Modeling of dopamine-dependent disorders in a transgenic mouse and therapeutic targeting of dopamine circuits through nicotinic acetylcholine receptors
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Schizophrenia and Parkinson's disease (PD) and related neurodevelopmental and neurodegenerative disorders are highly prevalent and extremely debilitating diseases. A common feature of these disorders is an impairment of dopamine (DA) transmission. Drugs used to treat these disorders either block (schizophrenia) or enhance (PD) DAergic tone. In both classes of diseases there are numerous side effects and shortcomings of drugs that directly target DA systems, thus the development of novel therapeutic strategies is critically needed. Recent evidence has indicated that nicotine from cigarette smoke improves schizophrenia symptoms and prevents the development of PD. These observations have encouraged researchers to explore the nicotinic acetylcholine system as a therapeutic target in these diseases. Receptors for endogenous acetylcholine and exogenous nicotine are superimposed on DAergic pathways, influence DA release and affect the survival and function of DA neurons. To investigate compounds that activate neuronal nicotinic acetylcholine receptors (nAChRs) in the diseased state, I have utilized a transgenic mouse model, th-fgfr1(tk-) , that features a developmental impairment of fibroblast growth factor receptor 1 (FGFR1) signaling in DA neurons leading to smaller and hypoplastic DA neuronal morphology. Adult th-fgfr1(tk-) have enhanced subcortical DA transmission and impaired cortical structure, thus leading to behavioral symptoms of schizophrenia across all domains of the disorder. Also, an increased vulnerability of midbrain DA neurons due to a developmental and constitutive reduction of FGFR1 signaling in adulthood creates the opportunity to target DA neurons with neurotoxins to induce a robust PD-like condition. In chapter 1, I will provide background about nAChRs and explore the endogenous relationship between nicotinic and DA pathways in the CNS. I will provide evidence that targeting of specific subtypes of nAChRs, which are expressed with tremendous diversity, may be more beneficial to treat different diseases that feature DAergic impairment. In chapter 2 I will focus on schizophrenia. First, the effects of a novel nicotinic compound that targets the homomeric &agr;7 nAChR subtype will be described in th-fgfr1(tk-) mice and in rats with DA agonist-induced psychosis. Then, I will explore the mechanisms underlying the improvement of sensorimotor gating deficits in th-fgfr1(tk-) mice by &agr;7 nAChR agonists in th-fgfr1(tk-) mice by measuring DA release in the striatum and frontal cortex during phasic stimulation using microdialysis and HPLC electrochemical detection. The effects of the commercially available smoking cessation aid Chantix, which activates a wide variety of CNS nAChRs, will be investigated on schizophrenia symptoms and other measures of emotional behavior in th-fgfr1(tk-) mice alone or with nAChR antagonists. Finally, a review will describe current research focusing on the &agr;7 nAChR and its role in the treatment of schizophrenia. In chapter 3 I will further describe the transgenic mouse model that was used as a tool in my studies in investigate nAChRs in DAergic diseases. DAergic disruptions in th-fgfr1(tk-) mice had been previously been established in our laboratory, and I further describe a developmental impairment of 5-HT systems that co-develop with DAergic dysfunction which creates a therapeutic opportunity that may also be found in the human schizophrenia disease. I will also explore the role of FGFs in schizophrenia and PD and describe how targeting FGF-compromised DA neurons with neurotoxins establishes a strong model for PD. Finally, I will describe a novel experimental paradigm in which unilaterally lesioned th-fgfr1(tk-) mice displayed spontaneous (non-drug induced) asymmetrical and global motor deficits that correlate with depletion of DA and DA metabolites as measured by HPLC-EC. Nicotine and two &agr;6-containing nAChR agonists were administered to determine potential therapeutic benefits of targeting these receptors in a hemiparkinsonian state. In total, this body of work will add to the growing body of evidence that drugs influencing nAChRs may be exceptional alternatives or supplements to current DA-dominated therapies for schizophrenia and PD. Also, this work further describes a transgenic mouse model with neurochemical, anatomical and behavioral similarities to human schizophrenia and increased susceptibility to neurotoxin challenges due to the developmental impairment and continued reduction of growth factor protection in adult DA neurons.