Cholinergic interneurons

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Berlanga, M.L., Olsen, C.M., Chen, V. et al. Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine. Neuroscience. 120 1149, 2003. 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

As dopamine deficiency of the nigrostriatal tract, resulting in an overactivity of cholinergic interneurons, is considered to be the fundamental pathophysiological mechanism for Parkinson s disease two approaches for pharmacological intervention seem rational. 

The efficacy of anticholinergic drugs in parkinsonism is likely due to the ability to block muscarinic receptors in the striatum. In the absence of the inhibitory action of dopamine, the actions of the intrastriatal cholinergic interneurons are unopposed, yielding enhanced stimulation of muscarinic receptors. Blockade of these receptors reduces striatal activity. The muscarinic antagonists exert only modest antiparkinsonian actions and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy. 

The brain stem cholinergic neurons are essential for the regulation of sleep-wake cycles via projections to the thalamus. The cholinergic interneurons in the striatum modulate striatal GABAergic neurons by opposing the effects of dopamine. Increased cholinergic tone in Parkinson s disease and decreased cholinergic tone in patients treated with neuroleptics are examples of an imbalance of these two systems in the striatum (Cala-bresi et al., 2000). 

Human galanin is composed of 30 amino acids and is widely distributed in the CNS. A primary residence is within sensory and selected forebrain cholinergic interneurons a detailed map of galanin distribution is available [Kordower et al. 1992]. Based on several models, galanin appears to be an endogenous analgesic [Wiesenfeld-Hallin et al. 1992] and an inhibitor of acetyl-... 

Bonsi R, Cuomo D., De Persis C., Centonze D., Bemardi G., Calabresi P., and Pisani A. (2005). Modulatory action of metabotropic glutamate receptor (mGluR) 5 on mGluRl function in striatal cholinergic interneurons. Neuiopharmacology 49(Suppl 1) 104—113. 

Benkirane S, Arbilla S, Langer SZ (1987) A functional response to D] dopamine receptor stimulation in the central nervous system inhibition of the release of [3H]-serotonin from the rat substantia nigra. Naunyn-Schmiedeberg s Arch Pharmacol 335 502-7 Bennett BD, Wilson CJ (1999) Spontaneous activity of neostriatal cholinergic interneurons in vitro. J Neurosci 19 5586-96... 

Yan Z, Song WJ, Surmeier J (1997) D2 dopamine receptors reduce N-type Ca2+ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway. J Neurophysiol 77 1003-15... 

Wang Z, Kai L, Day M, Ronesi J, Yin HH, Ding J, Tkatch T, Lovinger D, Surmeier DJ (2006) Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons. Neuron 50 443-52... 

The results obtained from in vitro superfusion experiments are in accord with the conclusion that the cholinergic interneurons possess a D-2 dopamine receptor. Dopamine inhibits the release of [3H]-acetylcholine from neostriatal tissue however, concentrations greater than 1 are required to achieve maximal inhibition. Because dopamine is removed from the extracellular space by the dopaminergic nerve terminals, it is difficult to... 

Both cholinergic interneurons and cholinergic projection neurons can be found in the CNS. Cholinergic intemeurons are mainly located in the striatum and nucleus accumbens. Most cholinergic projection neurons originate from the basal forebrain (projections to the cerebral cortex and hippocampus) and the brainstem (projections to mid-brain and brainstem) (Mesulam, 2004 Smythies, 2005). 

Alcantara AA, Chen V, Herring BE, Mendenhall JM, Berlanga ML. 2003. Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat. Brain Res 986 22-29. 

Reduced density of cholinergic interneurons in the ventral striatum in schizophrenia An in situ hybridization study. Biol Psychiatry 58 408-416. 

Holt DJ, Herman MM, Hyde TM, Kleinman JE, Sinton CM, et al. 1999. Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia. Neuroscience 94 21-31. 

Pisani A, Bonsi P, Centonze D, Calabresi P, Bernardi G. 2000. Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons. J Neurosci 20 RC69 (1-6). 

In the CPu, D, receptors are mostly localized in medium-sized GABAergic neurons, whereas large aspiny cholinergic interneurons do not express either Di receptor protein or Dj mRNA (Weiner et al., 1991 Huang et al., 1992 Bergson et al.,1995b). 

Immunohistochemical analysis with specific antibodies and in situ hybridization studies showed that D2 receptor protein and mRNA are located in about 50% of the medium sized neurons and in about 80% of the large cholinergic interneurons (Bouthenet et ah, 1987 Le Moine et ah, 1990a). 

Yan Z, Surmeier DJ (1997) D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal cholinergic interneurons through a PKA/PP1 cascade. Neuron 79 1115-1126. 

ACh interneurons interact with the dopaminergic system in several ways. Dopamine-dependent long-term potentiation (LTD) is mediated by D2 receptors (in the indirect pathway) but D2 receptors are also reported on cholinergic interneurons. Acetylcholine release activates mainly through Ml muscarinic receptors at glutamatergic axo-spinous synapses (Hersch et al., 1994). 

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