**2. Noradrenergic cell bodies**

### **2.1 Anatomical**

There are two major clusters of noradrenergic neurons in the central nervous system (CNS): the LC and the lateral tegmental neurons. In contrast to the significant loss of LC noradrenergic neurons in PD as indicated above, the lateral tegmental group does not appear to demonstrate much of a loss in PD (Saper et al., 1991). LC noradrenergic neurons send projections to forebrain regions via three different tracts: the central tegmental tract, the central gray dorsal longitudinal fasciculus tract, and the ventral tegmental-medial forebrain bundle. A fourth tract innervates the cerebellum, and a fifth tract innervates the spinal cord. The rostral portion of the LC innervates forebrain structures such as the hippocampus, whereas the caudal portion of the LC innervates hindbrain structures such as the cerebellum and spinal cord (Aston-Jones et al., 1995; Fallon & Loughlin, 1982; Loughin et al., 1982, 1986b). The degree of LC innervation to forebrain regions compared to the lateral tegmental neurons varies from region to region, but the hippocampus and cortex appear to receive sole innervation from the LC (Aston-Jones et al., 1995; Jones & Moore, 1977; Loughlin et al., 1986a, b; Mason & Fibiger, 1970; Moore & Bloom, 1979; Olsen & Fuxe, 1971; Ungerstedt, 1971; Waterhouse et al., 1983). Innervation from the LC to forebrain regions also appears to be ipsilateral for the majority of regions (Ader et al., 1980; Room et al., 1981). Since the LC contains more than half of all noradrenergic neurons in the CNS (Aston-Jones et al., 2000), a reduction in the number of these neurons could have major consequences on the activity of many forebrain regions.

#### **2.2 Synthesis of norepinephrine**

The major neurotransmitter localized to noradrenergic neurons is norepinephrine (NE). However, NE is not the only transmitter released from noradrenergic terminals. Noradrenergic neurons also co-localize and release several other neuropeptides such as galanin, enkepalin and neuropeptide Y. NE and DA share a common synthetic pathway. NE is synthesized by several enzymatic steps (Figure 1): tyrosine is converted to L-3, 4 dihydroxphenylalanine (L-DOPA) by tyrosine hydroxylase (TH); L-DOPA is converted to DA by aromatic amino acid decarboxylase (AADC), and then in noradrenergic neurons DA is converted to NE by dopamine β-hydroxylase (DBH). In adrenergic neurons, NE is then converted to epinephrine by phenylthanolamine-N-methyltransferase (PMNT). TH is considered the rate-limiting enzyme in the synthesis of NE and DA. However, there is evidence to indicate that DBH activity can affect NE levels in the CNS when DBH levels are altered genetically (Thomas et al., 1995, 1998; Bourdelat-Parks et al., 2005), with excessive stimulation of noradrenergic neurons (Scatton et al., 1984) or when DBH inhibitors such as disulfiram or nepicastat are administered (Goldstein, 1966; Musacchio et al., 1966; Bourdelat-Parks et al., 2005; Beliaev et al., 2006; Schroeder et al., 2010). DBH knockout mice lack the ability to convert DA to NE so the CNS levels of DA are elevated as compared to wild-type mice (Thomas et al., 1995, 1998). NE levels in the periphery and CNS can be restored in DBH knockout mice with the peripheral administration of L-3,4-dihydoxyphenylserine (DOPS). DOPS is converted to NE through AADC, in noradrenergic and non-noradrenergic neurons. TH knockout mice lack the ability to synthesize both DA and NE (Zhou & Palmiter, 1995).

1993; Zarow et al., 2003). The loss of LC noradrenergic neurons also precedes the loss of dopaminergic neurons in the progression of PD (Braak et al., 2003b, 2006), correlating to the

There are two major clusters of noradrenergic neurons in the central nervous system (CNS): the LC and the lateral tegmental neurons. In contrast to the significant loss of LC noradrenergic neurons in PD as indicated above, the lateral tegmental group does not appear to demonstrate much of a loss in PD (Saper et al., 1991). LC noradrenergic neurons send projections to forebrain regions via three different tracts: the central tegmental tract, the central gray dorsal longitudinal fasciculus tract, and the ventral tegmental-medial forebrain bundle. A fourth tract innervates the cerebellum, and a fifth tract innervates the spinal cord. The rostral portion of the LC innervates forebrain structures such as the hippocampus, whereas the caudal portion of the LC innervates hindbrain structures such as the cerebellum and spinal cord (Aston-Jones et al., 1995; Fallon & Loughlin, 1982; Loughin et al., 1982, 1986b). The degree of LC innervation to forebrain regions compared to the lateral tegmental neurons varies from region to region, but the hippocampus and cortex appear to receive sole innervation from the LC (Aston-Jones et al., 1995; Jones & Moore, 1977; Loughlin et al., 1986a, b; Mason & Fibiger, 1970; Moore & Bloom, 1979; Olsen & Fuxe, 1971; Ungerstedt, 1971; Waterhouse et al., 1983). Innervation from the LC to forebrain regions also appears to be ipsilateral for the majority of regions (Ader et al., 1980; Room et al., 1981). Since the LC contains more than half of all noradrenergic neurons in the CNS (Aston-Jones et al., 2000), a reduction in the number of these neurons could have major

The major neurotransmitter localized to noradrenergic neurons is norepinephrine (NE). However, NE is not the only transmitter released from noradrenergic terminals. Noradrenergic neurons also co-localize and release several other neuropeptides such as galanin, enkepalin and neuropeptide Y. NE and DA share a common synthetic pathway. NE is synthesized by several enzymatic steps (Figure 1): tyrosine is converted to L-3, 4 dihydroxphenylalanine (L-DOPA) by tyrosine hydroxylase (TH); L-DOPA is converted to DA by aromatic amino acid decarboxylase (AADC), and then in noradrenergic neurons DA is converted to NE by dopamine β-hydroxylase (DBH). In adrenergic neurons, NE is then converted to epinephrine by phenylthanolamine-N-methyltransferase (PMNT). TH is considered the rate-limiting enzyme in the synthesis of NE and DA. However, there is evidence to indicate that DBH activity can affect NE levels in the CNS when DBH levels are altered genetically (Thomas et al., 1995, 1998; Bourdelat-Parks et al., 2005), with excessive stimulation of noradrenergic neurons (Scatton et al., 1984) or when DBH inhibitors such as disulfiram or nepicastat are administered (Goldstein, 1966; Musacchio et al., 1966; Bourdelat-Parks et al., 2005; Beliaev et al., 2006; Schroeder et al., 2010). DBH knockout mice lack the ability to convert DA to NE so the CNS levels of DA are elevated as compared to wild-type mice (Thomas et al., 1995, 1998). NE levels in the periphery and CNS can be restored in DBH knockout mice with the peripheral administration of L-3,4-dihydoxyphenylserine (DOPS). DOPS is converted to NE through AADC, in noradrenergic and non-noradrenergic neurons. TH knockout mice lack the ability to synthesize both DA and NE (Zhou & Palmiter, 1995).

time that preclinical noradrenergic non-motor symptoms appear.

consequences on the activity of many forebrain regions.

**2.2 Synthesis of norepinephrine** 

**2. Noradrenergic cell bodies** 

**2.1 Anatomical** 

Fig. 1. Catecholamine biosynthesis and production of catecholamine knockout mice.
