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Papers by Jeanfrancois Doriat
Circulation Et Metabolisme Du Cerveau, 1995
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 1999
Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excito... more Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excitotoxicity and seizure mediation. A previous study has shown that an acute episode of seizures for 30 min in rats altered NMDA receptor characteristics, mainly in the very immature animal. In order to assess whether receptor modifications may also account for long-lasting cerebral disabilities, medium- and long-term consequences of repeated seizures in developing rats on brain NMDA receptor properties were investigated. Seizures were induced once a day for 3 consecutive days, either from post-natal day 5 (P5) to P7 or from P15 to P17. NMDA receptors were then analysed at P15, P25 and P60 (adulthood) by measuring specific binding of [3H]MK-801 on brain membrane preparations. In addition, allosteric modulation of NMDA receptors by exogenous glutamate and glycine was investigated. Seizures from P5 to P7 led to a 22% increase in the density of [3H]MK-801 binding sites measured at P15, but did ...
Pharmacology & Therapeutics, 1996
Adenosine participates in the physiology of central and peripheral tissues through several subtyp... more Adenosine participates in the physiology of central and peripheral tissues through several subtypes of G-protein-coupled receptors. Positively linked to adenylate cyclase, A1 receptors have been subdivided into AL, and AZ,, sites on the basis of their molecular, biochemical and pharmacological properties. They exhibit selective distribution, and are implicated in the modulation of psychomotor activity, circulation, respiration, and metabolism. Recent data support the evidence that adenosine A, receptor properties may prove useful in future drug development, and selective manipulation of receptor-associated biologic effects might be relevant in the treatment of various disorders, including psychiatric diseases, hypoxia/ischemia, inflammation or erythrocytosis.
Epilepsy Research, 1999
In order to assess long-lasting consequences of recurrent seizures during development, the effect... more In order to assess long-lasting consequences of recurrent seizures during development, the effects of repeated seizures in developing rats were investigated on brain adenosine A1 and A2A receptors. The characteristics of A1 and A2A receptors were analyzed by measuring the binding of the selective agonists [3H]CHA (N6-cyclohexyladenosine) and [3H]CGS 21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine), respectively, on cerebral membrane preparations, whereas receptor coupling to G-proteins was examined by using a GTP analogue (Gpp(NH)p; guanylyl-5'-imidodiphosphate). Seizures were induced by bicuculline once a day at two different developmental stages: either from postnatal day 5 to postnatal day 7 (P5-P7) or from P15 to P17. Adenosine receptors were then studied at P15, P25 and P60. P5-P7 seizures led to an increase in A1 receptor density at P60 and to a decrease in their coupling to G-proteins at P15, but they did not affect A2A receptors. P15-P17 seizures decreased the coupling of A1 receptors to G-proteins at P25 and P60, reduced the density of A2A receptors at P25 and increased their affinity at P60. These results depict a persistent sensitivity of both A1 and A2A brain adenosine receptors to repeated seizures, with selective receptor alterations according to the cerebral maturational stage when seizures occur. In respect to the neuromodulatory and anticonvulsant properties of adenosine, such changes might be implicated in long-term functional brain reorganization after early seizures and future susceptibility to convulsive disorders.
Developmental Brain Research, 1996
The neuromodulator adenosine is acting through specific receptors, A l and A2, coupled to their e... more The neuromodulator adenosine is acting through specific receptors, A l and A2, coupled to their effector systems via G-proteins. The regulatory effects of adenosine on locomotor activity have been attributed to an interaction with A 2 striatal receptors. The postnatal development of adenosine Aza receptors was analysed in rat striatal membranes and by quantitative autoradiography in brain sections using [3H]CGS 21680 as specific probe. At the concentration of radioligand used (5 nM), A2, sites were concentrated in the striatum at all ages, with minor developmental alterations in the expression pattern within the striatal regions. In membrane preparations, Scatchard analysis showed that the density of CGS 21680 binding sites was low at birth, around 3% of the adult value, and then increased, mostly between birth and 5 days and then from 15 days to adulthood. Concomitantly, the receptor affinity decreased sharply during brain development, K d values varying from 2 to 15.5 nM. The addition of a GTP analogue, guanylyl-5'-imidodiphosphate (Gpp(NH)p, 10 /xM), to the assay medium reduced significantly the receptor affinity throughout the postnatal development, reflecting a coupling to G-proteins at all ages, but it also suggested a weaker association at birth. These data show that the developmental properties of A 2a receptors contrast with those of A 1 receptors, and emphasize the role played by adenosine through its A 2 receptors in the maturation of striatum-related cerebral pathways.
