Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats

Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment

Letter regarding the article of Tauzin et al.

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Pulmonary transit time as a marker of diastolic dysfunction in Takotsubo syndrome

AIM: To evaluate the pulmonary transit time (PTT) and its derived parameters using cardiac magnetic resonance imaging (CMRI) as markers of diastolic dysfunction in Takotsubo syndrome (TS) and its relationship with transthoracic echocardiography and CMRI parameters. MATERIALS AND METHODS: Twenty-two patients with TS, who exhibited diastolic dysfunction as assessed by transthoracic echocardiography, were enrolled retrospectively and the PTT, pulmonary transit time index (PTTI), and pulmonary blood volume index (PBVI) were evaluated using first-pass CMRI. PTT was calculated as the number of cardiac cycles required for a bolus of contrast agent to move from the right ventricle (RV) to the left ventricle (LV), whereas PTTI represents the PTT interval corrected for the heart rate. Finally, PBVI was calculated as the product of PTTI, and RV stroke volume indexed for body surface area. Normal references of PTT, PTTI, and PBVI were evaluated in a cohort of 20 age- and sex-matched healthy controls. RESULTS: Compared with healthy subjects, TS patients showed significantly higher PTT, PTTI, and PBVI (p=0.0001, p=0.0001, and p=0.002, respectively). Using multivariable logistic regression, PBVI provided the best differentiation between TS and controls (AUC 0.84). PBVI was significantly associated with the index of diastolic dysfunction and left atrial strain parameters. In addition, PBVI demonstrated a significant correlation with global T2 mapping (r=0,520, p=0,019). CONCLUSION: PTT and the derived parameters, as assessed using first-pass CMRI, are potential tools for assessing LV diastolic dysfunction in patients with TS

New perspective for an old drug: Can naloxone be considered an antioxidant agent?

Background: Experimental evidence indicates that Naloxone (NLX) holds antioxidant properties. The present study aims at verifying the hypothesis that NLX could prevent oxidative stress induced by hydrogen peroxide (H2O2) in PC12 cells.Methods: To investigate the antioxidant effect of NLX, initially, we performed electrochemical experiments by means of platinum-based sensors in a cell-free system. Subsequently, NLX was tested in PC12 cells on H2O2induced overproduction of intracellular levels of reactive-oxygen-species (ROS), apoptosis, modification of cells' cycle distribution and damage of cells' plasma membrane.Results: This study reveals that NLX counteracts intracellular ROS production, reduces H2O2-induced apoptosis levels, and prevents the oxidative damage-dependent increases of the percentage of cells in G2/M phase. Likewise, NLX protects PC12 cells from H2O2- induced oxidative damage, by preventing the lactate dehydrogenase (LDH) release. Moreover, electrochemical experiments confirmed the antioxidant properties of NLX.Conclusion: Overall, these findings provide a starting point for studying further the protective effects of NLX on oxidative stress

Delving into the reducing effects of the GABAB positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABAB receptor (GABAB PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABAB PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder

Perturbation of serine enantiomers homeostasis in the striatum of MPTP-lesioned monkeys and mice reflects the extent of dopaminergic midbrain degeneration

Loss of dopaminergic midbrain neurons perturbs L-serine and D-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high -performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuro-active amino acids modulating glutamatergic neurotransmission, including L-glutamate, glycine, L-aspartate, D- aspartate, and their precursors L-glutamine, L-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine trans-porter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of D-serine and L-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of D-serine and L-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degener-ation of dopaminergic neurons

Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats

Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect. We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues. Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell. Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell. These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context

Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens

There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression of plasticity-related molecules were examined in the NAc of rats displaying anhedonic behavior (measured in the sucrose-consumption test) in response to chronic mild stress. To demonstrate the relevance of our measurements to depression, we tested whether the observed changes were sensitive to reversal with antidepressants (imipramine and fluoxetine). Data show that animals displaying anhedonic behavior display an hypertrophy of medium spiny neurons in the NAc and, in parallel, have increased expression of the genes encoding for brain-derived neurotrophic factor, neural cell adhesion molecule and synaptic protein synapsin 1. Importantly, the reversal of stress-induced anhedonia by antidepressants is linked to a restoration of gene-expression patterns and dendritic morphology in the NAc. Using an animal model of depression, we show that stress induces anhedonic behavior that is associated with specific changes in the neuronal morphology and in the gene-expression profile of the NAc that are effectively reversed after treatment with antidepressants.The present work was funded by the Portuguese Foundation for Technology (FCT), project PTDC/SAU-NEU/105180/2008. FM and PL are recipients of postdoctoral fellowships and MM is recipient of a doctoral fellowship, all from FCT, Portugal

Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease