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Anna Castane - One of the best experts on this subject based on the ideXlab platform.
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serotonergic mechanisms involved in antidepressant like responses evoked by glt 1 blockade in rat infralimbic cortex
Neuropharmacology, 2018Co-Authors: Julia Gasullcamos, Sara Martineztorres, Mireia Tarresgatius, Andres Ozaita, Francesc Artigas, Anna CastaneAbstract:Abstract Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by Dihydrokainic Acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.
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Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats
Translational Psychiatry, 2017Co-Authors: J Gasull-camós, Francesc Artigas, M Tarrés-gatius, Anna CastaneAbstract:Ketamine and deep brain stimulation produce rapid antidepressant effects in humans and rodents. An increased AMPA receptor (AMPA-R) signaling in medial prefrontal cortex (mPFC) has been suggested to mediate these responses. However, little research has addressed the direct effects of enhancing glutamate tone or AMPA-R stimulation in mPFC subdivisions. The current study investigates the behavioral and neurochemical consequences of glutamate transporter-1 (GLT-1) blockade or s-AMPA microinfusion in the infralimbic (IL) and prelimbic (PrL) cortex. Owing to the connectivity between the mPFC and raphe nuclei, the role of serotonin is also explored. The bilateral microinfusion of the depolarizing agent veratridine into IL -but not PrL- of rats evoked immediate antidepressant-like responses. The same regional selectivity was observed after microinfusion of Dihydrokainic Acid (DHK), a selective inhibitor of GLT-1, present in astrocytes. The DHK-evoked antidepressant-like responses appear to be mediated by an AMPA-R-driven enhancement of serotonergic activity, as (i) they were prevented by NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt) and mimicked by s-AMPA; (ii) DHK and s-AMPA elevated similarly extracellular glutamate in IL and PrL, although extracellular 5-HT and c-fos expression in the midbrain dorsal raphe increased only when these agents were applied in IL; and (iii) DHK antidepressant-like responses were prevented by 5-HT synthesis inhibition and mimicked by citalopram microinfusion in IL. These results indicate that an acute increase of glutamatergic neurotransmission selectively in IL triggers immediate antidepressant-like responses in rats, likely mediated by the activation of IL–raphe pathways, which then results in a fast increase of serotonergic activity.
Castañé Anna - One of the best experts on this subject based on the ideXlab platform.
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Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex
'Elsevier BV', 2018Co-Authors: Gasull-camós Júlia, Artigas Francesc, Tarrés-gatius Mireia, Martínez-torres Sara, Ozaita Andrés, Castañé AnnaAbstract:Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by Dihydrokainic Acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-68346 and BES2013-063241 to J.G-C; BFU2015-68568-P to A.O.) co-financed by European Regional Development Fund; Generalitat de Catalunya (CERCA Programme; 2014-SGR798, 2016FI-B00285 to M.T-G, 2016 FI-B00531 to S.M-T and ICREA Acadèmia to A.O.); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM).Peer reviewe
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Differential Patterns of Subcortical Activity Evoked by Glial GLT-1 Blockade in Prelimbic and Infralimbic Cortex: Relationship to Antidepressant-Like Effects in Rats
'Oxford University Press (OUP)', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Soto-montenegro, Maria Luisa, Casquero-veiga Marta, Desco Manuel, Castañé AnnaAbstract:Background: Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with Dihydrokainic Acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid receptor activation and increased serotonin release. Methods: 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with Dihydrokainic Acid or vehicle. Results: Dihydrokainic Acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, Dihydrokainic Acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. Conclusions: These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of Dihydrokainic Acid.This work was supported by Spanish Ministry of Economy and Competitiveness grants (SAF2012-35183, SAF2015-68346, ISCIII-FIS PI14/00860 and CPII14/00005, and BES2013-063241 J.GC.) cofinanced by European Regional Development Fund, Generalitat de Catalunya (2014-SGR798), Comunidad de Madrid (BRADE-CM S2013/ICE-2958), Mapfre foundation, Alicia Koplowitz Foundation (FAK16/01), and Centro de Investigación Biomédica en Red de Salud Mental.S
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Differential patterns of subcortical activity evoked by glial GLT-1 blockade in prelimbic and infralimbic cortex: Relationship to antidepressant-like effects in rats
'Oxford University Press (OUP)', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Casquero-veiga Marta, Desco Manuel, Soto-montenegro, María L., Castañé AnnaAbstract:[Background] Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with Dihydrokainic Acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid receptor activation and increased serotonin release. [Methods] 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with Dihydrokainic Acid or vehicle. [Results] Dihydrokainic Acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, Dihydrokainic Acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. [Conclusions] These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of Dihydrokainic Acid.This work was supported by Spanish Ministry of Economy and Competitiveness grants (SAF2012-35183, SAF2015-68346, ISCIII-FIS PI14/00860 and CPII14/00005, and BES2013-063241 J.GC.) cofinanced by European Regional Development Fund, Generalitat de Catalunya (2014-SGR798), Comunidad de Madrid (BRADE-CM S2013/ICE-2958), Mapfre foundation, Alicia Koplowitz Foundation (FAK16/01), and Centro de Investigación Biomédica en Red de Salud Mental.Peer reviewe
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Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats
'Springer Science and Business Media LLC', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Tarrés-gatius Mireia, Castañé AnnaAbstract:Ketamine and deep brain stimulation produce rapid antidepressant effects in humans and rodents. An increased AMPA receptor (AMPA-R) signaling in medial prefrontal cortex (mPFC) has been suggested to mediate these responses. However, little research has addressed the direct effects of enhancing glutamate tone or AMPA-R stimulation in mPFC subdivisions. The current study investigates the behavioral and neurochemical consequences of glutamate transporter-1 (GLT-1) blockade or s-AMPA microinfusion in the infralimbic (IL) and prelimbic (PrL) cortex. Owing to the connectivity between the mPFC and raphe nuclei, the role of serotonin is also explored. The bilateral microinfusion of the depolarizing agent veratridine into IL -but not PrL- of rats evoked immediate antidepressant-like responses. The same regional selectivity was observed after microinfusion of Dihydrokainic Acid (DHK), a selective inhibitor of GLT-1, present in astrocytes. The DHK-evoked antidepressant-like responses appear to be mediated by an AMPA-R-driven enhancement of serotonergic activity, as (i) they were prevented by NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt) and mimicked by s-AMPA; (ii) DHK and s-AMPA elevated similarly extracellular glutamate in IL and PrL, although extracellular 5-HT and c-fos expression in the midbrain dorsal raphe increased only when these agents were applied in IL; and (iii) DHK antidepressant-like responses were prevented by 5-HT synthesis inhibition and mimicked by citalopram microinfusion in IL. These results indicate that an acute increase of glutamatergic neurotransmission selectively in IL triggers immediate antidepressant-like responses in rats, likely mediated by the activation of IL–raphe pathways, which then results in a fast increase of serotonergic activity.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant numbers SAF2012-35183; SAF2015-68346; and BES2013-063241 to JG-C), co-financed by European Regional Development Fund (ERDF); Generalitat de Catalunya (grant number 2014-SGR798 and 2016FI-B00285 to MT-G) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM).Peer reviewe
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Boosting glutamatergic tone in infralimbic -but not prelimbic- cortex evokes antidepressant-like effects in rats through AMPA receptor activation
2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Castañé AnnaAbstract:Trabajo presentado en Neuroscience 2016, celebrado en San Diego, California, del 12 al 16 de noviembre de 2016Since the discovery of the antidepressant effects of ketamine, a growing number of clinical and preclinical studies have shown the capability of several drugs to induce rapid antidepressant responses. Ketamine is known to increase glutamate release in the medial prefrontal cortex (mPFC) and an increased AMPA receptor (AMPA-R) signaling has been suggested to mediate the effects of several fast-acting antidepressant strategies. The dorsal (prelimbic, PrL) and ventral (infralimbic, IL) subdivisions of mPFC exert a differential control over emotional behavior. Thus, the main goal of the present study was to investigate the possible involvement of excitatory neurotransmission in the IL and PrL cortex on mood regulation. Hence, we examined the potential antidepressant responses of boosting glutamatergic function in these mPFC subdivisions and studied the involvement of AMPA receptors (AMPA-R). We