Brain nicotinic acetylcholine receptors: native subtypes and their relevance

Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal α6β2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, α4β2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to α6β2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics. Keywordsα-ConotoxinMII; Nicotine; Nicotinic; Parkinson's disease; Nigrostriatal; Striatum Parkinson's disease and the nicotinic cholinergic systemThe pathological hallmarks of Parkinson's disease are the presence of intracellular Lewy bodies and an extensive degeneration of the nigrostriatal dopaminergic system. [1][2][3][4]. There is a ≥70% decline in striatal dopamine and ≥50% loss of nigral dopaminergic neurons with the onset of clinical symptoms, which include bradykinesia, rigidity, and tremor [1][2][3][4].Although Parkinson's disease has primarily been considered a dopaminergic disorder, it is becoming increasingly clear that multiple CNS systems are involved in its pathogenesis [5][6][7]. Braak and coworkers have also identified Lewy bodies in numerous non-dopaminergic brain regions including the locus coeruleus, raphe nuclei, thalamus, amygdala, olfactory nuclei, pedunculopontine nucleus, and cerebral cortex [5,6]. These observations are in agreement with much earlier studies, which indicated that multiple CNS neuronal systems are affected in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the...

Section: Rodentssupporting

confidence: 60%

Section: Nicotinic Receptors In the Nigrostriatal Systemmentioning

confidence: 99%

mentioning

confidence: 99%

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Nicotinic receptors as CNS targets for Parkinson's disease

Quik

Bordia

O’Leary

2007

“…Those receptors that are expressed on or near nerve terminals modulate calcium-dependent release of neurotransmitters [35,36,37,38] including dopamine [39,40,41,42], norepinephrine [43,44], glutamate [45,46], GABA [47], and acetylcholine [48,49]. Nicotinic agonist-stimulated release of dopamine has been studied extensively in the nucleus accumbens because these nAChRs may play a major role in regulating the reinforcing effects of nicotine [50,51,52].…”

Section: Nih Public Accessmentioning

confidence: 99%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

232

223

This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

“…Different DA neurons can be categorized based upon the expression of the specific subtype composition [27]. CNS nAChRs and their modulation of neurotransmitter release have been reviewed recently [47,48]. Thus, the presence of specific mRNAs encoding a particular subunit, the relative ratio of transcribed subunits, specific expression of nAChR subtypes by different DA neurons, and pharmacological history are all important to neuronal function and potentially play a role in the response to nicotine and to drugs which block the effect of nicotine.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

Dwoskin

Joyce

Zheng

et al. 2007

Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N′-bis-nicotinium analogs, affording a lead compound, N,N′-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC 50 = 500 nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1 μM) inhibited the response to acetylcholine at α3β4, α4β4, α4β2, and α1β1εδ receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity for the blood-brain barrier choline transporter, suggesting that is brain bioavailable. TMPD did not inhibit the hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence.