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.
α-ConotoxinMII; Nicotine; Nicotinic; Parkinson’s disease; Nigrostriatal; Striatum
A promising target for improved therapeutics in Parkinson's disease is the nicotinic acetylcholine receptor (nAChR). nAChRs are widely distributed throughout the brain, including the nigrostriatal system, and exert important modulatory effects on numerous behaviors. Accumulating evidence suggests that drugs such as nicotine that act at these sites may be of benefit for Parkinson's disease treatment. Recent work indicates that a potential novel therapeutic application is the use of nicotine to reduce levodopa-induced dyskinesias, a side effect of dopamine replacement therapy for Parkinson's disease. Several clinical trials also report that nicotine may diminish disease symptoms. Not only may nAChR drugs provide symptomatic improvement, but they may also attenuate the neurodegenerative process itself. This latter idea is supported by epidemiological studies which consistently demonstrate a ~50% reduced incidence of Parkinson's disease in smokers. Experimental work in parkinsonian animal models suggests that nicotine in tobacco may contribute to this protection. These combined findings suggest that nicotine and nAChR drugs offer the possibility of improved therapeutics for Parkinson's disease.
Nicotine; nicotinic receptors; levodopa; dyskinesias; neuroprotection; parkinsonian; Parkinson's disease
Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinson’s disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including α4β2, α6β2 and/or α7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine’s ability to reduce/halt the neuronal damage that arises in Parkinson’s disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson’s disease.
Neuroprotection; Nicotine; Nicotinic; Nigrostriatal damage; Parkinson’s disease
L-Dopa-induced dyskinesias are a serious side effect that develops in most Parkinson’s disease patients on dopamine replacement therapy. Few treatment options are available to manage dyskinesias; however, recent studies show that nicotine reduces these abnormal involuntary movements (AIMs) in parkinsonian animals by acting at nicotinic acetylcholine receptors (nAChRs). Identification of the nAChR subtypes that mediate this reduction in AIMs is important as it will help in the development of nAChR subtype selective drugs for their treatment. Here we investigate the role of α6β2* nAChRs, a subtype selectively present in the nigrostriatal pathway, using α6 nAChR subunit null mutant (α6(-/-)) mice. Wildtype and α6(-/-) mice were lesioned by unilateral injection of 6-hydroxydopamine (3 μg/μl) into the medial forebrain bundle. They were then given L-dopa (3 mg/kg) plus benserazide (15 mg/kg) 2-3 wk later. L-dopa-induced AIMs developed to a similar extent in α6(-/-) and wildtype mice. However, AIMs in α6(-/-) mice declined to ~50% of that in wildtype mice with continued L-dopa treatment. Nicotine treatment also decreased AIMs by ~50% in wildtype mice, although not in α6(-/-) mice. There were no effects on parkinsonism under any experimental condition. To conclude, the similar declines in L-dopa-induced AIMs in nicotine-treated wildtype mice and in α6(-/-) mice treated with and without nicotine indicate an essential role for α6β2* nAChRs in the maintenance of L-dopa-induced AIMs. These findings suggest that α6β2* nAChR drugs have potential for reducing L-dopa-induced dyskinesias in Parkinson’s disease.
alpha6; dyskinesia; L-dopa; nicotine; 6-hydroxydopamine; Parkinson’s disease
There is a well-established connection between smoking and depression, with depressed individuals over-represented among smokers and ex-smokers often experiencing increased depressive symptoms immediately after quitting. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for nicotine’s effects on depressive symptoms. In this article, we review the hypothesis that blockade rather than activation of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms based on clinical and preclinical studies of nicotinic drugs. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications.
nicotinic acetylcholine receptors; smoking; major depressive disorder; antidepressant medications; mecamylamine; varenicline; cytisine
Parkinson's disease (PD) has become a major health problem affecting 1.5% of the world's population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA) neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF)/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson's disease.