characterized the rapid behavioral consequences evoked by the bilateral microinfusion of a depolarizing drug, veratridine (50 pmol); a selective inhibitor of the glutamate transporter 1 (GLT-1; mostly present in astrocytes and main responsible for synaptic glutamate reuptake), Dihydrokainic Acid (DHK; 0.15, 1.5 and 5 nmol); or an AMPA-R agonist, s-AMPA (50 pmol), either in the PrL or IL. Neurochemical effects of these drugs over glutamate and serotonin (5-HT) concentration were determined by in vivo microdialysis in freely-moving rats. Veratridine reduced immobility time on the forced-swim test (FST) when infused into IL but not PrL. Likewise, DHK (5 nmol) and s-AMPA reduced both immobility on the FST and latency to feed on the novelty-suppressed feeding test (NSFT) when infused into IL, but not PrL. Lower doses of DHK were without effect. Furthermore, the local blockade of AMPA-R with NBQX (10 nmol) previous to DHK microinfusion into IL prevented DHK-induced reduction in immobility, supporting the involvement of IL AMPA-R in mediating rapid antidepressant responses. Microdialysis studies showed that the inhibition of GLT-1 with DHK increased extracellular glutamate to the same extent in IL and PrL. However 5-HT output increased only after GLT-1 blockade in IL, suggesting a differential control of both mPFC areas on serotonergic activity. Accordingly, s-AMPA increased glutamate and serotonin concentration in IL. Overall, the present results indicate that an acute increase of glutamatergic neurotransmission in the IL mPFC triggers immediate antidepressant-like responses in rats, which are mediated by AMPA-R activation and likely involve a PFC-driven enhancement of serotonergic activity.Peer Reviewe
Jack L Feldman - One of the best experts on this subject based on the ideXlab platform.
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generation and transmission of respiratory oscillations in medullary slices role of excitatory amino Acids
Journal of Neurophysiology, 1993Co-Authors: Gregory D Funk, Jeffrey C Smith, Jack L FeldmanAbstract:1. The involvement of excitatory amino Acid (EAA) receptors in the generation of respiratory rhythm and transmission of inspiratory drive to hypoglossal (XII) motoneurons was examined in an in vitro neonatal rat medullary slice preparation. Slices generated rhythmic inspiratory activity in XII nerves. The role of EAAs in rhythm generation was determined by analyzing perturbations of respiratory network activity after bath application of EAA receptor antagonists or local microinjection of antagonists into the main column of respiratory neurons in the ventrolateral medulla (ventral respiratory group), particularly in the pre-Botzinger complex (pre-BotC). The involvement of EAAs in drive transmission to XII motoneurons was examined by recording perturbations in XII nerve discharge or motoneuron synaptic inputs after microinjection of EAA receptor antagonists into either the XII motor nuclei or sites in the ventrolateral medulla containing interneurons of the drive transmission circuit. 2. Block of non-N-methyl-D-aspartate (non-NMDA) receptors by bath application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reversibly reduced XII nerve burst frequency and amplitude in a concentration-dependent manner, completely blocking respiratory motor output at concentrations > 4 microM. Activation of 2-amino-4-phosphonobutyric Acid (AP-4)-sensitive receptors with D,L AP-4 reduced XII nerve burst amplitude by 30% but did not alter burst frequency. Block of NMDA receptor channels by bath application of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-iminemaleate (MK-801) did not perturb the frequency or amplitude of motor output. Inhibition of EAA uptake in the slices by bath application of Dihydrokainic Acid reversibly increased the frequency and amplitude of XII motor discharge. 3. Block of non-NMDA receptors at multiple sites along the main column of respiratory neurons in the ventrolateral medulla, including the pre-BotC, by unilateral microinjection of CNQX produced a dose-dependent, bilateral reduction in XII nerve burst amplitude without substantial perturbations of the frequency of respiratory oscillations. Block of non-NMDA receptors within the pre-BotC at sites ventral to amplitude altering sites produced a reduction in frequency and ultimately bilateral block of respiratory network oscillations. 4. Non-NMDA receptor block within the XII motor nucleus by unilateral microinjection of CNQX produced a dose-dependent reduction in ipsilateral XII nerve discharge amplitude without perturbing the frequency of respiratory oscillations. Perturbations of contralateral XII nerve burst amplitude were significantly smaller. NMDA channel block within the XII motor nucleus did not affect inspiratory burst amplitude, whereas activation of AP-4 receptors caused a 30% reduction in amplitude.