Brain Research, 1998
To assess long-term metabolic consequences of recurrent ictal events arising during development, ... more To assess long-term metabolic consequences of recurrent ictal events arising during development, seizures were repeatedly generated in rats at different stages of cerebral maturation. Seizures were induced by i.p. injections of bicuculline for three consecutive days, starting from postnatal day 5 (P5), when the brain is very immature, or from P15, a period at which the brain is more structurally organized. Local cerebral metabolic rates for glucose were measured in 74 structures at P15, P25 and in adults (P60), by the autoradiographic method using 2-D-[14C]deoxyglucose. Repeated seizures in P5 to P7 pups led to a reduction (16-34%) of glucose consumption at P15, mainly significant in sensory, motor and functionally non-specific areas as well as in cerebellar nuclei. Selective decreases in metabolic activity were still recorded in adults, mostly in auditory system (20%) and cerebellar nuclei (27%). Seizures generated from P15 to P17 led to an overall mortality rate of 62% (versus 22% at P5 to P7). Surviving animals exhibited reduced metabolic rates for glucose (by 7-27%) at P25, significant in 23 structures, and depicting pronounced changes in limbic, hypothalamic, sensory and white matter areas, whereas brain functional activity finally returned to basal values at P60. Therefore, while younger rats seemed to better tolerate repeated bicuculline-induced seizures than older animals, the reverse was true for long-term metabolic effects, and the more immature the brain when seizures arise, the more persistent the functional consequences.
Circulation Et Metabolisme Du Cerveau, 1995
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 1999
Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excito... more Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excitotoxicity and seizure mediation. A previous study has shown that an acute episode of seizures for 30 min in rats altered NMDA receptor characteristics, mainly in the very immature animal. In order to assess whether receptor modifications may also account for long-lasting cerebral disabilities, medium- and long-term consequences of repeated seizures in developing rats on brain NMDA receptor properties were investigated. Seizures were induced once a day for 3 consecutive days, either from post-natal day 5 (P5) to P7 or from P15 to P17. NMDA receptors were then analysed at P15, P25 and P60 (adulthood) by measuring specific binding of [3H]MK-801 on brain membrane preparations. In addition, allosteric modulation of NMDA receptors by exogenous glutamate and glycine was investigated. Seizures from P5 to P7 led to a 22% increase in the density of [3H]MK-801 binding sites measured at P15, but did ...
Pharmacology & Therapeutics, 1996
Adenosine participates in the physiology of central and peripheral tissues through several subtyp... more Adenosine participates in the physiology of central and peripheral tissues through several subtypes of G-protein-coupled receptors. Positively linked to adenylate cyclase, A1 receptors have been subdivided into AL, and AZ,, sites on the basis of their molecular, biochemical and pharmacological properties. They exhibit selective distribution, and are implicated in the modulation of psychomotor activity, circulation, respiration, and metabolism. Recent data support the evidence that adenosine A, receptor properties may prove useful in future drug development, and selective manipulation of receptor-associated biologic effects might be relevant in the treatment of various disorders, including psychiatric diseases, hypoxia/ischemia, inflammation or erythrocytosis.
