Abstract
Regional brain distribution and metabolism of neurotransmitters and their response to drug treatment are fundamentally important for understanding the central effects of neuroactive substances. We used matrix-assisted laser desorption/ionization mass spectrometry imaging in combination with multivariate analysis to visualize in anatomical detail metabolic effects of aging and tacrine-mediated acetylcholinesterase inhibition on comprehensive neurotransmitter systems in multiple mouse brain regions of 12-week-old and 14-month-old mice. We detected age-related increases in 3,4-dihydroxyphenylacetaldehyde and histamine, indicating oxidative stress and aging deficits in astrocytes. Tacrine had a significant impact on the metabolism of neurotransmitters in both age groups; predominantly, there was an increased norepinephrine turnover throughout the brain and decreased 3-methoxy tyramine, a marker for dopamine release, in the striatum. The striatal levels of histamine were only elevated after tacrine administration in the older animals. Our results demonstrated that tacrine is a multitarget and region-specific neuroactive agent, inducing age-specific responses. Although well-studied, the complete mechanisms of the action of tacrine are not fully understood, and the current findings reveal features that may help explain its treatment-related effectiveness and central side effects.
Highlights
Progressive failure of defined neurotransmitter systems is involved in major neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease.[1]
Tandem MS (MS/MS) spectra were acquired from tissue sections and compared with authentic standards to corroborate the identification of DA, NE, 3,4-dihydroxyphenylglycol (DOPEG), 3-methoxy tyramine (3-MT), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) (Figure S2)
High NE levels were detected in the locus coeruleus (LC), the major NE-providing nucleus to the forebrain,[34] bed nucleus of the stria terminalis (BNST), and Hyp, but lower levels were found in the Hip, Th, and cortex regions (Figure S3d)
Summary
Progressive failure of defined neurotransmitter systems is involved in major neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease.[1]. Treatment through acetylcholinesterase (AChE) inhibition is one of only a few therapies with proven clinical utility for the treatment of dementia and AD.[9] Targeting the cholinergic system can in turn modulate monoaminergic systems through nicotinic and muscarinic cholinergic receptors located on monoaminergic neurons.[10−12] manipulation of the cholinergic system may influence the signaling of all other monoaminergic systems, and age-induced changes in neurotransmitter systems may affect the response to such pharmacological interventions.[13]. We recently showed that normal aging reduces the responsivity of the cholinergic system to the AChE inhibitor tacrine in the retrosplenial cortex (RSC).[14] In addition to being an AChE inhibitor, tacrine has been shown to have other effects on the cholinergic system, such as increasing the synthesis and release of acetylcholine (ACh) and regulating the muscarinic and nicotinic receptors.[15] tacrine has been reported to interact with the monoaminergic systems. Age-related alterations in the brain regional content of specific neurotransmitters are an additional factor that complicates the responsiveness to tacrine treatment.[14,23]
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