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role of excitatory amino Acids in the generation and transmission of respiratory drive in neonatal rat
The Journal of Physiology, 1991Co-Authors: J J Greer, Jeffrey C Smith, Jack L FeldmanAbstract:1. The involvement of excitatory amino Acids in the generation and transmission of rhythmic respiratory drive was studied in an in vitro neonatal rat brain stem-spinal cord preparation. The subclasses of excitatory amino Acid receptors studied included: (i) N-methyl-D-aspartate (NMDA) receptors, (ii) (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid hydrobromide (AMPA) and kainate (non-NMDA) receptors and (iii) 2-amino-4-phosphonobutyric Acid (AP-4)-sensitive receptors. Respiratory motoneurone population discharge was recorded from glossopharyngeal (IX), vagus (X), and hypoglossal (XII) cranial nerves, as well as cervical (C1-C5) and thoracic (T2-T5) spinal ventral roots. This activity is generated in the motoneurone pools that transmit respiratory drive to upper airway, accessory, diaphragm and intercostal muscles. Perturbations of motor nerve discharge were analysed after excitatory amino Acid receptor antagonists or agonists were added to bathing solutions surrounding either the spinal cord or brain stem. The excitatory amino Acid receptor antagonists included: (i) NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imin-H-maleate (MK-801) and (ii) non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The agonists included: (i) NMDA, (ii) non-NMDA receptor agonists AMPA and kainic Acid. The effects of perturbations of AP-4-sensitive receptors with AP-4, and of inhibiting excitatory amino Acid uptake with Dihydrokainic Acid (DHK) were also studied. 2. Block of non-NMDA receptors in the medulla by CNQX resulted in an antagonist concentration-dependent decrease in the respiratory motoneuronal burst frequency. Non-NMDA receptor activation with kainic Acid or AMPA caused a concentration-dependent increase in burst frequency, with competitive interactions with CNQX. 3. Inhibition of excitatory amino Acid uptake in the medulla with DHK resulted in a reversible, dose-dependent increase in respiratory frequency. A similar increase in respiratory frequency was induced by DHK when medullary NMDA receptors were blocked with MK-801, confirming that endogenously released excitatory amino Acids act at non-NMDA receptors to modulate rhythm. 4. Non-NMDA receptor block reduced and ultimately abolished the amplitude of integrated cranial and spinal respiratory motoneuronal discharge when added to the solution bathing the medulla and spinal cord, respectively. 5. NMDA receptor block in the medulla with MK-801 did not perturb the spontaneous respiratory burst frequency, although bath application of NMDA produced a dose-dependent increase in frequency, with non-competitive interactions with MK-801. MK-801 also did not perturb the amplitude of cranial or bulbospinal premotoneurone discharge.(ABSTRACT TRUNCATED AT 400 WORDS)
Gasull-camós Júlia - One of the best experts on this subject based on the ideXlab platform.
