Selective recovery of striatal 125I-α-conotoxinmii nicotinic receptors after nigrostriatal damage in monkeys

Lai, Albert; Sum, Jocelyn; Fan, Hong; McIntosh, J. M.; Quik, Maryka

doi:10.1016/j.neuroscience.2004.04.059

Cited by 7 publications

(6 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6-OHDA lesioning did not affect α4β2* nAChR binding levels, most likely because the majority of α4β2* nAChR in the striatum (80-85%) are not located on the lesioned nigrostriatal dopamine terminals (Quik et al, 2003). As expected, long term nicotine treatment increased α4β2* nAChRs in the intact and lesioned striatum of WT mice (Lai et al, 2004). Notably, there was also an increase in α4β2* nAChR binding levels in the α6L9S mice.…”

Section: Resultssupporting

confidence: 77%

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

et al. 2015

View full text Add to dashboard Cite

L-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of α6β2* nAChRs in LIDs, we used gain-of-function α6* nAChR (α6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and α6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3 μg/ml) into the medial forebrain bundle. Three to 4 wk later, they were administered L-dopa (3 mg/kg) plus benserazide (15 mg/kg) until stably dyskinetic. L-dopa-induced abnormal involuntary movements (AIMs) were similar in α6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300 μg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in α6L9S mice at a maximally tolerated nicotine dose of 20 μg/ml. However, the nAChR antagonist mecamylamine (1 mg/kg ip 30 min before L-dopa) reduced L-dopa-induced AIMs in both α6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in α6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive α6β2* nAChRs may desensitize less readily. The present data show that α6β2* nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease.

show abstract

Section: Resultssupporting

confidence: 77%

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

et al. 2015

View full text Add to dashboard Cite

show abstract

“…These toxin analogs are the most selective α6* nAChR antagonists reported to date. The wildtype α-CTx MII, as well as a number of α6* (the asterisk indicates the presence of additional subunits) selective α-CTx MII analogs, have been used to characterize nAChR subtypes that modulate dopamine release in rat (55–61), mice (62–65), and monkey striatum (66, 67). These studies indicate a role for α6β2* and α6α4β2* nAChRs in the modulation of dopamine release in the striatum and the nucleus accumbens.…”

Section: Neuronal Nachr-targeted α-Conotoxinsmentioning

confidence: 99%

“…Using the radiolabeled α-CTx MII, Quik and co-workers have found a selective downregulation of α-CTx MII binding sites within rodent and monkey striatum after nigorstriatal damage (79–82) as well as in humans with Parkinson’s (82). Direct measurement of α-CTx MII sites also shows preferential recovery of these sites in monkeys allowed to recover from nigrostriatal damage (66). Binding studies using an analog of α-CTx MII, α-CTx MII[E11A], have shown a selective loss of a specific subtype of nAChR (α6α4β2*) in rodent and monkey models of Parkinson’s disease.…”

Section: Neuronal Nachr-targeted α-Conotoxinsmentioning

confidence: 99%

Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors

2009

View full text Add to dashboard Cite

Cysteine-rich peptides from the venom of cone snails (Conus) target a wide variety of different ion channels. One family of conopeptides, the α-conotoxins, specifically target different isoforms of nicotinic acetylcholine receptors (nAChRs) found both in the neuromuscular junction and central nervous system. This family is further divided into subfamilies based on the number of amino acids between cysteine residues. The exquisite subtype selectivity of certain α-conotoxins has been key to the characterization of native nAChR isoforms involved in modulation of neurotransmitter release, the pathophysiology of Parkinson's disease and nociception. Structure/function characterization of α-conotoxins has led to the development of analogs with improved potency and/or subtype selectivity. Cyclization of the backbone structure and addition of lipophilic moieties has led to improved stability and bioavailability of α-conotoxins, thus paving the way for orally available therapeutics. The recent advances in phylogeny, exogenomics and molecular modeling promises the discovery of an even greater number of α-conotoxins and analogs with improved selectivity for specific subtypes of nAChRs.

show abstract

“…Parkinsonism was again assessed. The monkeys were euthanized 2 to 4 weeks after the final MPTP administration, at which time the effects of the lesion were maximal with little regeneration (Stanic et al, 2003;Lai et al, 2004).…”

