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Nicotine addiction continues to be a leading cause of preventable death worldwide. Despite the plethora of available treatments for smoking cessation, smoking relapse after attempts to quit remains high. It is possible that impairments in... more
Nicotine addiction continues to be a leading cause of preventable death worldwide. Despite the plethora of available treatments for smoking cessation, smoking relapse after attempts to quit remains high. It is possible that impairments in cognitive flexibility and underlying neurochemical circuits in nicotine addicts may foster maladaptive behaviors that affect individuals' ability to refrain from taking drugs. Here we characterized the effects of spontaneous nicotine withdrawal on cognitive flexibility in mice using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Adult male C57BL/6J mice were trained in an operant task that required the animals to switch from using a spatial response-driven strategy to a visual cue-based strategy to achieve rewards. Mice w...
Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent... more
Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here we investigated a post-translational modification of CHTs – poly-ubiquitination - and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines me...
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Abstract The prevalence of tobacco smoking in subjects with schizophrenia is strikingly higher than the normal population. Nicotine, a psychoactive ingredient of tobacco, induces diverse behavioral effects by activating nicotinic... more
Abstract The prevalence of tobacco smoking in subjects with schizophrenia is strikingly higher than the normal population. Nicotine, a psychoactive ingredient of tobacco, induces diverse behavioral effects by activating nicotinic acetylcholine receptors (nAChRs) and influencing chemical transmission and downstream cellular targets in the central nervous system. Substantial evidence from the preclinical and clinical studies indicates that nAChRs are dysregulated in schizophrenia. People diagnosed with schizophrenia experience a combination of positive, negative, and cognitive symptoms, and nicotine intake may represent a strategy to remediate these symptoms by normalizing nAChR deficit. However, the highly addictive properties of nicotine limit its use as a drug candidate. Therefore, efforts to develop chemical ligands that target specific nAChRs in the brain represent a viable therapeutic option to effectively manage the symptoms of schizophrenia.
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Aging is characterized by an increase in inter-individual variability in cognitive capacity. Slight decrements in learning and memory emerge; however, age-related shifts in attentional function remain controversial. In pathological aging,... more
Aging is characterized by an increase in inter-individual variability in cognitive capacity. Slight decrements in learning and memory emerge; however, age-related shifts in attentional function remain controversial. In pathological aging, however, attentional dysfunction is prominent and the circuitry critical to signal detection and thus attention as a whole, the corticopetal cholinergic system, exhibits substantial disruption and deterioration. One contributing factor to cholinergic dysfunction is the loss of neurotrophic support, specifically nerve growth factor's high-affinity receptor tropomyosin-related kinase A (trkA). Previous cross-sectional studies demonstrated that reduced trkA receptor levels selectively impaired attentional capacity in aged rats. However, it remains unclear if reduced trkA receptors in the basal forebrain (BF) interact with aging to elicit these attentional deficits. Thus developmental suppression of trkA receptors on attentional capacity and BF cho...
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Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcome. However, the most commonly prescribed... more
Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcome. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that makes drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests deficit in a...
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Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and underlying neurobiology can vary between individuals. Certain individuals exhibit significant age-related cognitive impairments, while others... more
Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and underlying neurobiology can vary between individuals. Certain individuals exhibit significant age-related cognitive impairments, while others maintain intact cognitive functioning with only minimal decline. Recent developments in genomic, proteomic, and functional imaging approaches have provided insights into the molecular and cellular substrates of cognitive decline in age-related neuropathologies. Despite the emergence of novel tools, accurately and reliably predicting longitudinal cognitive trajectories and improving functional outcomes for the elderly remains a major challenge. One promising approach has been the use of exosomes, a subgroup of extracellular vesicles that regulate intercellular communication and are easily accessible compared to other approaches. In the current review, we highlight recent findings which illustrate how the analysis of exosomes can improve our understand...
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Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a... more
Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, in vivo, CHT-mediated choline transport, and ACh release. Relative to wild type (WT) mice, CHT-mediated clearance of choline in mice expressing one or two Val89 alleles was reduced by over 80% cortex and by over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in to...
