Long-term exposure to high levels of corticosterone aggravates AF64A-induced cholinergic hypofunction in rat hippocampus in vivo.
Male Sprague-Dawley rats were bilaterally adrenalectomized and corticosterone (CORT) was substituted as subcutaneous pellets in two groups of animals: low- (L-CORT: 1 x 25 mg pellet) or high-level of CORT (H-CORT: 4 x 100 mg pellet). Between 14 and 19 days after CORT substitution, ethylcholine aziridinium (AF64A) was intracerebroventricularly (i.c.v.) injected in the CORT long-term exposed rats and the dose- and time-dependent effect of this treatment was measured on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in hippocampus and septum and on serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and noradrenaline (NA) levels in hippocampus. Rats were killed at 2, 4, 7 and 14 days after AF64A treatment. Starting 4 days after the i.c.v. administration of 0.5 or 1.0 nmol of AF64A, an aggravation of the reduction of ChAT activity was measured in the hippocampus of the H-CORT animals compared to the L-CORT ones. In the septum of the H-CORT rats, the activity of ChAT increased within the first week after the infusion of the toxin, while no significant effect was observed in the L-CORT group. As we observed with ChAT, AF64A induced a severe inhibition of AChE activity in the hippocampus of the H-CORT rats compared to the L-CORT ones. In the septum, an increase of AChE activity was observed in both groups of CORT-exposed animals. In the hippocampus of H-CORT animals, the exacerbation of the inhibition of ChAT and AChE activity was accompanied by a parallel decrease in the content of 5-HT and 5-HIAA starting 4 days after AF64A injections. Finally, NA content in hippocampus was not affected by the toxin in the CORT-substituted animals. These data demonstrate that: (1) long-term exposure to supraphysiological levels of CORT enhances the cholinodisruption induced in hippocampus by AF64A, at doses of 0.5 and 1.0 nmol/side; (2) high circulating plasma CORT concentrations impair hippocampal cholinergic neuronal capacity to recover from damage; and (3) the degree of inhibition of the serotoninergic system is augmented in H-CORT animals, most probably due to an adaptation of the serotoninergic neurons to the larger withdrawal of cholinergic function observed in this group.
Amoroso
D
D
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153.
Kindel
G
G
Wülfert
E
E
Hanin
I
I
D000110:Acetylcholinesterase / Q000378:metabolism*; D000315:Adrenalectomy; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007263:Infusions, Parenteral; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013238:Stereotaxic Techniques; D013997:Time Factors
D001388:Aziridines; D004343:Drug Implants; D009466:Neuromuscular Blocking Agents; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline; D003345:Corticosterone; D006854:Hydrocortisone; D009638:Norepinephrine