**9. Parkinson's disease (PD)**

PD, the second most common progressive neurodegenerative disorder, is associated with loss of dopaminergic neurons in SNpc that leads to striatal DA deficiency. This loss of dopaminergic neurons results in motor deficits characterized by akinesia, rigidity, resting tremor, and postural instability as well as non-motor symptoms that might also involve other neurotransmitter systems. The non-motor symptoms may involve emotional changes such as apathy, anxiety and depression, mild or severe cognitive impairment, sleep disturbance (either insomnia or hypersomnia), autonomic dysfunction affecting bladder (frequent and urgent need to urinate), blood pressure (orthostatic hypotension), sweat glands (excessive sweating), sensory dysfunction (feeling of pain, loss of acuity in vision and olfaction), gastrointestinal disturbance (constipation

and/or nausea) as well as "social symptoms" such as inability to recognize other's verbal and nonverbal cues or produce facial expression.

The neuronal degeneration in PD likely involves several cellular and molecular events including accumulation of misfolded proteins aggregates, failure of protein clearance pathways, mitochondrial damage, oxidative stress, neuroinflammation, immune dysregulation, apoptosis, excitotoxicity, Ca++ dysregulation, autophagy and dysbiosis. Implicated in neuronal degeneration are also mutations in genes such as Parkin RBR E3 ubiquitin protein ligase (PARK2), Leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1(PINK1), Parkinson disease protein 7 (PARK7), and Synuclein Alpha (SNCA) as well as polymorphism in DRD2 gene Taq1A (DRD2Taq1A) and DA receptor D2 (DRD2).

PD is believed to be a multifactorial disease, where both genes and environmental factors play a crucial role. Old age, starting at 60 years is considered the primary risk factor for PD. This risk increases with advanced age. In addition, it is postulated that exposure to environmental toxicants such as pesticides, herbicides, and heavy metals may increase the risk of PD.

Serendipitously, it was discovered in the early 1980's that administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an underground laboratory preparation, could result in motor symptom typical of PD. This discovery was the impetus to use MPTP, a potent analog of meperidine, an opioid analgesic, as a pharmacological model of PD. MPTP is metabolized into the neurotoxin MPP+ (1-methyl-4-phenylpyridinium), which is not only substrate for DA transporter (DAT) but is also a potent mitochondrial complex-I inhibitor. Because MPP++ selectively damages dopaminergic cells in SNpc, it is commonly used to investigate the mechanism of neurotoxicity and/or development of novel therapeutics. Similarly, rotenone, a pesticide that selectively inhibits mitochondrial complex I, is used to generate animal models of PD. Finally, exposure to heavy metals such as manganese or iron have also been implicated in PD etiology. Interestingly, reduction of iron content was associated with a remarkable improvement of the motor and non-motor deficits in an MPTP-induced monkey model of PD [12, 13].

Oxidative stress has also been linked with the onset and/or progression of several neurodegenerative diseases including PD. In fact, overproduction of reactive oxygen species correlates with AD, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis (MS) and PD [68]. It is noteworthy that oxidative stress and neuroinflammation are linked and affect one another [69].

#### **9.1 Treatment modalities for PD**

Despite tremendous effort in understanding the causes and/or treatment of PD, no cure is yet available. Current medications are geared toward replenishing central DA transmission, which can only offer symptomatic relief without dealing with the neurodegenerative aspect of the disease. In this case, DA replacement or use of DA agonists to directly stimulate DA receptors are the mainstay of therapy. Unfortunately, these therapies lose efficacy after few years and in some cases such as with L-Dopa treatment, the side effects, commonly referred to L-Dopa-induce dyskinesia can be just as bad if not worse than PD symptoms. Thus, to prolong the efficacy of L-Dopa, it is combined with carbidopa. Alternatively, DA agonists such as pramipexole or ropinirole are used first. Other options include use of monoamine oxidase inhibitors, such as selegiline or rasagiline, or catechol-O-methyltransferase (COMT) inhibitors, such as entacapone and tolcapone. Combination therapy using multiple

drugs with various mechanism of action may also be applied. Non-pharmacological interventions may include physical and occupational therapy, repetitive transcranial magnetic stimulation (rTMS), and in specific circumstances neurosurgery (i.e., deep brain stimulation), which is reserved for those who meet well-defined criteria. Moreover, significant effort is devoted in developing regenerative treatments in the form of autologous or stem cell-derived grafts as well as viral gene therapies designed to replace the function of the neurons that have been lost. Thus, as our knowledge of contributing factors and their mechanisms become more clear, potential development of novel therapies also become a reality [12, 13].

#### **9.2 ACh: PD**

The cholinergic neurons of the mesopontine tegmental area and the basal forebrain send projections throughout the brain, regulating many discrete functions. Along with dopaminergic loss, cholinergic dysfunction also plays a substantial role in many PD symptoms such as cognitive impairment, gait problems, freezing of gait, falls, REM sleep behavior disorder (RBD), depression, visual hallucination, psychosis, and olfactory impairment. Thus, cholinergic dysfunction in PD could be contributing to a specific phenotype. This contention is further supported by the finding that a combination of RBD and a history of falls was able to predict combined thalamic and cortical cholinergic deficits. Nonetheless, further elucidation of cholinergic dysfunction, particularly in early stages of the disease is warranted [1]. Below, an update of our current knowledge regarding cholinergic receptors and PD is provided.

