Alterations and interactions of subcortical modulatory systems in Alzheimer's disease

Mirjana Babić Leko, Patrick R. Hof, Goran Šimić

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

15 Scopus citations


The pathogenesis of Alzheimer's disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression of AD. In physiological conditions, all neurotransmitter systems function in concert and are interdependent at both the neuroanatomical and molecular levels. Through their early involvement in AD, cognitive and behavioral abilities that rely on their interactions also become disrupted. Considering that serotonin (5HT) regulates the release of noradrenaline (NA), dopamine (DA) and acetylcholine (ACh), any alteration in 5HT levels leads to disturbance of NA, DA, and ACh homeostasis in the brain. One of the earliest pathological changes during the prodromal phase of AD is a decrease of serotonergic transmission throughout the brain, with serotonergic receptors being also affected. Additionally, serotonergic and noradrenergic as well as serotonergic and dopaminergic nuclei are reciprocally interconnected. As the serotonergic dorsal raphe nucleus (DRN) is affected by pathological changes early in AD, and the noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental area (VTA) exhibit AD-related pathological changes, their connectivity also becomes altered in AD. Such disrupted interactions among neurotransmitter systems in AD can be used in the development of multi-target drugs. Some of the potential AD therapeutics (such as ASS234, RS67333, tropisetron) target multiple neurotransmitter systems to achieve the best possible improvement of cognitive and behavioral deficits observed in AD. Here, we review how serotonergic system interacts with other subcortical modulatory systems (noradrenergic, dopaminergic, cholinergic, and opioid systems) during AD.

Original languageEnglish
Title of host publication5-HT Interaction with Other Neurotransmitters
Subtitle of host publicationExperimental Evidence and Therapeutic Relevance - Part B
EditorsGiuseppe Di Giovanni, Giuseppe Di Giovanni, Philippe De Deurwaerdere
PublisherElsevier B.V.
Number of pages43
ISBN (Print)9780444642585
StatePublished - Jan 2021

Publication series

NameProgress in Brain Research
ISSN (Print)0079-6123
ISSN (Electronic)1875-7855


  • 5-Hydroxytryptamine (serotonin)
  • Acetylcholine
  • Alzheimer's disease
  • Dopamine
  • Interaction
  • Noradrenaline
  • Opioids


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