**5. LC innervation of dopaminergic regions**

As indicated above, LC noradrenergic neurons are reduced early in the progression of PD (Braak et al., 2003b, 2006). However, for the noradrenergic system to be involved in the progression of PD, LC noradrenergic neurons need to innervate the regions involved in the symptoms of PD (i.e., striatum and SN). There is evidence to indicate that the LC noradrenergic nervous system can modulate dopaminergic activity at the level of the striatum and the SN as well as the ventral tegmental area (VTA) at the anatomical, electrophysiological, neurochemical, and behavioral levels.

## **5.1 LC innervation to striatum**

LC noradrenergic neurons have direct projections to the striatum, though evidence indicates this innervation may be sparse (Aston-Jones et al., 1995; Jones & Moore, 1977; Jones & Yang, 1985; Mason & Fibiger, 1979; Swanson & Hartman, 1975). When measured, NE concentration in the striatum is low (especially compared to DA), while NET binding (a marker of noradrenergic terminals) is not detectable (Szot, Personal communication; Koob et al., 1975; Nomura et al., 1976). However, the striatum does contain a dense amount of betaadrenergic receptors (β-AR) (Byland & Snyder, 1976; Dolphin et al., 1979; Rainbow et al., 1984; Strazielle et al., 1999), as well as alpha2-AR (α2-AR) (Szot, Personal communication; Boyajian et al., 1987; Hudson et al., 1992; Nicholas et al., 1992; Scheinin et al., 1994; Strazielle et al., 1999; Zeng and Lynch, 1991) and alpha1-AR (α1-AR) (Szot, Personal communication; Rommelfanger et al., 2009; Strazielle et al., 1999) binding sites. Direct application of NE or administration of AR agents can affect the activity of striatal neurons and release of DA in the striatum (Bevam et al., 1975; Fujimoto et al., 1981; Lategan et al., 1990).

The Noradrenergic System is a Major Component in Parkinson's Disease 255

administered peripherally and depending on the dose and the number of times it is administered, a mild to severe degree of dopaminergic neuronal loss can be observed (Betarbet et al., 2002; Dauer & Przedborski, 2003; Jackson-Lewis & Przedborski, 2007; Luchtman et al., 2009). However, MPTP is not effective in rats (Jackson-Lewis & Przedborski, 2007). To reduce the number of SN dopaminergic neurons in rats, 6OHDA is administered directly into the medial forebrain bundle using stereotaxic surgery. The effect

of 6OHDA in the SN is rapid and appears permanent (Walsh et al., 2011).

**transgenic mice** 

neurons in the SN from damage.

**6.2.2 Neuroprotective effect of AR agents** 

**6.2 Enhanced LC function reduces dopaminergic neurotoxin-induced damage 6.2.1 Neuroprotective effect of enhanced noradrenergic function in tottering and NET** 

The tottering mouse has a mutation that results in hyperinnervation of noradrenergic terminals and increased concentration of NE throughout most regions of the forebrain. Administration of MPTP to these mutant mice has less of an effect on dopaminergic terminals in the striatum (i.e., loss of DA level) as compared to wild-type mice (Kilbourne et al., 1998). Another transgenic mouse that has enhanced noradrenergic function is the NET knockout mouse. NET knockout mice do not express the transporter protein for NE, which are localized specifically to noradrenergic neurons and responsible for removing NE from the synapse, resulting in enhanced NE in the synapse. Administration of MPTP to NET knockout mice, again, results in reduced damage to dopaminergic terminals in the striatum and DA levels in the striatum as compared to wild-type mice (Rommelfanger et al., 2004). These studies indicate that an enhanced noradrenergic system can protect dopaminergic

Another means of increasing noradrenergic function is to administer noradrenergic agonists. Administration of NET inhibitors to increase synaptic NE levels results in reduced dopaminergic damage on SN terminals in the striatum and DA levels, resembling the effect observed in the NET knockout mouse (Rommelfanger et al., 2004). Peripheral administration of α2-AR agonists such as clonidine and detomidine also reduces MPTPinduced reduction in striatal DA levels, while administration of α2-AR antagonists enhances MPTP-induced damage in mice (Fornai et al., 1995a). However, when 6OHDA is used as the dopaminergic neurotoxin in rats, the peripheral administration of α2-AR antagonists reduces the loss of DA in the striatum (Srinivasan & Schmidt, 2004b, c), the opposite of what is observed in mice with MPTP. The ability of α2-AR agents to either enhance or reduce damage on dopaminergic neurons could be attributed to the different species (rats versus mice) or the neurotoxin (MPTP versus 6OHDA) used. Another possible reason for the conflicting data of α2-AR agents is the complexity of the α2-AR. The α2-AR receptor is composed of three different subtypes: α2A-, α2B-, and α2C-AR. α2A- and α2C-ARs are localized on dendrites and terminals of noradrenergic neurons where they act as presynaptic autoreceptors to regulate the release of NE ( L'Heureux et al., 1986; Van Gaalen et al., 1997; Kawahara et al., 1999), as well as postsynaptic receptors on dendrites and terminals of NE target cell that regulate the release of other neurotransmitters (heteroreceptors). α2A-ARs are the most abundant α2-AR subtype in the brain, comprising approximately 90% of all central α2-ARs (Bucheler et al., 2002). The highest density of α2C-AR is in the striatum, while α2B-ARs have a very limited expression in the brain (Nicholas et al., 1993; Zeng & Lynch, 1991).
