ACETYLCHOLINE SYNTHESIS AND RELEASE FOLLOWING CONTINUOUS INTRACEREBRAL ADMINISTRATION OF NGF IN ADULT AND AGED FISCHER-344 RATS

NGF promotes the survival and enhances the neurotransmitter phenotype of basal forebrain and striatal cholinergic neurons in brain of rat. T he objective of the present study was to determine whether stimulation s of the cholinergic neuronal markers ChAT and high-affinity choline u ptake are reflected in enhanced synthesis and release of ACh. Enhancem ent of ACh release in brain of adult and aged rats could result in inc reased cholinergic neurotransmission, and altered animal behavior. NGF (1.2 mug/d) was administered intracerebroventricularly for 2 weeks by osmotic minipump to male Fischer-344 rats aged 4 and 24 months. Choli nergic neuronal functional parameters were measured in frontal cortex, hippocampus, and striatum. In young adult rats, increased ChAT and ch oline uptake activities were accompanied by enhanced ACh synthesis, ba sal and depolarization-induced release of both endogenous and newly sy nthesized transmitter, with the largest effect generally being observe d in striatum. In aged animals, the responses to NGF were less uniform . Whereas the pattern for changes in ChAT activity was similar to that seen in younger animals, choline uptake activity was increased only i n frontal cortex and striatum. Coincidentally, ACh synthesis was also increased only in these two brain regions. ACh content of synaptosomes was not affected by age or NGF treatment, and the ACh levels in micro waved samples of striatum and basal forebrain were not affected by NGF treatment. However, profound deficits in both basal and evoked releas e of newly synthesized ACh were observed in the aged rats. NGF treatme nt had no significant effect on the basal release of newly synthesized ACh in aged rats. Treatment enhanced depolarization-induced release o f both newly synthesized and endogenous transmitter in hippocampus and striatum, but not in frontal cortex. Although this release was increa sed up to 50% compared to aged-matched controls, the levels achieved w ere still only 40% of those observed in the normal adult controls.