Systemic administration of the benzodiazepine receptor partial inverse agonist FG-7142 disrupts corticolimbic network interactions

TY - JOUR

T1 - Systemic administration of the benzodiazepine receptor partial inverse agonist FG-7142 disrupts corticolimbic network interactions

AU - Stevenson, Carl W.

AU - Halliday, David M.

AU - Marsden, Charles A.

AU - Mason, Rob

PY - 2007/8

Y1 - 2007/8

N2 - The medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) coordinate various stress responses. Although the effects of stressors on mPFC and BLA activity have been previously examined, it remains unclear to what extent stressors affect functional interactions between these regions. In vivo electrophysiology in the anesthetized rat was used to examine mPFC and BLA activity simultaneously in response to FG-7142, a benzodiazepine receptor partial inverse agonist that mimics various stress responses, in an attempt to model the effects of stressors on corticolimbic functional connectivity. Extracellular unit and local field potential (LFP) recordings, using multielectrode arrays positioned in mPFC and BLA, were conducted under basal conditions and in response to systemic FG-7142 administration. This drug increased mPFC and BLA unit firing at the lowest dose tested, whereas higher doses of FG-7142 decreased various burst firing parameters in both regions. Moreover, LFP power was attenuated at lower (<1 Hz) and potentiated at higher frequencies in mPFC (1-12 Hz) and BLA (4-8 Hz). Interestingly, FG-7142 diminished synchronized unit firing, both within and between mPFC and BLA. Finally, FG-7142 decreased LFP synchronization between these regions. In a separate group of animals, pretreatment with the selective benzodiazepine receptor antagonist flumazenil blocked the changes in burst firing, LFP power and synchronized activity induced by FG-7142, confirming direct benzodiazepine receptor-mediated effects. These results indicate that FG-7142 disrupts corticolimbic network interactions via benzodiazepine receptor partial inverse agonism. Perturbation of mPFC-BLA functional connectivity induced by FG-7142 may provide a useful model of corticolimbic dysfunction induced by stressors.

AB - The medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) coordinate various stress responses. Although the effects of stressors on mPFC and BLA activity have been previously examined, it remains unclear to what extent stressors affect functional interactions between these regions. In vivo electrophysiology in the anesthetized rat was used to examine mPFC and BLA activity simultaneously in response to FG-7142, a benzodiazepine receptor partial inverse agonist that mimics various stress responses, in an attempt to model the effects of stressors on corticolimbic functional connectivity. Extracellular unit and local field potential (LFP) recordings, using multielectrode arrays positioned in mPFC and BLA, were conducted under basal conditions and in response to systemic FG-7142 administration. This drug increased mPFC and BLA unit firing at the lowest dose tested, whereas higher doses of FG-7142 decreased various burst firing parameters in both regions. Moreover, LFP power was attenuated at lower (<1 Hz) and potentiated at higher frequencies in mPFC (1-12 Hz) and BLA (4-8 Hz). Interestingly, FG-7142 diminished synchronized unit firing, both within and between mPFC and BLA. Finally, FG-7142 decreased LFP synchronization between these regions. In a separate group of animals, pretreatment with the selective benzodiazepine receptor antagonist flumazenil blocked the changes in burst firing, LFP power and synchronized activity induced by FG-7142, confirming direct benzodiazepine receptor-mediated effects. These results indicate that FG-7142 disrupts corticolimbic network interactions via benzodiazepine receptor partial inverse agonism. Perturbation of mPFC-BLA functional connectivity induced by FG-7142 may provide a useful model of corticolimbic dysfunction induced by stressors.

KW - amygdala

KW - coherence

KW - local field potential

KW - prefrontal cortex

KW - synchronization

KW - MEDIAL PREFRONTAL CORTEX

KW - BASOLATERAL AMYGDALOID COMPLEX

KW - FEAR-POTENTIATED STARTLE

KW - SPATIAL WORKING-MEMORY

KW - RAT FRONTAL-CORTEX

KW - CONDITIONED FEAR

KW - IN-VIVO

KW - FUNCTIONAL CONNECTIVITY

KW - GABA(A) RECEPTOR

KW - NERVOUS-SYSTEM

U2 - 10.1002/syn.20414

DO - 10.1002/syn.20414

M3 - Literature review

VL - 61

SP - 646

EP - 663

JO - Synapse

JF - Synapse

IS - 8

ER -