Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release
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Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release. / Bortz, D M; Mikkelsen, J D; Bruno, J P.
In: Neuroscience, Vol. 255, 2013, p. 55-67.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release
AU - Bortz, D M
AU - Mikkelsen, J D
AU - Bruno, J P
N1 - Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
PY - 2013
Y1 - 2013
N2 - The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels. The lower dose (1.0μg in 0.4μL) evoked a rapid rise (∼1.0s) in glutamate (1.41±0.30μM above baseline). The higher dose (5.0μg) produced a similarly rapid, yet larger increase (3.51±0.36μM above baseline). After each dose, the glutamate signal was cleared to basal levels within 7-18s. SSR180711-evoked glutamate was mediated by the α7 nAChR as co-infusion of the selective α7 nAChR antagonist α-bungarotoxin (10.0μM)+SSR1808711 (5.0μg) reduced the effect of 5.0μg alone by 87% (2.62 vs. 0.35μM). Finally, the clearance of the SSR180711 (5.0μg)-evoked glutamate was bidirectionally affected by drugs that inhibited (threo-beta-benzyl-oxy-aspartate (TβOA), 100.0μM) or facilitated (ceftriaxalone, 200mg/kg, i.p.) excitatory amino acid transporters. TβOA slowed both the clearance (s) and rate of clearance (μM/s) by 10-fold, particularly at the mid-late stages of the return to baseline. Ceftriaxone reduced the magnitude of the SSR180711-evoked increase by 65%. These results demonstrate that pharmacological stimulation of α7 nAChRs within the prefrontal cortex is sufficient to evoke rapid yet transient increases in glutamate levels. Such increases may underlie the cognition-enhancing effects of the drug in animals; further justifying studies on the use of α7 nAChR-positive modulators in treating cognition-impairing disorders in humans.
AB - The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels. The lower dose (1.0μg in 0.4μL) evoked a rapid rise (∼1.0s) in glutamate (1.41±0.30μM above baseline). The higher dose (5.0μg) produced a similarly rapid, yet larger increase (3.51±0.36μM above baseline). After each dose, the glutamate signal was cleared to basal levels within 7-18s. SSR180711-evoked glutamate was mediated by the α7 nAChR as co-infusion of the selective α7 nAChR antagonist α-bungarotoxin (10.0μM)+SSR1808711 (5.0μg) reduced the effect of 5.0μg alone by 87% (2.62 vs. 0.35μM). Finally, the clearance of the SSR180711 (5.0μg)-evoked glutamate was bidirectionally affected by drugs that inhibited (threo-beta-benzyl-oxy-aspartate (TβOA), 100.0μM) or facilitated (ceftriaxalone, 200mg/kg, i.p.) excitatory amino acid transporters. TβOA slowed both the clearance (s) and rate of clearance (μM/s) by 10-fold, particularly at the mid-late stages of the return to baseline. Ceftriaxone reduced the magnitude of the SSR180711-evoked increase by 65%. These results demonstrate that pharmacological stimulation of α7 nAChRs within the prefrontal cortex is sufficient to evoke rapid yet transient increases in glutamate levels. Such increases may underlie the cognition-enhancing effects of the drug in animals; further justifying studies on the use of α7 nAChR-positive modulators in treating cognition-impairing disorders in humans.
KW - Animals
KW - Bridged Bicyclo Compounds, Heterocyclic/pharmacology
KW - Glutamic Acid/metabolism
KW - Nicotinic Agonists/pharmacology
KW - Prefrontal Cortex/drug effects
KW - Rats
KW - Rats, Wistar
KW - Receptors, Nicotinic/metabolism
U2 - 10.1016/j.neuroscience.2013.09.047
DO - 10.1016/j.neuroscience.2013.09.047
M3 - Journal article
C2 - 24095692
VL - 255
SP - 55
EP - 67
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -
ID: 204115397