Behavioral and neurobiological alterations induced by the immunotoxin 192-IgG-saporin: cholinergic and non-cholinergic effects following i.c.v. injection.
192-IgG-Saporin is an anti-neuronal immunotoxin that combines the 192 monoclonal antibody to the p75 neurotrophin receptor found on terminals and cell bodies of neurons in the cholinergic basal forebrain with the ribosome-inactivating protein saporin. Bilateral intraventricular injection of the 192-saporin produced a variety of dose-related behavioral, neurochemical, and histological alterations in adult male rats. While both the 2 micrograms and 4 micrograms dose produced comparable cholinergic hypofunction only the high dose produced behavioral changes. Behavioral deficits induced by the 4 micrograms dose of 192-saporin induced alterations in rotorod performance and reactivity on the hot-plate which recovered over 8 weeks. In addition, the 4 micrograms dose produced a persistent impairment in the acquisition and performance of standard Morris water maze task as well as a cued version of the task. The neurobiological alterations induced by 192-saporin involved both cholinergic and non-cholinergic systems. Both doses of 192-saporin produced a 60-80% decrease in high affinity choline transport in the hippocampus and cortex without altering this parameter in the striatum. In addition, there was a significant dose-related decrease of norepinephrine in the hippocampus in the high dose group. 192-saporin did not alter the content of dopamine, serotonin, or their metabolites in any region examined. 192-saporin also produced a loss of Purkinje cells in the cerebellum. This cell type also expresses the p75 receptor and appears to be a target for intraventricular 192-saporin. This complex interplay of factors makes the i.c.v. model of 192-saporin very problematic for studying the functional properties of the cholinergic basal forebrain. However, recent data suggest that injection of 192-saporin directly into components of the cholinergic basal forebrain can be used to further elaborate the function of this brain system and to model disorders of cholinergic hypofunction such as Alzheimer's disease.
Walsh
T J
TJ
Department of Psychology, Rutgers University, New Brunswick, NJ 08903, USA.
Kelly
R M
RM
Dougherty
K D
KD
Stackman
R W
RW
Wiley
R G
RG
Kutscher
C L
CL
D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000648:ultrastructure; D000922:Immunotoxins / Q000494:pharmacology*; D007278:Injections, Spinal; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013997:Time Factors
D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins