Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an ...experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.
Dear Editors, We read with interest the publication by Wei et al., Mitochondrial DNA Point Mutations and Relative Copy Number in 1363 Disease and Control Human Brains, Acta Neuropathol Commun. 2017; ...5: 13 4. We disagree with the authors’ conclusion that their data indicate that, “single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative disease.” There are 4 specific reasons why we disagree with this conclusion, and instead we assert that their data are not contradictory to our own previously published data indicating significantly elevated levels of heteroplasmic mtDNA mutations in dopaminergic neurons in the substantia nigra (SN) of Parkinson’s disease (PD) patients compared to controls at very early pathological stages of PD 2. 1) Wei et al. looked at cerebellar tissue for 1189 out of the 1363 cases, and so their data do not address the levels of mtDNA mutations within a pathologically affected tissue in PD. In contrast, in our prior publication we looked specifically at the SN; 2) Wei et al. looked at brain homogenate rather than specifically at vulnerable neurons. In contrast, in our prior publication we looked specifically at dopaminergic neurons isolated by laser capture microdissection (LCM); 3) Wei et al. did not discuss the pathological stage of the disease for the brain tissue that was studied. In most cases, postmortem brain tissue available from PD patients is at an advanced pathological stage at which point most dopaminergic SN neurons have died. In contrast, in our prior publication we analyzed SN neurons from early pathological stages of PD separately from tissue demonstrating advanced pathological stages. 4) Wei et al. defined mutations as being homoplasmic if they were present in <10% or >90% of reads. However, our prior studies found numerous point mutations in mtDNA that were individually rare (present in <10% of mtDNA copies), but that, in aggregate, reach a high mutational burden. In agreement with Wei et al., we previously reported no differences in heteroplasmic mtDNA point mutations in PD compared to controls when analyzing late-stage brain homogenate (SN in the case of our study) 3. We hypothesized that mutations might preferentially accumulate in neurons rather than other cell types, which we later confirmed 1, and that those neurons that accumulate high levels of mutations die, and so are not present for analysis in end-stage tissue. This led to our subsequent study using LCM to analyze heteroplasmic mtDNA point mutation levels in early-stage dopaminergic SN neurons, which revealed significantly higher levels of mutations compared to levels in either age-matched controls or in advanced stage PD SN neurons. Therefore, in contrast to their conclusion, the data presented in Wei et al. does not contradict our prior work, and does not provide an argument against our hypothesis that somatic mtDNA point mutations accumulate within dopaminergic SN neurons and contribute to the degenerative process in PD. Sincerely, David K. Simon, MD PhD
Abstract Considering the importance of a deeper understanding of the effect throughout life of opioid analgesia at birth, our objective was to determine whether morphine administration in early life, ...once a day for 7 days in 8-day-old rats, alters the nociceptive response over the short (P16), medium (P30), and long term (P60) and to evaluate which system is involved in the altered nociceptive response. The nociceptive responses were assessed by the formalin test, and the behavior analyzed was the total time spent in biting and flicking of the formalin-injected hindpaw, recorded during the first 5 min (phase I) and from 15–30 min (phase II). The morphine group showed no change in nociceptive response at P16, but at P30 and P60, the nociceptive response was increased in phase I, and in both phases, respectively. At P30 and P60, the animals received a non-steroidal anti-inflammatory drug (indomethacin) or NMDA receptor antagonist (ketamine) 30 min before the formalin test. The increase in the nociceptive response was completely reversed by ketamine, and partially by indomethacin. These results indicate that early morphine exposure causes an increase in the nociceptive response in adult life. It is possible that this lower nociception threshold is due to neuroadaptations in nociceptive circuits, such as the glutamatergic system. Thus, this work demonstrates the importance of evaluating clinical consequences related to early opioid administration and suggests a need for a novel design of agents that may counteract opiate-induced neuroplastic changes.
▶ Low exploratory (LE) and high exploratory mice (HE): control or USCS conditions. ▶ OF task: HEcontrol≫LEcontrol; LEUSCS and HE USCS↓exploration; HEUSCS≫LEUSCS. ▶ Corticosterone levels: ...HEcontrol<than LEcontrol and HEUSCS≫LEUSCS.
Stress affects learning and memory processes and sensitivity to stress greatly varies between individuals. We studied behavioral and neurobiological effects of unpredictable subchronic stress (USCS) in two behavioral extremes of mice from the same strain (CF1) selected by their exploratory behavior of the central arena of an open field. The top and bottom 25% explorers were classified as low exploratory (LE) and high exploratory (HE) mice, respectively. The open field task, the novel object recognition task (NOR), sucrose intake and tail suspension task were evaluated in LE and HE groups exposed to USCS for two weeks or control conditions. Also serum corticosterone and hippocampal BDNF and S100B levels were analyzed. Both stressed groups exhibited less exploratory activity when submitted to USCS, but their difference in exploratory behavior remained. This short stress protocol did not induce changes in sucrose intake or immobility in the tail suspension task. Also, LE mice exhibited impaired NOR performance after USCS, whereas HE mice changed their pattern of exploration towards less exploration of the familiar object. HE had lower corticosterone levels than LE mice, but corticosterone levels increased after stress only in HE mice. Hippocampal BDNF in LE was lower than in HE but decreased after USCS only in HE mice, whereas S100B levels were not different between groups and did not change with USCS. In conclusion, our results suggest that individual differences in exploratory behavior in rodents from the same strain influence cognitive and biochemical response to stress.
Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been ...reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A(1) receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A(1) receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A(1) receptors immunocontent in the frontal cortex. The selective adenosine A(1) receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A(1) receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.
A cafeína é a substância psicoativa mais consumida no mundo. Ela aumenta o estado de alerta, estabiliza o humor e também pode proporcionar melhora no desempenho cognitivo. Diversos estudos ...epidemiológicos e com roedores indicam uma relação inversa entre consumo de cafeína (um antagonista dos receptores de adenosina) e o comprometimento da memória associado ao envelhecimento e à Doença de Alzheimer. Considerando que o comprometimento da sinalização encefálica da insulina é um componente importante da fisiopatologia da Doença de Alzheimer, a estreptozotocina vem sendo utilizada, via intracerebroventricular, para produzir um modelo de Doença de Alzheimer com características neuroquímicas, fisiopatológicas e comportamentais semelhantes à Doença de Alzheimer em humanos. Dessa forma, está tese teve como objetivo avaliar as alterações dos receptores de adenosina e a imunoreatividade neuronal no hipocampo de ratos submetidos à administração intracerebroventricular de estreptozotocina, bem como um possível efeito protetor da cafeína sobre esses parâmetros e sobre a memória de reconhecimento. Como resultado, encontramos comprometimento da memória, modificação do imunoconteúdo e da expressão do receptor de adenosina A2A e perda neuronal no hipocampo no modelo animal de Doença de Alzheimer. O tratamento crônico com cafeína foi eficaz na prevenção do comprometimento da memória e das alterações neuronais observadas no hipocampo do modelo de Doença de Alzheimer. Essas observações fornecem suporte adicional para a possibilidade de que o consumo de cafeína poderia ser uma estratégia para prevenir o déficit mnemónico. No entanto, o efeito positivo da cafeína foi observado somente no modelo de Doença de Alzheimer. Nos animais controles, a cafeína não produziu nenhum efeito sobre a memória.
Caffeine is the most consumed psychoactive substance in the world, utilized to increase alertness, stabilize humor and enhance cognitive performance. Several epidemiological and animal studies indicate an inverse correlation between caffeine intake (an adenosine receptors antagonist) and memory impairment associated with ageing and Alzheimer’s disease. Considering that impaired brain insulin signaling is a main feature of Alzheimer’s disease, intracerebroventricular streptozotocin has been used as a model of Alzheimer’s disease with features resembling those of Alzheimer's disease patients. Therefore, the aim of this thesis was to evaluate the adenosine receptors immunocontent and neuronal immunoreactivity in the hippocampus of rats submitted to intracerebroventricular streptozotocin, as well as a possible protective effect of caffeine on these parameters and on recognition memory. The results showed memory impairment, modification of A2A adenosine receptor immunocontent and neuronal loss in the hippocampus of the animal model of Alzheimer’s disease induced by streptozotocin. Chronic caffeine treatment was effective in preventing the memory impairment and neuronal changes observed in Alzheimer’s disease rats. These assessments provide additional support for the hypothesis that caffeine consumption might be a valid strategy in preventing mnemonic deficit. Nonetheless, the positive effects of caffeine consumption were observed only among Alzheimer’s disease rats. Caffeine consumption had no effect over control animal’s performance.
Abstract In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that ...influences the dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5 mg/kg, i.p.) and to model misuse, they received an acute overdosage (50 mg/kg, i.p). The involvement of adenosine A1 receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50 mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A1 receptor antagonist (DPCPX 1 mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50 mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50 mg/kg increased 88% adenosine A1 receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A1 receptor density. Our findings ruled out the participation of adenosine A1 receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A1 receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.
Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been ...reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A1 receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A1 receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A1 receptors immunocontent in the frontal cortex. The selective adenosine A1 receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A1 receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.
► Methylphenidate (5mg/kg) acutely administered improved recognition memory. ► The overdosage (50mg/kg) disrupted recognition memory. ► DPCPX prevented the disruption of recognition memory by the overdosage. ► Adenosine A1 receptors seem to be involved in memory impairment by methylphenidate.
In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that influences the ...dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5 mg/kg, i.p.) and to model misuse, they received an acute overdosage (50 mg/kg, i.p). The involvement of adenosine A sub(1) receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50 mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A sub(1) receptor antagonist (DPCPX 1 mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50 mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50 mg/kg increased 88% adenosine A sub(1) receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A sub(1) receptor density. Our findings ruled out the participation of adenosine A sub(1) receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A sub(1) receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.
Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been ...reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A sub(1) receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A sub(1) receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5 mg/kg, i.p.), or an acute overdosage (50 mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5 mg/kg improved whereas 50 mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A sub(1) receptors immunocontent in the frontal cortex. The selective adenosine A sub(1) receptor antagonist, (DPCPX 1 mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A sub(1) receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.