Epilepsy Research, 1999
In order to assess long-lasting consequences of recurrent seizures during development, the effect... more In order to assess long-lasting consequences of recurrent seizures during development, the effects of repeated seizures in developing rats were investigated on brain adenosine A1 and A2A receptors. The characteristics of A1 and A2A receptors were analyzed by measuring the binding of the selective agonists [3H]CHA (N6-cyclohexyladenosine) and [3H]CGS 21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine), respectively, on cerebral membrane preparations, whereas receptor coupling to G-proteins was examined by using a GTP analogue (Gpp(NH)p; guanylyl-5'-imidodiphosphate). Seizures were induced by bicuculline once a day at two different developmental stages: either from postnatal day 5 to postnatal day 7 (P5-P7) or from P15 to P17. Adenosine receptors were then studied at P15, P25 and P60. P5-P7 seizures led to an increase in A1 receptor density at P60 and to a decrease in their coupling to G-proteins at P15, but they did not affect A2A receptors. P15-P17 seizures decreased the coupling of A1 receptors to G-proteins at P25 and P60, reduced the density of A2A receptors at P25 and increased their affinity at P60. These results depict a persistent sensitivity of both A1 and A2A brain adenosine receptors to repeated seizures, with selective receptor alterations according to the cerebral maturational stage when seizures occur. In respect to the neuromodulatory and anticonvulsant properties of adenosine, such changes might be implicated in long-term functional brain reorganization after early seizures and future susceptibility to convulsive disorders.
Developmental Brain Research, 1996
The neuromodulator adenosine is acting through specific receptors, A l and A2, coupled to their e... more The neuromodulator adenosine is acting through specific receptors, A l and A2, coupled to their effector systems via G-proteins. The regulatory effects of adenosine on locomotor activity have been attributed to an interaction with A 2 striatal receptors. The postnatal development of adenosine Aza receptors was analysed in rat striatal membranes and by quantitative autoradiography in brain sections using [3H]CGS 21680 as specific probe. At the concentration of radioligand used (5 nM), A2, sites were concentrated in the striatum at all ages, with minor developmental alterations in the expression pattern within the striatal regions. In membrane preparations, Scatchard analysis showed that the density of CGS 21680 binding sites was low at birth, around 3% of the adult value, and then increased, mostly between birth and 5 days and then from 15 days to adulthood. Concomitantly, the receptor affinity decreased sharply during brain development, K d values varying from 2 to 15.5 nM. The addition of a GTP analogue, guanylyl-5'-imidodiphosphate (Gpp(NH)p, 10 /xM), to the assay medium reduced significantly the receptor affinity throughout the postnatal development, reflecting a coupling to G-proteins at all ages, but it also suggested a weaker association at birth. These data show that the developmental properties of A 2a receptors contrast with those of A 1 receptors, and emphasize the role played by adenosine through its A 2 receptors in the maturation of striatum-related cerebral pathways.
Brain Research, 1998
To assess long-term metabolic consequences of recurrent ictal events arising during development, ... more To assess long-term metabolic consequences of recurrent ictal events arising during development, seizures were repeatedly generated in rats at different stages of cerebral maturation. Seizures were induced by i.p. injections of bicuculline for three consecutive days, starting from postnatal day 5 (P5), when the brain is very immature, or from P15, a period at which the brain is more structurally organized. Local cerebral metabolic rates for glucose were measured in 74 structures at P15, P25 and in adults (P60), by the autoradiographic method using 2-D-[14C]deoxyglucose. Repeated seizures in P5 to P7 pups led to a reduction (16-34%) of glucose consumption at P15, mainly significant in sensory, motor and functionally non-specific areas as well as in cerebellar nuclei. Selective decreases in metabolic activity were still recorded in adults, mostly in auditory system (20%) and cerebellar nuclei (27%). Seizures generated from P15 to P17 led to an overall mortality rate of 62% (versus 22% at P5 to P7). Surviving animals exhibited reduced metabolic rates for glucose (by 7-27%) at P25, significant in 23 structures, and depicting pronounced changes in limbic, hypothalamic, sensory and white matter areas, whereas brain functional activity finally returned to basal values at P60. Therefore, while younger rats seemed to better tolerate repeated bicuculline-induced seizures than older animals, the reverse was true for long-term metabolic effects, and the more immature the brain when seizures arise, the more persistent the functional consequences.