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Cortical remodeling is linked to age-related cognitive changes in humans; however, the mechanisms underlying cortical reorganization in aging remain unknown. Here we examined the consequences of mild cholinergic thinning of the prefrontal... more
Cortical remodeling is linked to age-related cognitive changes in humans; however, the mechanisms underlying cortical reorganization in aging remain unknown. Here we examined the consequences of mild cholinergic thinning of the prefrontal cortex (PFC) and parietal cortex (PC) on attention performance-associated changes in cortical activity in young and aged rats. Prefrontal manipulation produced attentional deficits in aged but not young rats regardless of cholinergic pruning. Stereological assessment of c-fos expression revealed age-related reductions in occipital activity and a corresponding increase in PC activity, but these patterns did not correlate with performance. PC cholinergic deafferentation produced opposite changes in PFC recruitment between young and aged rats. Cholinergic pruning reversed the effects of PFC/PC cholinergic manipulations on the activity of CaMKII- and GAD-positive neurons in aged rats. Our results indicate that cortical shifts depend on multiple factors...
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Research Interests: Psychology, Cognition, Neurobiology of Learning and Memory, Medicine, Prefrontal Cortex, and 11 moreExecutive Function, Mice, Nicotine, Animals, Male, Mecamylamine, Brain-derived neurotrophic factor (BDNF), Corpus striatum, Psychology and Cognitive Sciences, Medical and Health Sciences, and Substance Withdrawal Syndrome
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The prefrontal cortex (PFC) governs top-down control of attention and is known to be vulnerable in aging. Cortical reorganization with increased PFC recruitment is suggested to account for functional compensation. Here, we hypothesized... more
The prefrontal cortex (PFC) governs top-down control of attention and is known to be vulnerable in aging. Cortical reorganization with increased PFC recruitment is suggested to account for functional compensation. Here, we hypothesized that reduced PFC output would exert differential effects on attentional capacities in young and aged rats, with the latter exhibiting a more robust decline in performance. A chemogenetic approach involving designer receptors exclusively activated by designer drugs was utilized to determine the impact of silencing PFC projection neurons in rats performing an operant attention task. Visual distractors were presented in all behavioral testing sessions to tax attentional resources. Under control conditions, aged rats exhibited impairments in discriminating signals with the shortest duration from non-signal events. Surprisingly, chemogenetic inhibition of PFC output neurons did not worsen performance amongst aged animals. Conversely, significant impairment...
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Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as... more
Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as altered protein quality control (PQC), reactive oxygen species (ROS) themselves might constitute a molecular mediator of neuronal PQC by modulating BCL-2 associated athanogene (BAG) family members. Present results reveal H 2 O 2 replicated and exacerbated a reduction in neuronal BAG3 induced by the expression of HIV-1 viral proteins (i.e., Tat and Nef), while also causing an upregulation of BAG1. Such a reciprocal regulation of BAG3 and BAG1 levels was also indicated in two animal models of HIV, the doxycycline-inducible Tat (iTat) and the Tg26 mouse. Inhibiting oxidative stress via antioxidants in primary culture was capable of partially preserving neuronal BAG3 levels as well as electrophysiological functioning otherwise altered by HIV-1 viral proteins...
The valid measurement of cognitive decline in laboratory animals is key to productive research on age-related cognitive disorders and the development of treatments for the prevention and symptomatic treatment of age-related cognitive... more
The valid measurement of cognitive decline in laboratory animals is key to productive research on age-related cognitive disorders and the development of treatments for the prevention and symptomatic treatment of age-related cognitive decline. This article addresses the major aspects of validity of animal models of cognitive decline. Specifically, the focus on the determination of construct validity of the model is explained and justified. In this context, we discuss the limitations of models of cognitive decline that are based on spontaneously aged animals. Research on age-related cognitive decline in animals requires the determination of precise interrelationships between defined changes in neuronal mechanisms and cognitive decline.
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Previous research emphasized the vulnerability of forebrain cholinergic systems and associated cognitive functions to the consequences of traumatic brain injury. Here we addressed the reverse question: Considering accumulating evidence... more
Previous research emphasized the vulnerability of forebrain cholinergic systems and associated cognitive functions to the consequences of traumatic brain injury. Here we addressed the reverse question: Considering accumulating evidence indicating elevated cognitive and neuronal vulnerabilities in humans expressing low-capacity cholinergic systems or with declining cholinergic systems, do even relatively mild injuries cause more severe cognitive decline in such subjects, and what cholinergic mechanisms contribute to such an interaction? Using mice heterozygous for the choline transporter (CHT+/- mice) as a model for a limited cholinergic capacity, we investigated the cognitive and neuronal consequences of repeated, mild concussion injuries (rmCc). Following five rmCc, and compared with WT mice, CHT+/- mice exhibited severe and lasting impairments in sustained attention performance, consistent with effects of cholinergic losses on attention. However, rmCc did not affect the integrity ...