#### **9.3 mAChRs: PD**

It is now well-accepted that the striatum is the primary input structure of the basal ganglia, which participates in motivational and goal-directed behaviors. Basal ganglia output is controlled by local cholinergic interneurons (ChIs) and dopaminergic afferents. In general, the release of the neurotransmitters DA and ACh, acting through their respective receptors, elicits opposite effects on medial spiny neurons (MSNs). MSNs constitute 90–95% of all striatal neurons, while the remaining population consists of local ChIs and GABAergic interneurons in the striatum. Interestingly, a novel receptor-receptor interaction (i.e., heteromerization) between DA D2 receptor (D2R) and the muscarinic acetylcholine M1 receptor (M1R) was observed. This D2R-M1R complex coordinates a sophisticated interplay between the dopaminergic and cholinergic neurotransmission systems. Based on the existence of this heteromer within the striatum the use of anticholinergics drugs in the treatment of PD was suggested. Indeed, it was demonstrated that an M1R-selective antagonist could potentiate the antiparkinsonian-like efficacy of an ineffective D2R-selective agonist in a rodent model of experimental parkinsonism. Overall, the novel D2R-M1R heteromer could serve as a specific drug target to alleviate motor deficits in PD but with less side effects compared to other drugs [70].

Although giant, aspiny ChIs only represent 1–3% of striatal neurons, they are responsible for the highest concentration of ACh in the brain and interact with DA inputs to regulate motor function. ChIs possess an intrinsic firing activity referred to as autonomous pacemakers which modulate the activities of neuronal afferents. ChIs effects are mediated by both mAChRs and nAChRs. As mentioned earlier, the excitatory M1-like receptors (M1R, M3 R and M5R) transduce their signals through Gq/11proteins, whereas the inhibitory M2-like receptors (M2 R and M4R) are coupled

#### *Central Nicotinic and Muscarinic Receptors in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.112447*

to Gi/o proteins. The complexity of the striatal circuitry is underscored by the variety of DARs, mAChRs and nAChRs, their subcellular location in ChIs and MSNs as well as their interaction [70].

Due to the development of improved pharmacological agents targeting specific mAChR subtypes, the interest to modulate striatal function by anticholinergic drugs has been renewed in recent years. This is due to the findings that pharmacological blockade of mAChR subtypes, specifically M1R and M4R, can significantly add to other antiparkinsonian treatments. On the other hand, wild-type mice treated with M1R-selective agonist (i.e., telenzepine) had reduced anxiety-like behaviors. Moreover, mice deficient in M1R- exhibit an increased locomotor activity as well as elevated extracellular striatal DA levels. These mice, however, do not exhibit impairment in contextual fear condition, a test of hippocampal-dependent learning. Thus, M1R antagonist can be of benefit in motor impairments, whereas M1R agonist can have anxiolytic and, in some cases, (see above) cognitive enhancement effects. Moreover, M1R antagonists may suppress D2R-MSNs more efficiently than D1R-MSNs, through their interaction with potassium channels. Interestingly, striatal D2R-M1R formation might result in further differentiation of M1R signalization between the striato-pallidal and striato-nigral neurons. Additional support for reciprocal interaction between D2Rs and M1Rs is provided by the findings that systemic administration of scopolamine (i.e., non-selective mAChR antagonist) and benztropine (i.e., moderate M1R-selective antagonist) reduce the affinity of raclopride and spiperone (both D2R antagonists) for D2R in monkey brains [70].

Thus, it may be suggested that the dopaminergic-cholinergic imbalance, which is seen in most movement disorders, may be normalized by a combination of selective D2R agonist and M1R antagonist [70].

#### **9.4 nAChRs: PD**

The cholinergic system, particularly nAChRs are essential in modulating the striatal cells regulating cognitive and motor functions. Thus, nAChRs stimulation reduces neuroinflammation and facilitates neuronal survival, neurotransmitter release, and synaptic plasticity. PD is associated with loss of striatal nAChRs, which may aggravate the loss of dopaminergic neurons in this area, leading to pathological consequences. Additionally, nAChRs activation may also stimulate other brain cells supporting cognitive and motor functions [71].

Furthermore, the impairments in DA release observed in various animal models of PD (e.g., 6-OHDA lesioned rodents), appear to be exacerbated by loss of nAChRs activation. This suggests that DAergic imbalance may be ameliorated by nicotinic agonists and hence, nicotinic receptors may offer therapeutic targets for PD. In this regard, several in-vitro and in-vivo studies including primates and genetically modified mice have shown protective effects of nicotine against neuronal damage and/or neurotoxicity induced by 6-OHDA, MPTP, rotenone, methamphetamine, glutamate and β-amyloid. These effects are mediated via selective nAChR subtypes containing β2 and α7 subunits. Protective effects of nicotine against endogenous substances such as salsolinol and aminochrome that selectively damage dopaminergic cells have also been observed. More recently, protective effects of nicotine against toxicity induced by iron and manganese were also observed in cell culture. Interestingly, nicotinic cholinergic system may also play a role in L-Dopa-induced dyskinesias. Finally. an inverse relationship between PD incidence and any form of nicotine intake such as cigarette smoking, smokeless tobacco, exposure to environmental tobacco smoke or even from a dietary

source such as peppers, also suggest a therapeutic potential for nicotine in PD. Hence, targeting nicotinic cholinergic receptors could be a novel intervention in PD. Nicotine's effects are likely to involve suppression of pro-inflammatory cytokines and stimulation of neurotrophic factors as well as suppression of oxidative stress [12, 13].