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Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex
'Elsevier BV', 2018Co-Authors: Gasull-camós Júlia, Artigas Francesc, Tarrés-gatius Mireia, Martínez-torres Sara, Ozaita Andrés, Castañé AnnaAbstract:Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by Dihydrokainic Acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-68346 and BES2013-063241 to J.G-C; BFU2015-68568-P to A.O.) co-financed by European Regional Development Fund; Generalitat de Catalunya (CERCA Programme; 2014-SGR798, 2016FI-B00285 to M.T-G, 2016 FI-B00531 to S.M-T and ICREA Acadèmia to A.O.); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM).Peer reviewe
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Differential Patterns of Subcortical Activity Evoked by Glial GLT-1 Blockade in Prelimbic and Infralimbic Cortex: Relationship to Antidepressant-Like Effects in Rats
'Oxford University Press (OUP)', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Soto-montenegro, Maria Luisa, Casquero-veiga Marta, Desco Manuel, Castañé AnnaAbstract:Background: Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with Dihydrokainic Acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid receptor activation and increased serotonin release. Methods: 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with Dihydrokainic Acid or vehicle. Results: Dihydrokainic Acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, Dihydrokainic Acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. Conclusions: These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of Dihydrokainic Acid.This work was supported by Spanish Ministry of Economy and Competitiveness grants (SAF2012-35183, SAF2015-68346, ISCIII-FIS PI14/00860 and CPII14/00005, and BES2013-063241 J.GC.) cofinanced by European Regional Development Fund, Generalitat de Catalunya (2014-SGR798), Comunidad de Madrid (BRADE-CM S2013/ICE-2958), Mapfre foundation, Alicia Koplowitz Foundation (FAK16/01), and Centro de Investigación Biomédica en Red de Salud Mental.S
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Differential patterns of subcortical activity evoked by glial GLT-1 blockade in prelimbic and infralimbic cortex: Relationship to antidepressant-like effects in rats
'Oxford University Press (OUP)', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Casquero-veiga Marta, Desco Manuel, Soto-montenegro, María L., Castañé AnnaAbstract:[Background] Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with Dihydrokainic Acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid receptor activation and increased serotonin release. [Methods] 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with Dihydrokainic Acid or vehicle. [Results] Dihydrokainic Acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, Dihydrokainic Acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. [Conclusions] These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of Dihydrokainic Acid.This work was supported by Spanish Ministry of Economy and Competitiveness grants (SAF2012-35183, SAF2015-68346, ISCIII-FIS PI14/00860 and CPII14/00005, and BES2013-063241 J.GC.) cofinanced by European Regional Development Fund, Generalitat de Catalunya (2014-SGR798), Comunidad de Madrid (BRADE-CM S2013/ICE-2958), Mapfre foundation, Alicia Koplowitz Foundation (FAK16/01), and Centro de Investigación Biomédica en Red de Salud Mental.Peer reviewe
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Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats
'Springer Science and Business Media LLC', 2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Tarrés-gatius Mireia, Castañé AnnaAbstract:Ketamine and deep brain stimulation produce rapid antidepressant effects in humans and rodents. An increased AMPA receptor (AMPA-R) signaling in medial prefrontal cortex (mPFC) has been suggested to mediate these responses. However, little research has addressed the direct effects of enhancing glutamate tone or AMPA-R stimulation in mPFC subdivisions. The current study investigates the behavioral and neurochemical consequences of glutamate transporter-1 (GLT-1) blockade or s-AMPA microinfusion in the infralimbic (IL) and prelimbic (PrL) cortex. Owing to the connectivity between the mPFC and raphe nuclei, the role of serotonin is also explored. The bilateral microinfusion of the depolarizing agent veratridine into IL -but not PrL- of rats evoked immediate antidepressant-like responses. The same regional selectivity was observed after microinfusion of Dihydrokainic Acid (DHK), a selective inhibitor of