RÉSUMÉ
The 340B program grants eligible health care providers ("covered entities") access to discounted prices for outpatient prescription drugs. Covered entities frequently rely on retail pharmacies ("contract pharmacies") to dispense discounted drugs. This analysis describes contract pharmacy participation by ownership: the top 4 chains, grocery chains, small chains, and institutional independent pharmacies. We found that 71% of pharmacies in the top 4 chains were contract pharmacies. Forty one percentage of institutional pharmacies, 38% of grocery store pharmacies, and 22% of independent pharmacies participated in 340B in 2022. The median number of contracts per pharmacy was 2 among the top 4 chains and grocery store pharmacies vs 1 for all other pharmacy types. The median farthest distance in miles from contracting covered entities was largest for the top 4 chains (19 miles) and small chains (18 miles) and smallest for independent and institutional pharmacies (10 miles). The top 4 chains held the highest proportion of contracts with core safety-net providers (75% vs 61% of institutional pharmacies).
RÉSUMÉ
Within the adult mammalian dentate gyrus (DG) of the hippocampus, glutamate stimulates neural stem cell (NSC) self-renewing proliferation, providing a link between adult neurogenesis and local circuit activity. Here, we show that glutamate-induced self-renewal of adult DG NSCs requires glutamate transport via excitatory amino acid transporter 1 (EAAT1) to stimulate lipogenesis. Loss of EAAT1 prevented glutamate-induced self-renewing proliferation of NSCs in vitro and in vivo, with little role evident for canonical glutamate receptors. Transcriptomics and further pathway manipulation revealed that glutamate simulation of NSCs relied on EAAT1 transport-stimulated lipogenesis. Our findings demonstrate a critical, direct role for EAAT1 in stimulating NSCs to support neurogenesis in adulthood, thereby providing insights into a non-canonical mechanism by which NSCs sense and respond to their niche.
RÉSUMÉ
This cross-sectional study assesses the increases and decreases over time in the number of pharmacy contracts, distance from contracting pharmacies, and proportion of pharmacy contracts with safety-net practices in the US.
Sujet(s)
Pharmacies , Coûts des médicaments , Coûts et analyse des coûts , MarketingRÉSUMÉ
This manuscript reviews several key observations from the research program of Professor John P. Bruno that are believed to have significantly advanced our understanding of the brain's mediation of behavior. This review focuses on findings within several important research areas in behavioral neuroscience, including a) age-dependent neurobehavioral plasticity following brain damage; b) the role of the cortical cholinergic system in attentional processing and cognitive flexibility; and c) the design and validation of animal models of cognitive deficits in schizophrenia. In selecting these observations, emphasis was given to examples in which the heuristic potency was increased by maximizing the resolution and microanalysis of behavioral assays in the same fashion as one typically refines neuronal manipulations. Professor Bruno served the International Behavioral Neuroscience Society (IBNS) as an IBNS Fellow (1995-present) and President of the IBNS (2001-02).
Sujet(s)
Troubles de la cognition , Schizophrénie , Animaux , Cortex préfrontalRÉSUMÉ
Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.
RÉSUMÉ
RATIONALE: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. OBJECTIVES: The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). METHODS: DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. RESULTS: Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. CONCLUSIONS: These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
Sujet(s)
Encéphale/métabolisme , Mémoire à court terme/physiologie , Performance psychomotrice/physiologie , Récepteurs du N-méthyl-D-aspartate/métabolisme , Récepteur nicotinique de l'acétylcholine alpha7/métabolisme , Analgésiques/pharmacologie , Animaux , Encéphale/effets des médicaments et des substances chimiques , Acide kynurénique/pharmacologie , Cynurénine/pharmacologie , Mâle , Mémoire à court terme/effets des médicaments et des substances chimiques , Nicotine/pharmacologie , Performance psychomotrice/effets des médicaments et des substances chimiques , Rats , Rat Wistar , Récepteurs du N-méthyl-D-aspartate/agonistes , Récepteur nicotinique de l'acétylcholine alpha7/agonistesRÉSUMÉ
Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABAAR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.
