Cognitive implications of age-related changes in serotonergic and nicotinic cholinergic neurotransmission.

摘要

In an effort to further elucidate the neural substrates responsible for age-related cognitive decline, the integrity of the serotonergic and nicotinic cholinergic neurotransmitter systems was assessed in the prefrontal cortex (PFC), medial temporal lobe cortex (MTL), claustrum, amygdala, and hippocampus of behaviorally characterized young (4--13 year old) and old (21--31 year old) rhesus monkeys. Levels of the 5-HT1A and 5-HT2A receptors as well as the serotonin transporter (5-HTU) were assessed using [3H]-8-hydroxy-2(diN-propylamino)tetralin ([3H] DPAT), (+/-)-1-1(2,5,dimethoxy-4-[125]iodophenyl)-2-aminopropane ([ 125I] DOI), and [3H] citalopram, respectively. Levels of the nicotinic alpha-bungarotoxin sensitive receptors were assessed using [125I] alpha-bungarotoxin ([125I] BTX) while alpha-bungarotoxin insensitive receptors were assessed using [125I] (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([125I] IPH) and, in the hippocampus and MTL only, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine ([125I] A-85380). Age-related changes in the binding of all six ligands were observed but the pattern varied according to the region assessed and ligand in question. Binding of [3H] citalopram and [ 125I] IPH declined significantly in every region assessed while age-related decrements in the binding of [125I] DOI and [3H] DPAT were concentrated in the PFC and hippocampus with the binding of [ 125I] DOI also declining significantly in the MTL. The binding of [125I] BTX declined significantly with age in discrete regions of the hippocampus and amygdala but increased in the middle and deep strata throughout the PFC while age-related decrements in the binding of [ 125I] A-85380 were observed in specific subdivisions of the MTL but not the hippocampus. Several correlations between cognitive performance and the binding of serotonergic and nicotinic ligands were noted. Of particular interest were correlations between the binding of [125I] DOI and [125I] BTX within the PFC with rule learning, [ 125I] BTX and [3H] DPAT in the hippocampus with short-term memory, [125I] BTX in the PFC and [3H] DPAT in the hippocampus with working memory, [3H] DPAT and [ 125I] BTX in the hippocampus with executive function, and [ 125I] IPH in the MTL and hippocampus with attention. The results of this study indicate pervasive, age-related alterations in serotonergic and nicotinic receptors, especially within the PFC and hippocampus, where such changes may contribute to age-associated cognitive impairments.