GLT-1, present in astrocytes. The DHK-evoked antidepressant-like responses appear to be mediated by an AMPA-R-driven enhancement of serotonergic activity, as (i) they were prevented by NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt) and mimicked by s-AMPA; (ii) DHK and s-AMPA elevated similarly extracellular glutamate in IL and PrL, although extracellular 5-HT and c-fos expression in the midbrain dorsal raphe increased only when these agents were applied in IL; and (iii) DHK antidepressant-like responses were prevented by 5-HT synthesis inhibition and mimicked by citalopram microinfusion in IL. These results indicate that an acute increase of glutamatergic neurotransmission selectively in IL triggers immediate antidepressant-like responses in rats, likely mediated by the activation of IL–raphe pathways, which then results in a fast increase of serotonergic activity.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant numbers SAF2012-35183; SAF2015-68346; and BES2013-063241 to JG-C), co-financed by European Regional Development Fund (ERDF); Generalitat de Catalunya (grant number 2014-SGR798 and 2016FI-B00285 to MT-G) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM).Peer reviewe
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Boosting glutamatergic tone in infralimbic -but not prelimbic- cortex evokes antidepressant-like effects in rats through AMPA receptor activation
2017Co-Authors: Gasull-camós Júlia, Artigas Francesc, Castañé AnnaAbstract:Trabajo presentado en Neuroscience 2016, celebrado en San Diego, California, del 12 al 16 de noviembre de 2016Since the discovery of the antidepressant effects of ketamine, a growing number of clinical and preclinical studies have shown the capability of several drugs to induce rapid antidepressant responses. Ketamine is known to increase glutamate release in the medial prefrontal cortex (mPFC) and an increased AMPA receptor (AMPA-R) signaling has been suggested to mediate the effects of several fast-acting antidepressant strategies. The dorsal (prelimbic, PrL) and ventral (infralimbic, IL) subdivisions of mPFC exert a differential control over emotional behavior. Thus, the main goal of the present study was to investigate the possible involvement of excitatory neurotransmission in the IL and PrL cortex on mood regulation. Hence, we examined the potential antidepressant responses of boosting glutamatergic function in these mPFC subdivisions and studied the involvement of AMPA receptors (AMPA-R). We characterized the rapid behavioral consequences evoked by the bilateral microinfusion of a depolarizing drug, veratridine (50 pmol); a selective inhibitor of the glutamate transporter 1 (GLT-1; mostly present in astrocytes and main responsible for synaptic glutamate reuptake), Dihydrokainic Acid (DHK; 0.15, 1.5 and 5 nmol); or an AMPA-R agonist, s-AMPA (50 pmol), either in the PrL or IL. Neurochemical effects of these drugs over glutamate and serotonin (5-HT) concentration were determined by in vivo microdialysis in freely-moving rats. Veratridine reduced immobility time on the forced-swim test (FST) when infused into IL but not PrL. Likewise, DHK (5 nmol) and s-AMPA reduced both immobility on the FST and latency to feed on the novelty-suppressed feeding test (NSFT) when infused into IL, but not PrL. Lower doses of DHK were without effect. Furthermore, the local blockade of AMPA-R with NBQX (10 nmol) previous to DHK microinfusion into IL prevented DHK-induced reduction in immobility, supporting the involvement of IL AMPA-R in mediating rapid antidepressant responses. Microdialysis studies showed that the inhibition of GLT-1 with DHK increased extracellular glutamate to the same extent in IL and PrL. However 5-HT output increased only after GLT-1 blockade in IL, suggesting a differential control of both mPFC areas on serotonergic activity. Accordingly, s-AMPA increased glutamate and serotonin concentration in IL. Overall, the present results indicate that an acute increase of glutamatergic neurotransmission in the IL mPFC triggers immediate antidepressant-like responses in rats, which are mediated by AMPA-R activation and likely involve a PFC-driven enhancement of serotonergic activity.Peer Reviewe
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Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms
Neuropsychopharmacology, 2015Co-Authors: Catherine S John, William A Carlezon, Bruce M Cohen, Dost Ongur, Elizabeth I Sypek, Anita J BechtholtAbstract:Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, Dihydrokainic Acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.