Sujet(s)
Neurones GABAergiques/physiologie , Acide kynurénique/toxicité , Cortex préfrontal/physiologie , Récepteur nicotinique de l'acétylcholine alpha7/antagonistes et inhibiteurs , Récepteur nicotinique de l'acétylcholine alpha7/physiologie , Animaux , Relation dose-effet des médicaments , Neurones GABAergiques/effets des médicaments et des substances chimiques , Perfusions intraventriculaires , Acide kynurénique/administration et posologie , Mâle , Techniques de culture d'organes , Cortex préfrontal/effets des médicaments et des substances chimiques , Rats , Rat Sprague-DawleyRÉSUMÉ
RATIONALE: Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine receptors (α7nAChRs) and antagonist at glutamatergic N-methyl-D-aspartate receptors (NMDARs), are elevated in the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA's immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ. OBJECTIVES: The present experiments examined whether prenatal kynurenine exposure results in age-dependent changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function. METHODS: Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/day; progeny = EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e., prior to puberty (postnatal day [PD] 32), or as adults (PD70) for brain KYNA levels, α7nAChR and NMDAR gene expression, and performance on a trace fear conditioning (TFC) task. RESULTS: KYNA levels were comparable between juvenile ECON and EKYN rats, whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30-40 %) in EKYN rats at both ages. Compared to ECON adults, there was a 50 % reduction in NR1, and a trend toward decreased α7nAChR expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly better in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits. CONCLUSIONS: Collectively, our results provide evidence that KP changes in the fetal brain alter neuronal development and cause age-dependent effects on neurochemistry and cognitive performance.
Sujet(s)
Encéphale/effets des médicaments et des substances chimiques , Cognition/effets des médicaments et des substances chimiques , Cynurénine/pharmacologie , Effets différés de l'exposition prénatale à des facteurs de risque , Récepteurs du N-méthyl-D-aspartate/effets des médicaments et des substances chimiques , Schizophrénie , Récepteur nicotinique de l'acétylcholine alpha7/effets des médicaments et des substances chimiques , Facteurs âges , Animaux , Encéphale/métabolisme , Conditionnement psychologique/effets des médicaments et des substances chimiques , Peur , Femelle , Humains , Acide kynurénique/métabolisme , Mâle , Grossesse , Rats , Récepteurs du N-méthyl-D-aspartate/métabolisme , Récepteur nicotinique de l'acétylcholine alpha7/métabolismeRÉSUMÉ
The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the α7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ.
Sujet(s)
Encéphale/effets des médicaments et des substances chimiques , Encéphale/croissance et développement , Cognition/effets des médicaments et des substances chimiques , Cynurénine/toxicité , Effets différés de l'exposition prénatale à des facteurs de risque , Animaux , Attention/effets des médicaments et des substances chimiques , Attention/physiologie , Encéphale/anatomopathologie , Encéphale/physiopathologie , Cognition/physiologie , Épines dendritiques/effets des médicaments et des substances chimiques , Épines dendritiques/anatomopathologie , Épines dendritiques/physiologie , Régime alimentaire , Femelle , Acide glutamique/métabolisme , Acide kynurénique/métabolisme , Cynurénine/sang , Mâle , Grossesse , ARN messager , Rat Wistar , Récepteurs métabotropes au glutamate/métabolisme , Apprentissage inversé/effets des médicaments et des substances chimiques , Apprentissage inversé/physiologie , Schizophrénie , Récepteur nicotinique de l'acétylcholine alpha7/métabolismeRÉSUMÉ
