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1.  Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates 
Journal of Neurochemistry  2008;105(5):1861-1872.
Despite a dramatic loss of nigrostriatal dopaminergic neurons in Parkinson’s disease, clinical symptoms only arise with 70–80% reduction of striatal dopamine. The mechanisms responsible for this functional compensation are currently under debate. Although initial studies showed an enhanced pre-synaptic dopaminergic function with nigrostriatal degeneration, more recent work suggests that functional compensation is not dopamine-mediated. To address this issue, we used cyclic voltammetry to directly measure endogenous dopamine release from striatal slices of control monkeys and animals with a moderate or severe MPTP-induced dopaminergic lesion. The moderately lesioned monkeys were asymptomatic, while the severely lesioned animals were parkinsonian. In monkeys with a moderate lesion, a 300% increase was obtained in endogenous striatal dopamine release. In contrast, in striatal slices from severely lesioned animals, a small % of evoked dopamine signals were similar in amplitude to control while the greater majority were undetectable. These findings suggest that pre-synaptic dopaminergic compensation develops in residual dopaminergic terminals with moderate lesioning, but that this response is lost with severe nigrostriatal damage. Such an interpretation is supported by the results of dopamine turnover studies. This enhanced pre-synaptic dopaminergic activity may be important in maintaining normal motor function during the initial stages of Parkinson’s disease.
PMCID: PMC3264543  PMID: 18248617
compensation; dopamine release; MPTP; non-human primate; Parkinson’s disease; voltammetry
2.  Chronic Nicotine Treatment Increases nAChRs and Microglial Expression in Monkey Substantia Nigra after Nigrostriatal Damage 
Our previous work had shown that long-term nicotine administration improved dopaminergic markers and nicotinic receptors (nAChRs) in the striatum of monkeys with nigrostriatal damage. The present experiments were done to determine whether nicotine treatment also led to changes in the substantia nigra, the region containing dopaminergic cell bodies. Monkeys were chronically treated with nicotine in the drinking water for 6 months after which they were injected with low dose MPTP for a further 6-month period. Nicotine was administered until the monkeys were euthanized 2 months after the last MPTP injection. Nicotine treatment did not affect the dopamine transporter or the number of tyrosine hydroxylase positive cells in the substantia nigra of lesioned monkeys. However, nicotine administration did lead to a greater increase in α3/α6β2* and α4β2* nAChRs in lesioned monkeys compared to controls. Nicotine also significantly elevated microglia and reduced the number of extracellular neuromelanin deposits in the substantia nigra of MPTP-lesioned monkeys. These findings indicate that long-term nicotine treatment modulates expression of several molecular measures in monkey substantia nigra that may result in an improvement in nigral integrity and/or function. These observations may have therapeutic implications for Parkinson’s disease.
PMCID: PMC3133952  PMID: 19685015
Neuromelanin; Nicotine; Nicotinic receptor; Substantia nigra; Parkinson’s disease
3.  Cotinine Selectively Activates a Subpopulation of α3/α6β2* Nicotinic Receptors in Monkey Striatum 
The nicotine metabolite cotinine is an abundant long-lived bio-active compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the central nervous system has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Because considerable evidence now demonstrates the presence of multiple nAChRs in the striatum, the present experiments were done to determine the subtypes through which cotinine exerts its effects in monkeys, a species that expresses similar densities of striatal α4β2* (nAChR containing the α4 and β2 subunits, but not α3 or α6) and α3/α6β2* (nAChR composed of the α3 or α6 subunits and β2) nAChRs. Competition binding studies showed that cotinine interacts with both α4β2* and α3/α6β2* nAChR subtypes in the caudate, with cotinine IC50 values for inhibition of 5-[125I]iodo-3-[2(S)-azetinylmethoxy]pyridine-2HCl ([125I]A-85380) and 125I-α-conotoxinMII binding in the micromolar range. This interaction at the receptor level is of functional significance because cotinine stimulated both α4β2* and α3/α6β2* nAChR [3H]dopamine release from caudate synaptosomes. Our results unexpectedly showed that nicotine evokes [3H]dopamine release from two α3/α6β2* nAChR populations, one of which was sensitive to cotinine and the other was not. This cotinine-insensitive subtype was only present in the medial caudate and was preferentially lost with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of α4β2* nAChR-mediated dopamine release. These data demonstrate that cotinine functionally discriminates between two α3/α6β2* nAChRs in monkey striatum, with the cotinine-insensitive α3/α6β2* nAChR preferentially vulnerable to nigrostriatal damage.
PMCID: PMC3134143  PMID: 18305015
4.  Multiple roles for nicotine in Parkinson’s disease 
Biochemical pharmacology  2009;78(7):677.
There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson’s disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson’s disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson’s disease incidence with tobacco use. In addition, recent work shows that nicotine reduces L-dopa-induced abnormal involuntary movements, a debilitating complication of L-dopa therapy for Parkinson’s disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson’s disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the α4β2*, α6β2* and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson’s disease, with a minimum of adverse side effects.
PMCID: PMC2815339  PMID: 19433069
L-Dopa-induced dyskinesias; Neuroprotection; Nicotine; Nicotinic; Nigrostriatal; Parkinson’s disease
5.  Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys 
Journal of neurochemistry  2009;109(3):826-837.
Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, and the results compared to those in which rats received nicotine only after lesioning. Nicotine pretreatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and α6β2* and α4β2* nicotinic receptors (nAChRs). In contrast, nicotine administered two weeks after lesioning, when 6-OHDA-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with 125I-α-conotoxinMII (α-CtxMII) and the α-CtxMII analog E11A were next done to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of α6α4β2* and α6(nonα4)β2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal α6α4β2* nAChRs.
PMCID: PMC2677631  PMID: 19250334
MPTP; nicotine; neuroprotection; neurorestoration; 6-OHDA; Parkinson's disease
6.  Paraquat exposure reduces nicotinic receptor-evoked dopamine release in monkey striatum 
Paraquat, an herbicide widely used in the agricultural industry, has been associated with lung, liver, and kidney toxicity in humans. In addition, it is linked to an increased risk of Parkinson’s disease. For this reason, we had previously investigated the effects of paraquat in mice and showed that it influenced striatal nicotinic receptor (nAChR) expression but not nAChR-mediated dopaminergic function. Since non-human primates are evolutionarily closer to humans and may better model the effects of pesticide exposure in man, we examined the effects of paraquat on striatal nAChR function and expression in monkeys. Monkeys were administered saline or paraquat once weekly for six weeks, after which nAChR levels and receptor-evoked 3H-dopamine (3H-DA) release were measured in striatum. The functional studies showed that paraquat exposure attenuated dopamine (DA) release evoked by α3/α6β2* nAChRs, a subtype present only on striatal dopaminergic terminals, with no decline in release mediated by α4β2* nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased α4β2* but not α3/α6β2* nAChR expression. The differential effects of paraquat on nAChR expression and receptor-evoked 3H-DA release emphasize the importance of evaluating changes in functional measures. The finding that paraquat treatment has a negative impact on striatal nAChR-mediated dopaminergic activity in monkeys but not mice indicates the need for determining the effects of pesticides in higher species.
PMCID: PMC2657317  PMID: 18606871

Results 1-6 (6)