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blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia
Neuropsychopharmacology, 2012Co-Authors: Catherine S John, Karen L Smith, Ashlee Vant Veer, Heinrich S Gompf, William A Carlezon, Bruce M Cohen, Dost Ongur, Anita J BechtholtgompfAbstract:Major depression is associated with both dysregulated glutamatergic neurotransmission and fewer astrocytes in limbic areas including the prefrontal cortex (PFC). These deficits may be functionally related. Notably, astrocytes regulate glutamate levels by removing glutamate from the synapse via the glutamate transporter (GLT-1). Previously, we demonstrated that central blockade of GLT-1 induces anhedonia and c-Fos expression in the PFC. Given the role of the PFC in regulating mood, we hypothesized that GLT-1 blockade in the PFC alone would be sufficient to induce anhedonia in rats. We microinjected the GLT-1 inhibitor, Dihydrokainic Acid (DHK), into the PFC and examined the effects on mood using intracranial self-stimulation (ICSS). At lower doses, intra-PFC DHK produced modest increases in ICSS thresholds, reflecting a depressive-like effect. At higher doses, intra-PFC DHK resulted in cessation of responding. We conducted further tests to clarify whether this total cessation of responding was related to an anhedonic state (tested by sucrose intake), a nonspecific result of motor impairment (measured by the tape test), or seizure activity (measured with electroencephalogram (EEG)). The highest dose of DHK increased latency to begin drinking without altering total sucrose intake. Furthermore, neither motor impairment nor evidence of seizure activity was observed in the tape test or EEG recordings. A decrease in reward value followed by complete cessation of ICSS responding suggests an anhedonic-like effect of intra-PFC DHK; a conclusion that was substantiated by an increased latency to begin sucrose drinking. Overall, these results suggest that blockade of astrocytic glutamate uptake in the PFC is sufficient to produce anhedonia, a core symptom of depression.
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blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory
Neuropsychopharmacology, 2010Co-Authors: Anita J Bechtholtgompf, William A Carlezon, Dost Ongur, Hali V Walther, Martha A Adams, Bruce M CohenAbstract:Mood disorders are associated with regional brain abnormalities, including reductions in glial cell and neuron number, glutamatergic irregularities, and differential patterns of brain activation. Because astrocytes are modulators of neuronal activity and are important in trafficking the excitatory neurotransmitter glutamate, it is possible that these pathologies are interrelated and contribute to some of the behavioral signs that characterize depression and related disorders. We tested this hypothesis by determining whether depressive-like signs were induced by blocking central astrocytic glutamate uptake with the astrocytic glutamate transporter (GLT-1) inhibitor, Dihydrokainic Acid (DHK), in behavioral tests that quantify aspects of mood, including reward and euthymia/dysthymia: intracranial self-stimulation (ICSS) and place conditioning. We found that DHK elevated ICSS thresholds, a depressive-like effect that could reflect reduced sensitivity to reward (anhedonia) or increased aversion (dysphoria). However, DHK treatment did not establish conditioned place aversions, suggesting that this treatment does not induce dysphoria. To identify the brain regions mediating the behavioral effects of DHK, we examined c-Fos expression in areas implicated in motivation and emotion. DHK increased c-Fos expression in many of these regions. The dentate gyrus of the hippocampus was robustly activated, which led us to explore whether DHK alters hippocampal learning. DHK impaired spatial memory in the MWM. These findings identify disruption of astrocyte glutamate uptake as one component of the complex circuits that mediate anhedonia and cognitive impairment, both of which are common symptoms of depression. These finding may have implications for the etiology of depression and other disorders that share the features of anhedonia and cognitive impairment.