RATIONALE: Cognitive dysfunctions, including deficits in hippocampus-mediated learning and memory, are core features of the psychopathology of schizophrenia (SZ). Increased levels of kynurenic acid (KYNA), an astrocyte-derived tryptophan metabolite and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, have been implicated in these cognitive impairments. OBJECTIVES: Following recent suggestive evidence, the present study was designed to narrow the critical time period for KYNA elevation to induce subsequent cognitive deficits. METHODS: KYNA levels were experimentally increased in rats (1) prenatally (embryonic day (ED) 15 to ED 22) or (2) during adolescence (postnatal day (PD) 42 to PD 49). The KYNA precursor kynurenine was added daily to wet mash fed to (1) dams (100 mg/day; control: ECon; kynurenine-treated: EKyn) or (2) adolescent rats (300 mg/kg/day; control: AdCon; kynurenine-treated: AdKyn). Upon termination of the treatment, all animals were fed normal chow until biochemical analysis and behavioral testing in adulthood. RESULTS: On the last day of continuous kynurenine treatment, forebrain KYNA levels were significantly elevated (EKyn +472 %; AdKyn +470 %). KYNA levels remained increased in the hippocampus of adult EKyn animals (+54 %), but were unchanged in adult AdKyn rats. Prenatal, but not adolescent, kynurenine treatment caused significant impairments in two hippocampus-mediated behavioral tasks, passive avoidance and Morris water maze. CONCLUSIONS: Collectively, these studies provide evidence that a continuous increase in brain KYNA levels during the late prenatal period, but not during adolescence, induces hippocampus-related cognitive dysfunctions later in life. Such increases may play a significant role in illnesses with known hippocampal pathophysiology, including SZ.
Sujet(s)
Troubles de la cognition/induit chimiquement , Cynurénine/toxicité , Troubles de la mémoire/induit chimiquement , Effets différés de l'exposition prénatale à des facteurs de risque/physiopathologie , Facteurs âges , Animaux , Apprentissage par évitement/effets des médicaments et des substances chimiques , Comportement animal/effets des médicaments et des substances chimiques , Femelle , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/physiopathologie , Acide kynurénique/métabolisme , Cynurénine/administration et posologie , Mâle , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Grossesse , Rats , Rat Wistar , Facteurs temps , Distribution tissulaireRÉSUMÉ
Increased brain levels of the tryptophan metabolite kynurenic acid (KYNA) have been linked to cognitive dysfunctions in schizophrenia and other psychiatric diseases. In the rat, local inhibition of kynurenine aminotransferase II (KAT II), the enzyme responsible for the neosynthesis of readily mobilizable KYNA in the brain, leads to a prompt reduction in extracellular KYNA levels, and secondarily induces an increase in extracellular glutamate, dopamine, and acetylcholine levels in several brain areas. Using microdialysis in unanesthetized, adult rats, we now show that the novel, systemically active KAT II inhibitor BFF-816, applied orally at 30 mg/kg in all experiments, mimics the effects of local enzyme inhibition. No tolerance was seen when animals were treated daily for 5 consecutive days. Behaviorally, daily injections of BFF-816 significantly decreased escape latency in the Morris water maze, indicating improved performance in spatial and contextual memory. Thus, systemically applied BFF-816 constitutes an excellent tool for studying the neurobiology of KYNA and, in particular, for investigating the mechanisms linking KAT II inhibition to changes in glutamatergic, dopaminergic, and cholinergic function in brain physiology and pathology.
Sujet(s)
Encéphale/effets des médicaments et des substances chimiques , Antienzymes/pharmacologie , Composés hétérocycliques 3 noyaux/pharmacologie , Thiazolidinediones/pharmacologie , Transaminases/antagonistes et inhibiteurs , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Antienzymes/administration et posologie , Composés hétérocycliques 3 noyaux/administration et posologie , Mâle , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Microdialyse , Rats , Rat Sprague-Dawley , Schizophrénie/traitement médicamenteux , Thiazolidinediones/administration et posologieRÉSUMÉ
Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists.