Mesostriatal dopaminergic neurons and striatal cholinergic interneurons participate in signaling the motivational significance of environmental stimuli and regulate striatal plasticity. Dopamine (DA) and acetylcholine (ACh) have potent interactions within the striatum at multiple levels that include presynaptic regulation of neurotransmitter release and postsynaptic effects in target cells (including ACh neurons). These interactions may be highly variable given the dynamic changes in the firing activities of parent DA and ACh neurons. Here, we consider how striatal ACh released from cholinergic interneurons acting at both nicotinic and muscarinic ACh receptors powerfully modulates DA transmission. This ACh–DA interaction varies in a manner that depends on the frequency of presynaptic activation, and will thus strongly influence how DA synapses convey discrete changes in DA neuron activity that are known to signal events of motivational salience. Furthermore, this ACh modulation of DA transmission within striatum occurs via different profiles of nicotinic and muscarinic receptors in caudate–putamen compared to nucleus accumbens, which may ultimately enable region-specific targeting of striatal function.
dopamine; striatal territories; acetylcholine receptors; release probability; cholinergic interneuron
Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.
Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice.
Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.
Although evidence suggests that the prevalence of Parkinson’s disease (PD) is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the α7 nicotinic acetylcholine receptor (α7-nAChR) seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model occurs via α7-nAChR-mediated inhibition of astrocytes.
Both in vivo (MPTP) and in vitro (1-methyl-4-phenylpyridinium ion (MPP+) and lipopolysaccharide (LPS)) models of PD were used to investigate the role(s) of and possible mechanism(s) by which α7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF)-α assays, and western blotting, were used to elucidate the mechanisms of the α7-nAChR-mediated neuroprotection.
Systemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP+-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-α and inhibition of extracellular regulated kinase1/2 (Erk1/2) and p38 activation in astrocytes, and these effects were also reversed by MLA.
Taken together, our results suggest that α7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine.
α7 nicotinic acetylcholine receptor; Parkinson’s disease; Astrocyte; Neuroinflammation; Neuroprotection
Although a relative newcomer to the nicotinic acetylcholine receptor (nAChR) family, substantial evidence suggests that α6 containing nAChRs play a key role in CNS function. This subtype is unique in its relatively restricted localization to the visual system and catecholaminergic pathways. These latter include the mesolimbic and nigrostriatal dopaminergic systems, which may account for the involvement of α6 containing nAChRs in the rewarding properties of nicotine and in movement. Here, we review the literature on the role of α6 containing nAChRs with a focus on the striatum and nucleus accumbens. This includes molecular, electrophysiological and behavioral studies in control and lesioned animal models, as well as in different genetic models. Converging evidence suggest that the major α6 containing nAChRs subtypes in the nigrostriatal and mesolimbic dopamine system are the α6β2β3 and α6α4β2β3 nAChR populations. They appear to have a dominant role in regulating dopamine release, with consequent effects on nAChR-modulated dopaminergic functions such as reinforcement and motor behavior. Altogether these data suggest that drugs directed to α6 containing nAChRs may be of benefit for the treatment of addiction and for neurological disorders with locomotor deficits such as Parkinson’s disease.
Addiction; Cyclic voltammetry; Nucleus accumbens; Parkinson’s disease; Striatum
Of the thousands of proven carcinogens and toxic agents contained within a cigarette, nicotine, while being the addictive agent, is often viewed as the least harmful of these compounds. Nicotine is a lipophilic molecule whose effects on neuronal nicotinic acetylcholine receptors (nAChR) have been primarily focused on its physiologic impact within the confines of the brain and peripheral nervous system. However, recently, many studies have found neuronal nAChRs to be expressed on many different nonneuronal cell types throughout the body, where increasing evidence suggests they have important roles in determining the consequences of nicotine use on multiple organs systems and diseases as diverse as ulcerative colitis, chronic pulmonary obstructive disease, and diabetes, as well as the neurologic disorders of Parkinson’s and Alzheimer’s disease. This review highlights current evidence for the expression of peripheral nAChRs in cells other than neurons and how they participate in fundamental processes, such as inflammation. Understanding these processes may offer novel therapeutic strategies to approach inflammatory diseases, as well as precautions in the design of interventional drugs.