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Neuregulin 3 (NRG3) and ErbB4 have been linked to nicotine addiction; however, the neuronal mechanisms and behavioral consequences of NRG3-ErbB4 sensitivity to nicotine remain elusive. Recent literature suggests that relapse to smoking is... more
Neuregulin 3 (NRG3) and ErbB4 have been linked to nicotine addiction; however, the neuronal mechanisms and behavioral consequences of NRG3-ErbB4 sensitivity to nicotine remain elusive. Recent literature suggests that relapse to smoking is due to a lack of impulsive control, which is thought to be due to altered functioning within the orbitofrontal cortex (OFC). Therefore, we examined circuitry changes within this structure following nicotine application. We report that nicotine controls synaptic plasticity in the OFC through NRG3/ErbB4-dependent regulation of GABAergic inhibition. We observed that both nicotine and NRG3 facilitated the conversion of long-term potentiation into long-term depression at cortical layer 3/5 synapses. Induction of long-term depression by nicotine relied on nicotinic receptor activation and key regulators of NRG3 signaling: (1) release of intracellular calcium, (2) activation of the BACE1 beta-secretase, and (3) ErbB4 receptor activation. Nicotine-induced ...
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The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on... more
The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contributi...
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Some rats (sign-trackers; STs) are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact Pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional... more
Some rats (sign-trackers; STs) are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact Pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo as compared to GTs following reverse-dialysis to el...
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Sustained attention, the ability to detect rare and unpredictable events, is central to cognitive performance. This construct can be tested in rodents using a Sustained Attention Task (SAT), where rats are trained to detect an... more
Sustained attention, the ability to detect rare and unpredictable events, is central to cognitive performance. This construct can be tested in rodents using a Sustained Attention Task (SAT), where rats are trained to detect an unpredictably occurring signal (a brief light presentation) from non-signal events. The traditional version of this task utilizes an operant chamber with a central panel light for the signal and two retractable response levers. Adaptation of SAT to the increasingly popular touchscreen operant chambers, which do not have levers or fixed lights, could enhance the versatility of the task. Here we developed a touchscreen version of SAT where the light signal is presented in the center of the touchscreen, followed by a tone to indicate the beginning of the response period. Rats indicate their choice during this period by touching their nose to one of two touchscreen response areas. The remaining parameters were kept similar to the traditional version. Rats acquired...
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Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective... more
Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective behaviors. However, the causal mechanisms linking BDNF hypofunction with executive deficits are not well understood. Here, we assessed the consequences of BDNF hemizygosity on cognitive flexibility in mice performing an operant conditioning task. As dopaminergic-glutamatergic interaction in the striatum is important for cognitive processing, and BDNF heterozygous (BDNF(+/-)) mice display a higher dopamine tone in the dorsal striatum, we also assessed the effects of partial striatal dopamine depletion on task performance and glutamate release. BDNF(+/-) mice acquired discrimination learning as well as new rule learning during set-shifting as efficiently as wild-type mice. However, partial removal of striatal dopaminergic inputs with 6-hydroxydopamine (6-O...
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In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main... more
In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (...
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Even though smoking rates have long been on the decline, nicotine addiction still affects 20% of the US population today. Moreover, nicotine dependence shows high comorbidity with many mental illnesses including, but are not limited to,... more
Even though smoking rates have long been on the decline, nicotine addiction still affects 20% of the US population today. Moreover, nicotine dependence shows high comorbidity with many mental illnesses including, but are not limited to, attention deficit hyperactivity disorder, anxiety disorders, and depression. The reason for the high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine. While nicotine may alleviate the symptoms of mental disorders, nicotine abstinence has been shown to worsen the symptoms of these disorders. In this chapter, we review the studies from animal and human research examining the bidirectional relationship between nicotine and attention deficit hyperactivity disorder, anxiety disorders, and depression as well as studies examining the roles of specific subunits of nicotinic acetylcholine receptors (nAChRs) in the interaction between nicotine and these mental illnesses. The results of these studies suggest that activation, desensitization, and upregulation of nAChRs modulate the effects of nicotine on mental illnesses.
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Stressful life events and stress-related psychiatric disorders impair sustained attention, the ability to monitor rare and unpredictable stimulus events over prolonged periods of time. Despite the link between stress and attentional... more
Stressful life events and stress-related psychiatric disorders impair sustained attention, the ability to monitor rare and unpredictable stimulus events over prolonged periods of time. Despite the link between stress and attentional disruptions, the neurobiological basis for stress regulation of attention systems remains underexplored. Here we examined whether corticotropin releasing factor (CRF), which orchestrates stress responses and is hypersecreted in patients with stress-related psychiatric disorders, impairs sustained attention. To this end, male and female rats received central infusions of CRF prior to testing on an operant sustained attention task (SAT), where rats were trained to discriminate signaled from non-signaled events. CRF caused a dose-dependent decrease in SAT performance in both male and female rats. Females were more impaired than males following a moderate dose of CRF, particularly during the middle part of the session. This sex difference was moderated by ov...