Sujet(s)
Trouble déficitaire de l'attention avec hyperactivité/traitement médicamenteux , Composés hétérocycliques bicycliques/usage thérapeutique , Hippocampe/physiologie , Agonistes nicotiniques/usage thérapeutique , , Facteurs âges , Analyse de variance , Anesthésiques locaux/toxicité , Animaux , Animaux nouveau-nés , Trouble déficitaire de l'attention avec hyperactivité/induit chimiquement , Trouble déficitaire de l'attention avec hyperactivité/physiopathologie , /effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Hippocampe/effets des médicaments et des substances chimiques , Mâle , Odorisants , Rats , Rat Wistar , Tétrodotoxine/toxicité , Toucher/physiologieRÉSUMÉ
The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
Sujet(s)
Encéphale/anatomopathologie , Encéphale/physiologie , Cynurénine/métabolisme , Maladies du système nerveux/métabolisme , Maladies du système nerveux/anatomopathologie , Transduction du signal/physiologie , Animaux , HumainsRÉSUMÉ
Levels of kynurenic acid (KYNA), an endogenous product of tryptophan degradation, are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia (SZ). This increase has been implicated in the cognitive dysfunctions seen in the disease, as KYNA is an antagonist of the α7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, both of which are critically involved in cognitive processes and in a defining neurodevelopmental period in the pathophysiology of SZ. We tested the hypothesis that early developmental increases in brain KYNA synthesis might cause biochemical and functional impairments in adulthood. To this end, we stimulated KYNA formation by adding the KYNA precursor kynurenine (100 mg/day) to the chow fed to rat dams from gestational day 15 to postnatal day 21 (PD 21). This treatment raised brain KYNA levels in the offspring by 341% on PD 2 and 210% on PD 21. Rats were then fed normal chow until adulthood (PD 56-80). In the adult animals, basal levels of extracellular KYNA, measured in the hippocampus by in vivo microdialysis, were elevated (+12%), whereas extracellular glutamate levels were significantly reduced (-13%). In separate adult animals, early kynurenine treatment was shown to impair performance in two behavioral tasks linked to hippocampal function, the passive avoidance test and the Morris water maze test. Collectively, these studies introduce a novel, naturalistic rat model of SZ, and also suggest that increases in brain KYNA during a vulnerable period in brain development may play a significant role in the pathophysiology of the disease.
Sujet(s)
Troubles de la cognition/induit chimiquement , Cynurénine/toxicité , Effets différés de l'exposition prénatale à des facteurs de risque/physiopathologie , Facteurs âges , Analyse de variance , Animaux , Animaux nouveau-nés , Chromatographie en phase liquide à haute performance , Troubles de la cognition/physiopathologie , Techniques électrochimiques , Femelle , Acide glutamique/métabolisme , Acide kynurénique/métabolisme , Cynurénine/administration et posologie , Cynurénine/analogues et dérivés , Cynurénine/sang , Cynurénine/métabolisme , Mâle , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Mémoire/effets des médicaments et des substances chimiques , Microdialyse , Grossesse , Effets différés de l'exposition prénatale à des facteurs de risque/induit chimiquement , Rats , Rat Wistar , Comportement spatial/effets des médicaments et des substances chimiquesRÉSUMÉ
RATIONALE: Cognitive deficits represent a core symptom cluster in schizophrenia (SZ) that is predictive of outcome but not effectively treated by current antipsychotics. Thus, there is a need for validated animal models for testing potential pro-cognitive drugs. OBJECTIVE: As kynurenic acid levels are increased in prefrontal cortex (PFC) of individuals with SZ, we acutely increased brain levels of this astrocyte-derived, negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs) by administration of its bioprecursor kynurenine and measured the effects on extracellular kynurenic acid and glutamate levels in PFC and also performance in a set-shifting task. RESULTS: Injections of kynurenine (100 mg/kg, i.p.) increased extracellular kynurenic acid (1,500%) and decreased glutamate levels (30%) in PFC. Kynurenine also produced selective deficits in set-shifting. Saline- and kynurenine-treated rats similarly acquired the compound discrimination and intra-dimensional shift (saline, 7.0 and 6.3 trials, respectively; kynurenine, 8.0 and 6.7). Both groups required more trials to acquire the initial reversal (saline, 15.3; kynurenine, 22.2). Only kynurenine-treated rats were impaired in acquiring the extra-dimensional shift (saline, 8.2; kynurenine, 21.3). These deficits were normalized by administering the α7nAChR positive allosteric modulator galantamine (3.0 mg/kg, i.p) prior to kynurenine, as trials were comparable between galantamine + kynurenine (7.8) and controls (8.2). Bilateral local perfusion of the PFC with galantamine (5.0 µM) also attenuated kynurenine-induced deficits. CONCLUSIONS: These results validate the use of animals with elevated brain kynurenic acid levels in SZ research and support studies of drugs that normalize brain kynurenic acid levels and/or positively modulate α7nAChRs as pro-cognitive treatments for SZ.
