Cholinergic system

ACh

Cholinergic system uses acetylcholine (ACh) as the neurotransmitter. Parasympathetic nervous system is almost exclusively cholinergic. Pre- and postganglionic neurons of the sympathetic nervous system are also cholinergic.

Cholinergic system includes the muscarinic and nicotinid acetylcholine receptors (mAChR and nAChR), vesicular acetylcholine transporter (VAChT), acetylcholinesterase (AChE), and choline acetyltransferase (ChAT).

Central nervous system

In the CNS the major cholinergic projection systems are (Roy et al., 2016):

  1. the nucleus basalis of Meynert, supplying cholinergic projections throughout the cerebral cortex and hippocampus
  2. pedunculopontine nucleus pars compacta, projecting to the forebrain and subcortical structures such as thalamus
  3. striatal cholinergic neurons

Muscarinic acetylcholine receptors (mAChRs) are highly expressed in caudate nucleus and nucleus accumbens, less in somatosensory, primary motor, and temporal cortices, and very little in the cerebellar cortex (Roy et al., 2016).

Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the entorhinal, temporal, and primary motor cortices, and in the hippocampus and thalamus (Roy et al., 2016).

Dementia is associated with loss of cholinergic neurotransmission; therefore AChE inhibitors (donepezil, rivastigmine) have been used as treatment for the dementia symptoms in AD and PD. AChE inhibitors have been labeled with positron emitting isotopes to be used in PET imaging of dementia as markers of the integrity of the cortical cholinergic system; these tracers include [11C]MP4A and [11C]PMP. The effect of AChE inhibitors can be studied using FDG. Cholinergic perturbation is also apparent in traumatic brain injury (TBI), which can be seen as decreased AChE activity using [11C]MP4A PET (Östberg et al., 2011); in TBI patients with treatment response to rivastigmine the baseline AChE activity is lower than in non-responders (Östberg et al., 2018). [11C]Donepezil is a reversible antagonist radioligand of AChE (inhibitor, not a substrate), and can be used for imaging cholinergic mechanisms also in peripheral organs (Gjerløff et al., 2014).

nAChRs have been targeted with [11C]nicotine, α4β2-nAChRs specifically with [18F]FA, [18F]AZAN, and [18F]flubatine, and α7-nAChRs with [11C]CHIBA1001 and [18F]ASEM. PET tracers for mAChRs include [11C]NMPB. Also PET tracers for VAChT have been introduced, including [18F]FEOBV.

Components of cholinergic system are upregulated in active inflammatory cells, which use ACh as a paracrine signalling molecule (Kawashima et al., 2012; Fujii et al., 2017) and therefore the tracers of the cholinergic system may be useful in research and diagnosis of infection and inflammation and cancer (Stokholm et al., 2016; Jørgensen et al., 2017; Boswijk et al., 2017).

Nicotine increases the release of many neurotransmitters, including ACh. It has neuroprotective actions, possibly via α7-nAChRs. Continuous exposure to nicotine causes upregulation of nAChRs in smokers.


See also:



References:

Eisenmenger LB, Huo EJ, Hoffman JM, Minoshima S, Matesan MC, Lewis DH, Lopresti BJ, Mathis CA, Okonkwo DO, Mountz JM. Advances in PET imaging of degenerative, cerebrovascular, and traumatic causes of dementia. Semin Nucl Med. 2016; 46(1): 57-87.

Gjerløff T, Jakobsen S, Nahimi A, Munk OL, Bender D, Alstrup AKO, Vase KH, Hansen SB, Brooks DJ, Borghammer P. In vivo imaging of human acetylcholinesterase density in peripheral organs using 11C-donepezil: dosimetry, biodistribution, and kinetic analyses. J Nucl Med. 2014; 55: 1818-1824. doi: 10.2967/jnumed.114.143859.

Maziere M. Cholinergic neurotransmission studied in vivo using positron emission tomography or single photon emission computerized tomography. Pharmac Ther. 1995; 66: 83-101.

Roy R, Niccolini F, Pagano G, Politis M. Cholinergic imaging in dementia spectrum disorders. Eur J Nucl Med Mol Imaging 2016; 43: 1376-1386. doi: 10.1007/s00259-016-3349-x.



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Created at: 2016-05-28
Updated at: 2018-01-12
Written by: Vesa Oikonen