Section: Materials the Radioligands [mentioning

confidence: 99%

“…Although the mechanism(s) by which this enhanced evoked-release in selected regions may occur is not presently known, the possibilities include: 1) spare receptors or a larger intracellular pool of receptors in some regions that can be mobilized to the nerve terminal surface under conditions of damage; 2) enhanced coupling of nicotinic receptors to the dopamine exocytotic process; 3) a change in release properties through decreased autoinhibition by the D2 receptor in the presence of lower synaptic dopamine levels; and/or 4) compensatory increases in the vesicular monoamine transporter, such that quantal release from vesicles is enhanced. There may also be selective recovery of dopaminergic nerve terminals in the putamen, although compensatory sprouting and other regenerative changes generally tend to occur over a longer time frame (Stanic et al, 2003;Lai et al, 2004).…”

mentioning

confidence: 99%

Decrease in α3^/α6^Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage

et al. 2005

View full text Add to dashboard Cite

Nicotinic acetylcholine receptors (nAChRs) are decreased in the striata of patients with Parkinson's disease (PD) or in experimental models after nigrostriatal damage. Because presynaptic nAChRs on striatal dopamine terminals mediate dopamine release, receptor loss may contribute to behavioral deficits in PD. The present experiments were done to determine whether nAChR function is affected by nigrostriatal damage in nonhuman primates, because this model shares many features with PD. Initial characterization of nicotine-evoked [ 3 H]dopamine release from monkey striatal synaptosomes revealed that release was calcium-dependent and inhibited by selective nAChR antagonists. It is noteworthy that a greater proportion (ϳ70%) of release was inhibited by the ␣3*/␣6* antagonist ␣-conotoxinMII (␣-CtxMII) compared with rodents. Monkeys were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and [ 3 H]dopamine release, dopamine transporter, and nAChRs were measured. As anticipated, lesioning decreased the transporter and ␣3*/␣6* nAChRs in caudate and putamen. In contrast, ␣3*/␣6* nAChR-evoked [ 3 H]dopamine release was reduced in caudate but not putamen, demonstrating a dissociation between nAChR sites and function. A different pattern was observed in the mesolimbic dopamine system. Dopamine transporter levels in nucleus accumbens were not reduced after MPTP, as expected; however, there was a 50% decline in ␣3*/␣6* nAChR sites with no decrease in ␣3*/␣6* receptor-evoked dopamine release. No declines in ␣-CtxMIIresistant nAChR (␣4*) binding or nicotine-evoked release were observed in any region. These results show a selective preservation of ␣3*/␣6* nAChR-mediated function in the nigrostriatal and mesolimbic dopamine systems after nigrostriatal damage. Maintenance of function in putamen, a region with a selective loss of dopaminergic terminals, may be important in PD.Parkinson's disease (PD) is characterized by motor and cognitive deficits and is manifested by reductions in dopaminergic neurons in substantia nigra and dopamine levels in striatum (Olanow, 2004). PD is also associated with decreases in striatal nicotinic acetylcholine receptors (nAChRs), including those containing ␣4*, ␣3*, and/or ␣6* but not ␣7* subunits (* denotes nicotinic receptors containing the indicated ␣ and/or ␤ subunit and also additional undefined subunits; Quik, 2004). Similar declines in nAChRs in Parkinsonian animal models support these findings (Quik et al., 2001(Quik et al., , 2003Champtiaux et al., 2002;Kulak et al., 2002;Zoli et al., 2002).Receptor binding and immunoprecipitation studies have revealed multiple nAChR subtypes on striatal dopaminergic terminals, including both ␣4* and ␣6* in rodents (Klink et al., 2001;Champtiaux et al., 2002Champtiaux et al., , 2003Zoli et al., 2002;Cui et al., 2003) and ␣3*, ␣4*, and ␣6* in monkeys Quik et al., 2001Quik et al., , 2002Quik et al., , 2005. In monkey, moderate nigrostriatal damage induced by the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prefer...

show abstract

Selective recovery of striatal 125I-α-conotoxinmii nicotinic receptors after nigrostriatal damage in monkeys

Cited by 7 publications

References 27 publications

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors

Decrease in α3^/α6^Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage

Contact Info

Product

Resources

About

Selective recovery of striatal 125I-α-conotoxinmii nicotinic receptors after nigrostriatal damage in monkeys

Cited by 7 publications

References 27 publications

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

Evidence for a role for α6∗ nAChRs in l-dopa-induced dyskinesias using parkinsonian α6∗ nAChR gain-of-function mice

Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors

Decrease in α3*/α6*Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage

Contact Info

Product

Resources

About

Decrease in α3^/α6^Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage