Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.
BACKGROUND
Basal forebrain cortical cholinergic projections have been hypothesized to mediate the enhanced cardiovascular defensive response initiated by the putative anxiogenic benzodiazepine receptor (BZR) partial inverse agonist FG 7142 (FG). The present study was designed to test the broader hypothesis that the integrity of this cholinergic projection is required for the mediation of the bidirectional modulatory effects of BZR agonists and inverse agonists on anxiety and associated cardiovascular reactivity.


OBJECTIVE
The interactions between the effects of 192 IgG-saporin-induced lesions of basal forebrain corticopetal cholinergic neurons and of the BZR agonist chlordiazepoxide (CDP) and FG on the performance of rats tested in a conditioned suppression paradigm and on associated cardiovascular reactivity were assessed.


METHODS
Lesioned and control animals were equipped with a telemetric device to record heart rate, trained in an operant lever task, and then tested for suppression of responding during presentation of a conditioned stimulus (CS) and a general contextual cue that was previously associated with shock. FG, CDP (8 mg/kg) and vehicle were administered IP in separate extinction sessions.


RESULTS
In control animals, operant responding was suppressed during presentation of the CS and contextual cue. Administration of FG enhanced this suppression, while CDP attenuated it. Lesions attenuated overall response suppression as well as the modulatory effects of BZR ligands on responding during presentation of the contextual stimulus. Likewise, lesions attenuated the cardioacceleratory response to the contextual stimulus and the ability of the BZR ligands to modulate this response.


CONCLUSIONS
The behavioral and autonomic responses to anxiety-related stimuli, as well as the modulatory effects of BZR ligands, are mediated in part via cortical cholinergic inputs.
Stowell
J R
JR
Department of Psychology, The Ohio State University, Columbus 43210, USA.
Berntson
G G
GG
Sarter
M
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D014151:Anti-Anxiety Agents; D002243:Carbolines; D018756:GABA Antagonists; C035874:FG 7142; D002707:Chlordiazepoxide