Sujet(s)
Cognition/effets des médicaments et des substances chimiques , Galantamine/pharmacologie , Acide kynurénique/métabolisme , Cynurénine/toxicité , Animaux , Encéphale/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Troubles de la cognition/traitement médicamenteux , Troubles de la cognition/physiopathologie , Modèles animaux de maladie humaine , Acide glutamique/métabolisme , Mâle , Nootropiques/pharmacologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Rats , Rat Wistar , Récepteurs nicotiniques/effets des médicaments et des substances chimiques , Récepteurs nicotiniques/métabolisme , Schizophrénie/traitement médicamenteux , Schizophrénie/physiopathologie , Récepteur nicotinique de l'acétylcholine alpha7RÉSUMÉ
These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic-cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.
Sujet(s)
Neurones cholinergiques/métabolisme , Hippocampe/physiopathologie , Cortex préfrontal/physiologie , Schizophrénie/métabolisme , Acétylcholine/métabolisme , Animaux , Animaux nouveau-nés , Mâle , Rats , Rat Wistar , Transmission synaptique/physiologieRÉSUMÉ
Sustaining and recovering attentional performance requires interactions between the brain's motivation and attention systems. The first experiment demonstrated that in rats performing a sustained attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex. Because stimulation of NMDA receptors in the shell of the nucleus accumbens activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAc shell, but not core, improved dSAT performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intracortical infusions of the cholinotoxin 192 IgG-saporin, attenuated the beneficial effects of NMDA on dSAT performance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors.
Sujet(s)
Acétylcholine/métabolisme , Attention/physiologie , Lobe frontal/métabolisme , Transmission synaptique/physiologie , Analyse de variance , Animaux , Attention/effets des médicaments et des substances chimiques , Chromatographie en phase liquide à haute performance , Agonistes des acides aminés excitateurs/pharmacologie , Lobe frontal/effets des médicaments et des substances chimiques , Mâle , Microdialyse , N-Méthyl-aspartate/pharmacologie , Voies nerveuses/effets des médicaments et des substances chimiques , Voies nerveuses/métabolisme , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Noyau accumbens/effets des médicaments et des substances chimiques , Noyau accumbens/métabolisme , Rats , Rat Wistar , Récepteurs du N-méthyl-D-aspartate/métabolisme , Transmission synaptique/effets des médicaments et des substances chimiquesRÉSUMÉ
The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits alpha7 nicotinic acetylcholine receptors (alpha7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the alpha7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by (S)-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.