nicotine; inflammation; nicotinic receptors; nonneuronal
L-dopa is one of the best treatments for the motor symptoms of Parkinson’s disease. However, its use is limited by the fact that it provides only symptomatic relief and chronic therapy leads to dyskinesias. There is therefore a continual search for novel therapeutic approaches. Nicotine, a drug that acts at nicotinic acetylcholine receptors (nAChRs), has been shown to protect against nigrostriatal damage and reduce L-dopa-induced dyskinesias. NAChRs may therefore represent novel targets for Parkinson's disease management. Since there are multiple nAChRs throughout the body, it is important to understand the subtypes involved in striatal function to allow for the development of drugs with optimal beneficial effects. Here we discuss recent work from our laboratory which indicates that α6β2* and α4β2* nAChRs are key in regulating striatal dopaminergic function. Experiments in parkinsonian rats using cyclic voltammetry showed that both α6β2* and α4β2* nAChR-mediated evoked-dopamine release in striatal slices is affected by nigrostriatal damage. These subtypes also appear to be important for neuroprotection against nigrostriatal damage and the nicotine-mediated reduction in L-dopa-induced dyskinesias in parkinsonian animal models. Our combined findings indicate that α4β2* and α6β2* nAChRs may represent useful therapeutic targets for Parkinson’s disease.
Dopamine; Dyskinesias; Neuroprotection; Nicotinic receptors; Parkinson's; disease nigrostriatal damage
Nicotine treatment has long been associated with alterations in α4β2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of chronic nicotine treatment on the α6β2* nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal α6β2* nAChR function and expression. Chronic nicotine via drinking water enhanced non-burst and burst endogenous dopamine release from rat striatal slices. In control animals, α6β2* nAChR blockade with α-conotoxinMII (α-CtxMII) decreased release with non-burst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate α6β2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, α6β2* nAChR blockade elicited a similar pattern of dopamine release with non-burst and burst firing. To elucidate the α6β2* nAChR subtypes altered with chronic nicotine treatment, we used the novel α-CtxMII analogue E11A, in combination with α4 nAChR knockout mice. 125I-α-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the α6α4β2* subtype, but increased the α6(nonα4)β2* nAChR population. These data indicate that α6β2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the α6(nonα4)β2* nAChR subtype, and suggest that the α6α4β2* nAChR and/or α4β2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, α6β2* nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.
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.
MPTP; nicotine; neuroprotection; neurorestoration; 6-OHDA; Parkinson's disease
Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to tri-chloroethylene may contribute to the development of Parkinson’s disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene. In our experiments, oral administration of trichloroethylene induced a significant loss of dopaminergic neurons in the substantia nigra pars compacta in a dose-dependent manner, whereas the number of both cholinergic and GABAergic neurons were not decreased in the striatum. There was a robust decline in striatal levels of 3, 4-dihydroxyphenylacetic acid without a significant depletion of striatal dopamine. Rats treated with trichloroethylene showed defects in rotarod behavior test. We also found a significantly reduced mitochondrial complex I activity with elevated oxidative stress markers and activated microglia in the nigral area. In addition, we observed intracellular α-synuclein accumulation in the dorsal motor nucleus of the vagus nerve, with some in nigral neurons, but little in neurons of cerebral cortex. Overall, our animal model exhibits some important features of Parkinsonism, and further supports that trichloroethylene may be an environmental risk factors for Parkinson’s disease.
neurodegeneration; Parkinson’s disease; substantia nigra; trichloroethylene; tyrosine hydroxylase; α-synuclein
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.
