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.