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ABSTRACT Changes in acetylcholine (ACh) release in the forebrain represent a critical step in the activation of larger neuronal circuits mediating cognitive functions. Therefore, the development of methods which allow the assessment of... more
ABSTRACT Changes in acetylcholine (ACh) release in the forebrain represent a critical step in the activation of larger neuronal circuits mediating cognitive functions. Therefore, the development of methods which allow the assessment of ACh release at a high temporal and spatial resolution is of immense significance for behavioral and cognitive neuroscience research. In this chapter, we review evidence from in vivo studies utilizing choline-sensitive microelectrodes for the detection of rapid changes in extracellular choline levels as a spatially discrete and sensitive measure of cortical cholinergic transmission. We then summarize empirical data from our lab based on studies involving electrochemical recordings and real-time monitoring of ACh release in animals performing a cued-appetitive response task. Phasic cholinergic activation in the prefrontal cortex, demonstrated by second-based increases in cholinergic transmission during behaviorally significant cues triggering reward approach, suggests that cholinergic transients encode specific information pertaining to the detection of attention-demanding cues. These findings indicate that cortical cholinergic transmission mediates defined cognitive operations which are contrary to the traditional description of cortical ACh as a slowly acting neuromodulator influencing different arousal states.
Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD... more
Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD pathology including the cognitive symptoms and selective vulnerability of cortically projecting basal forebrain (BF) cholinergic neurons are not well explained by this hypothesis. Specifically, it is not clear why cognitive decline appears early when the loss of BF cholinergic neurons and plaque deposition are manifested late in AD. Soluble oligomeric forms of Aβ are proposed to appear early in the pathology and to be better predictors of synaptic loss and cognitive deficits. The present study was designed to examine the impact of Aβ oligomers on attentional functions and presynaptic cholinergic transmission in young and aged rats. Chronic intracranial infusions of Aβ oligomers produced subtle decrements in the ability of rats to sustain attentional perf...
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A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of... more
A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of patients with or without medication. The current study investigated the relationship between these biochemical measures in first-episode psychotic patients (N=16) at baseline and after 6 months of antipsychotic treatment (N=5 each with risperidone and olanzapine) and compared them to matched normal subjects. The indices of oxidative stress included: antioxidant enzymes; superoxide dismutase, glutathione peroxidase and catalase; and the oxidative injury as the levels of plasma lipid peroxides. The key membrane EPUFA's been; linolenic acid, arachidonic acid, nervonic acid, docosapentaenoic acid and docosahexaenoic acid. Furthermore, the changes in these biochemical measures were correlated with clinical symptomatology. Data indicated that, at bas...
Research Interests: Oxidative Stress, Antioxidants, Humans, Omega Fatty Acids, Catalase, and 15 moreGlutathione Peroxidase, Clinical Sciences, Antioxidant enzyme, Adult, Oxidative Damage, Combination drug therapy, Erythrocyte Membrane, Erythrocytes, Alkanes, Arachidonic Acid, Docosahexaenoic Acid, Biochemistry and cell biology, Antipsychotic agents, Linolenic Acid, and Lipid peroxides
Our study is designed to correlate nitrite concentration, an index of nitric oxide (NO) release with mast cell peroxidase (MPO), a marker of cardiac mast cell degranulation and cardioprotective effect of ischaemic preconditioning in... more
Our study is designed to correlate nitrite concentration, an index of nitric oxide (NO) release with mast cell peroxidase (MPO), a marker of cardiac mast cell degranulation and cardioprotective effect of ischaemic preconditioning in isolated perfused rat heart subjected to 30 min of global ischaemia and 30 min of reperfusion. Ischaemic preconditioning, comprised of four episodes of 5 min global ischaemia and 5 min of reperfusion, markedly reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary effluent and incidence of ventricular premature beats (VPBs) and ventricular tachycardia and fibrillation (VT/VF) during reperfusion phase. Ischaemia-reperfusion induced release of MPO was markedly reduced in ischaemic preconditioned hearts. Increased release of nitrite was noted during reperfusion phase after sustained ischaemia in preconditioned hearts as compared to control hearts. No alterations in the release of nitrite was observed immediately after ischae...