Parkinson’s disease (PD) is a neurological disorder characterized by the manifestation of motor symptoms, such as akinesia, muscle rigidity and tremor at rest. These symptoms are classically attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra (SNc), which results in a marked dopamine depletion in the striatum. It is well established that dopamine neurons in the SNc innervate not only the striatum, which is the main target, but also other basal ganglia nuclei including the two segments of globus pallidus and the subthalamic nucleus (STN). The role of dopamine and its depletion in the striatum is well known, however, the role of dopamine depletion in the pallidal complex and the STN in the genesis of their abnormal neuronal activity and in parkinsonian motor deficits is still not clearly determined. Based on recent experimental data from animal models of Parkinson’s disease in rodents and non-human primates and also from parkinsonian patients, this review summarizes current knowledge on the role of dopamine in the modulation of basal ganglia neuronal activity and also the role of dopamine depletion in these nuclei in the pathophysiology of Parkinson’s disease.
dopamine; extrastriatal dopamine; basal ganglia; globus pallidus; subthalamic nucleus; Parkinson’s disease
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.
Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.
Parkinson's disease; motor and non-motor symptoms; noradrenaline; dopamine; locus coeruleus
Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.
To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.
This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.
The striatum is one of the major forebrain regions that strongly express muscarinic and nicotinic cholinergic receptors. This article reviews the current knowledge and our new findings about the striatal cholinoceptive organization and its role in a variety of cognitive functions. Pharmacological and genetic manipulations have indicated that the cholinergic and dopaminergic system in the striatum modulate each other’s function. In addition to modulating the dopaminergic system, nicotinic cholinergic receptors facilitate GABA release, whereas muscarinic receptors attenuate GABA release. The striatal cholinergic system has also been implicated in various cognitive functions including procedural learning and intradimensional set shifting. Together, these data indicate that the cholinergic system in the striatum is involved in a diverse set of cognitive functions through interactions with other neurotransmitter systems including the dopaminergic and GABAergic systems.
Cognitive strategy; T-maze; set-shifting; reversal learning; place navigation; nicotinic; muscarinic; striatum; aging; basal ganglia
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including: resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of non-motor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA responsive motor deficits, α-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine, serotonin), which are known to regulate some of these behaviors that the VMAT2-deficient mice may display some of the non-motor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the non-motor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the non-motor symptoms of PD and interventions aimed at restoring monoamine function may be beneficial in treating the disease.
VMAT2; dopamine; norepinephrine; serotonin; depression; olfaction
L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40–50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine’s antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson’s disease.
A-85380; dyskinesia; L-dopa; nicotine; nicotinic; varenicline
Acetylcholine (ACh), the first neurotransmitter discovered, participates in many CNS functions including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic (nAChR) and muscarinic (mAChR) type cholinergic receptors. The goal of this review is to synthesize a growing literature that supports the potential role of ACh as a treatment target for stimulant addiction. ACh interacts with the dopaminergic reward system in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). In the VTA, both nAChR and mAChR stimulate the dopaminergic system. In the NAc, cholinergic interneurons integrate cortical and subcortical information related to reward. In the PFC, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic agonists in the development of stimulant addiction. Muscarinic agonists seem to have an inhibitory role depending on the subtype of mAChR. In human studies acetylcholine esterase (AChE) inhibitors, which increase synaptic ACh levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted.
acetylcholine; dopamine; nicotinic; muscarinic; stimulant addiction; brain reward system
Parkinson’s disease is a progressive age-related neurodegenerative disease with invariant loss of substantia nigra dopamine neurons and striatal projections. This disorder is well known for the associated motoric symptoms including resting tremor and the inability to initiate movement. However, it is now apparent that Parkinson’s disease is a multi-system disorder with patients exhibiting symptoms derived from peripheral nervous system and extra-nigral dysfunctions in addition to the prototypical nigrostriatal damage. Although the etiology for sporadic Parkinson’s disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded α-synuclein at the forefront. The disease is currently without a cure and most therapies target the motoric symptoms relying on increasing dopamine tone. In this review, the role of α-synuclein in disease pathogenesis and as a potential therapeutic target focusing on toxic conformers of this protein is considered. The addition of protofibrillar/oligomer-directed neurotherapeutics to the existing armamentarium may extend the symptom-free stage of Parkinson’s disease as well as alleviate pathogenesis.