including only participants who were female (HR 1.31, 95% CI 1.09–1.58), older (HR 1.36, 95% CI 1.07–1.72), or took a long nap (HR 1.34, 95% CI 1.05–1.63), napping was significantly associated with a higher risk of CVD. Dose–response analysis showed a J-curve relation between nap time and incident CVD. The HR decreased from 0 to 25 min/day, followed by a sharp increase in the risk at longer times. A positive linear relationship between nap time and all-cause mortality was also observed.ConclusionsLong napping was associated with increased risks of incident CVD and all-cause mortality. Further, large-scale studies and genetic studies need to confirm our conclusion and investigate the underlying mechanisms driving these associations.     

Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose–response meta-analysis

Journal of Neurology - A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close...     

Nut consumption and the risk of coronary artery disease: A dose–response meta-analysis of 13 prospective studies

Introduction

Epidemiological studies evaluating the association of nut with risk of coronary artery disease (CAD) have produced inconsistent results. We conducted a meta-analysis to summarize the evidence from prospective cohort studies regarding the association between nut consumption and risk of CAD.

Materials and methods

Pertinent studies were identified by searching Web of Knowledge, Pubmed and Wan Fang Med Online up to January 2014. Random-effect model was used to combine the results. Dose–response relationship was assessed by restricted cubic spline. Publication bias was estimated using Begg’ funnel plot and Egger’s regression asymmetry test.

Results

Nine articles with 13 prospective studies involving 6,127 CAD cases and 347,477 participants were included in this meta-analysis. Pooled results suggested that highest nut consumption amount versus lowest amount was significantly associated with the risk of CAD [summary relative risk (RR) = 0.660, 95%CI = 0.581-0.748, I² = 39.6%]. Linear dose–response relationship was found between nut consumption and CAD risk, and the risk of CAD decreased by 5% for every 1 serving/week increase intake of nut. A protective effect for CAD was found when consumed more than 2 servings/week of nut. The RR of CAD was 0.96 (0.89-1.02), 0.91 (0.82-0.99), 0.85 (0.77-0.95), 0.80 (0.72-0.89), 0.75 (0.65- 0.85) and 0.70 (0.58-0.83) for 1, 2, 3, 4, 5 and 6 servings/week of nut consumption, respectively.

Conclusions

Our analysis indicated that nut consumption has a protective effect on CAD.     

Indications of a dose–response relationship between cannabis use and age at onset in bipolar disorder

Cannabis use seems to play a causal role in the development of psychotic disorders. Recent evidence suggests that it may also precipitate onset in bipolar disorder. We here investigate if there is a dose–response relationship between cannabis use and age at onset in bipolar disorder, and whether there are interactions between cannabis use and illness characteristics (presenting polarity and presence of psychosis). Consecutively recruited patients with a DSM-IV, SCID verified diagnosis of bipolar I, II or NOS disorder (n=324) participated. Two-way ANCOVAS were used to investigate the effect of levels of cannabis use (<10 times during one month lifetime, >10 times during one month lifetime or a cannabis use disorder) on age at onset, including interaction effects with illness characteristics, while controlling for possible confounders. There was a significant association indicating a dose–response relationship between cannabis use and age at onset, which remained statistically significant after controlling for possible confounders (gender, bipolar subtype, family history of severe mental illness and alcohol or other substance use disorders). There were no interaction effects between cannabis use and presenting polarity or presence of psychosis. Doses of cannabis used may affect the age at onset of bipolar disorder.     

Protective effect of zinc on amyloid-ß 25–35 and 1–40 mediated toxicity

Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease, the insoluble aggregates of the peptide being the major constituents of senile plaques. In this study, we evaluated the effect of Zn(2+) (5, 50 and 200 microM) on Abeta induced toxicity using the human teratocarcinome (NT2) cell line. Our results proved that 50 and 200 microM Zn(2+) protected NT2 cells from Abeta 25-35 toxicity. Zinc was also shown to be effective by preventing the loss of mitochondrial membrane potential (DeltaPsi(m)) induced by Abeta 25-35, not allowing cytochrome c release from mitochondria, and subsequently, caspase 3 activation. However, when the cells were treated with Abeta 1-40, only Zn(2+) 5 microM had a protective effect. We have further observed that 5 microM Zn(2+) prevented Abeta 1-40 aggregation into a beta-sheet structure. Considering the results presented, we argue that Zn(2+) has a concentration-dependent protective effect.     

Association between obstructive sleep apnoea syndrome and the risk of cardiovascular diseases: an updated systematic review and dose–response meta-analysis

ObjectiveThe aim of this study was to summarize the evidence concerning the relationship between obstructive sleep apnoea syndrome (OSAS) and the risk of cardiovascular diseases (CVDs).MethodsA systematic search was carried out using PubMed and Web of Science up to September 10, 2019. Categorical as well as linear and non-linear dose–response meta-analyses were respectively performed to evaluate the association between the severity of OSAS and the risk of CVDs. Apnoea-hypopnea index (AHI) was used as an indicator of OSAS severity.ResultsThis study included 10 cohort studies targeting a total of 36,347 subjects and 3362 patients with CVDs. The pooled RRs of overall CVDs were 1.13 (95% confidence interval [CI] = 1.02–1.24) for mild versus non/normal OSAS, 1.16 (95% CI = 1.02–1.32) for moderate versus non/normal OSAS, 1.26 (95% CI = 1.15–1.39) for moderate-severe versus non/normal OSAS, and 1.41 (95% CI = 1.22–1.63) for severe versus non/normal OSAS. The linear dose–response meta-analysis showed that every 10 events/hour increment in AHI value was associated with a 9% increased risk of suffering from CVDs. The non-linear dose–response meta-analysis showed that the risk of CVDs increased continuously with the increment in AHI.ConclusionThe present systematic review and meta-analysis provide evidence for a positive association between OSAS and the risk of CVDs, despite the severity of OSAS. The relative risk of CVDs increases continuously with the increment in AHI.