Research Interests: Mast Cells, Peroxidase, Nitric oxide, Female, Animals, and 13 moreCreatine Kinase, Rats, Myocardium, Peroxidases, Wistar Rats, Lactate dehydrogenase, Ventricular Tachycardia, Molecular and Cellular Biochemistry, Nitrites, Biochemistry and cell biology, Ischaemia/reperfusion, Myocardial Ischemia, and In Vitro Techniques
The present study was designed to investigate the role of cardiac mast cells in the cardioprotective effect of norepinephrine-induced preconditioning. Isolated rat heart was subjected to 30 min of global ischemia followed by 30 min of... more
The present study was designed to investigate the role of cardiac mast cells in the cardioprotective effect of norepinephrine-induced preconditioning. Isolated rat heart was subjected to 30 min of global ischemia followed by 30 min of reperfusion. Both ischemic and norepinephrine (100 microM) preconditioning markedly reduced ischemia-reperfusion-induced release of lactate dehydrogenose (LDH) in the coronary effluent and the incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion phase. Ischemic and norepinephrine preconditioning also significantly reduced ischemia-reperfusion-induced release of mast cell peroxidase (MPO), a marker of mast cell degranulation. However, MPO release increased immediately after ischemic or norepinephrine preconditioning. Histological study with ruthenium red (0.005%) staining confirmed cardiac mast cell degranulation in ischemic and norepinephrine preconditioned isolated rat hearts. These fi...
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Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease... more
Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease patients. A considerable deficiency of cholinergic neurons is a consistent finding in Alzheimer's disease. Therefore, many therapeutic strategies to augment cerebral concentration of acetylcholine such as cholinergic precursors, cholinergic receptor agonists, cholinesterase inhibitors and acetylcholine release modulators have been evaluated in Alzheimer's disease. Although cholinesterase inhibitors such as tacrine and galanthamine offer modest clinical benefits, other cholinergic agents have proved to be of limited therapeutic value. Efforts to enhance monoaminergic neurotransmission have also been largely disappointing. Therefore, emphasis is not being put on the use of combination of two class of drugs. Moreover, use of therapeutic agents b...
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Recent evidence suggests that diminished ability to control cocaine seeking arises from perturbations in glutamate homeostasis in the nucleus accumbens. However, the neurochemical substrates underlying cocaine-induced neuroadaptations in... more
Recent evidence suggests that diminished ability to control cocaine seeking arises from perturbations in glutamate homeostasis in the nucleus accumbens. However, the neurochemical substrates underlying cocaine-induced neuroadaptations in the dorsal striatum and how these mechanisms link to behavioral plasticity is not clear. We employed glutamate-sensitive microelectrodes and amperometry to study the impact of repeated cocaine administration on glutamate dynamics in the dorsolateral striatum of awake freely-moving rats. Depolarization-evoked glutamate release was robustly increased in cocaine-pretreated rats challenged with cocaine. Moreover, the clearance of glutamate signals elicited either by terminal depolarization or blockade of non-neuronal glutamate transporters slowed down dramatically in cocaine-sensitized rats. Repeated cocaine exposure also reduced the neuronal tone of striatal glutamate. Ceftriaxone, a β-lactam antibiotic that activates the astrocytic glutamate transporter, attenuated the effects of repeated cocaine exposure on synaptic glutamate release and glutamate clearance kinetics. Finally, the antagonism of AMPA glutamate receptors in the dorsolateral striatum blocked the development of behavioral sensitization to repeated cocaine administration. Collectively, these data suggest that repeated cocaine exposure disrupts presynaptic glutamate transmission and transporter-mediated clearance mechanisms in the dorsal striatum. Moreover, such alterations produce an over activation of AMPA receptors in this brain region leading to the sensitized behavioral response to repeated cocaine.
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Research Interests: Cognitive Science, Animal Behavior, Electrochemistry, Prefrontal Cortex, Cues, and 15 moreAnimals, Male, Reaction Time, Motor Cortex, Acetylcholine, Basal forebrain, Microelectrodes, Cognitive Performance, Rats, Analysis of Variance, Control Region, Neuron, Neurosciences, Medial Prefrontal Cortex, and Food Deprivation
Page 1. Neurotransmitter Interactions and Cognitive Function Edited by Edward D. Levin 2006 Birkhäuser Verlag/Switzerland Forebrain dopaminergic-cholinergic interactions, attentional effort, psychostimulant addiction and schizophrenia ...