Sujet(s)
Astrocytes/métabolisme , Acide glutamique/métabolisme , Acide kynurénique/métabolisme , Antagonistes nicotiniques/métabolisme , Cortex préfrontal/métabolisme , Animaux , Anticholinestérasiques/pharmacologie , Antienzymes/pharmacologie , Antagonistes des acides aminés excitateurs/métabolisme , Antagonistes des acides aminés excitateurs/pharmacologie , Liquide extracellulaire/effets des médicaments et des substances chimiques , Liquide extracellulaire/métabolisme , Galantamine/pharmacologie , Acide kynurénique/pharmacologie , Cynurénine/métabolisme , Mâle , Microdialyse , Antagonistes nicotiniques/pharmacologie , Cortex préfrontal/cytologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Rats , Rat Sprague-Dawley , Récepteurs nicotiniques/métabolisme , Schizophrénie/traitement médicamenteux , Schizophrénie/métabolisme , Schizophrénie/physiopathologie , Récepteur nicotinique de l'acétylcholine alpha7RÉSUMÉ
Abnormal mesolimbic control of cortical cholinergic activity has been hypothesized to contribute to the cognitive symptoms of schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in prefrontal cortex (PFC), an activation thought to contribute to attentional processing. Thus, the effects of intra-NAC perfusion of NMDA (250-400 microM) on ACh release in PFC were determined in rats receiving lesions of the ventral hippocampus (VH) as neonates (nVHLX), a neurodevelopmental model of schizophrenia, or as adults (aVHLX). NMDA elevated ACh release (100-150% above baseline) in adults sham-lesioned as neonates or in aVHLX rats. Adult nVHLX were unresponsive to NAC NMDA receptor stimulation. The inability of nVHLX to respond to NMDA emerged over development as a separate experiment demonstrated that evoked ACh release was normal before puberty (100-150% increase) yet, in these same nVHLX animals, absent after puberty. Amphetamine-evoked ACh release was assessed in nVHLX animals to exclude potential limitations in release capacity. Amphetamine produced greater increases in ACh release than in shams, indicating that nVHLX does not impair the capacity of cholinergic neurons to release ACh. Finally, the ability of 13 days of pretreatment with clozapine (1.25 mg/kg/day) to reinstate NMDA-evoked cortical ACh efflux was determined. Clozapine treatment normalized NMDA-evoked ACh release in nVHLX animals. These experiments show that mesolimbic regulation of cortical ACh release is disrupted in postpubertal nVHLX rats and normalized by low-dose treatment of clozapine; supporting the usefulness of nVHLX animals for research on the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.
Sujet(s)
Acétylcholine/métabolisme , Clozapine/pharmacologie , Hippocampe/physiopathologie , Voies nerveuses/physiopathologie , Schizophrénie/physiopathologie , Vieillissement , Amfétamine/administration et posologie , Amfétamine/pharmacologie , Animaux , Animaux nouveau-nés , Modèles animaux de maladie humaine , Acide iboténique , Mâle , Microinjections , N-Méthyl-aspartate/administration et posologie , N-Méthyl-aspartate/pharmacologie , Noyau accumbens/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Rats , Rat Wistar , Schizophrénie/induit chimiquement , Facteurs tempsRÉSUMÉ
These experiments utilized an enzyme-based microelectrode selective for the second-by-second detection of extracellular glutamate to reveal the alpha 7-based nicotinic modulation of glutamate release in the prefrontal cortex (PFC) of freely moving rats. Rats received intracortical infusions of the nonselective nicotinic agonist nicotine (12.0 mM, 1.0 microg/0.4 microl) or the selective alpha 7 agonist choline (2.0 mM/0.4 microl). The selectivity of drug-induced glutamate release was assessed in subgroups of animals pretreated with the alpha 7 antagonist, alpha-bungarotoxin (alpha-BGT, 10 microM), or kynurenine (10 microM) the precursor of the astrocyte-derived, negative allosteric alpha 7 modulator kynurenic acid. Local administration of nicotine increased glutamate signals (maximum amplitude = 4.3 +/- 0.6 microM) that were cleared to baseline levels in 493 +/- 80 seconds. Pretreatment with alpha-BGT or kynurenine attenuated nicotine-induced glutamate by 61% and 60%, respectively. Local administration of choline also increased glutamate signals (maximum amplitude = 6.3 +/- 0.9 microM). In contrast to nicotine-evoked glutamate release, choline-evoked signals were cleared more quickly (28 +/- 6 seconds) and pretreatment with alpha-BGT or kynurenine completely blocked the stimulated glutamate release. Using a method that reveals the temporal dynamics of in vivo glutamate release and clearance, these data indicate a nicotinic modulation of cortical glutamate release that is both alpha 7- and non-alpha 7-mediated. Furthermore, these data may also provide a mechanism underlying the recent focus on alpha 7 full and partial agonists as therapeutic agents in the treatment of cortically mediated cognitive deficits in schizophrenia.