NOS in the Nervous System

NO as a neuronal messenger molecule was first described by Garthwaite et al. (1988), who showed that cerebellar granule cells release NO after 

---

The nNOS knockout mice provide a unique opportunity to explore many of the postulated functions of NO in the nervous system. In the nNOS null mice LTP induced by weak intensity tetanic stimulation was only slightly reduced (O Dell et al., 1994). This LTP was blocked by NOS inhibitors, just as it is in the wild type (O Dell et al., 1994), suggesting that eNOS expressed in the hippocampus may be more important than nNOS to LTP. 

NADPH diaphorase histochemistry is now the most widely used method for revealing the distribution of NOS in the nervous system. Using this approach, the anatomy of putative NO-producing neurons has been described in the nervous systems of several mammalian species, a variety of other vertebrate species, and invertebrates (7—11). A major advantage of the NADPH diaphorase method over such alternatives as NOS immunocytochemistry and in situ hybridization is that the only specific reagents required are NBT and NADPH, both of which can be easily purchased Moreover, to date anti-NOS antibodies have been raised only to forms of the enzyme obtained from mammals and... 

Finally, perhaps one of the oddest of recent discoveries is that toxic gases, such as nitric oxide (NO) and carbon monoxide (CO), can act as dual first/second messengers in the nervous system (Haley, 1998). Our current ideas of how drugs affect the complex events and regulation of synaptic neurotransmission are very simplistic and the real situation is obviously vastly more complicated. Some of these issues will be addressed in more detail in Chapter 14. 

Rats exposed to 16-1,694 mg/kg/day and mice exposed to 25-2,642 mg/kg/day phenol in drinking water exhibited no abnormal histology of the brain after 13 weeks of exposure (NCI 1980). Histopathological changes in the brain were not evident after 103 weeks of exposure to 322 or 645 mg/kg/day in male rats, 360 or 721 mg/kg/day in female rats, 590 or 1,180 mg/kg/day in male mice, and 602 or 1,204 mg/kg/day in female mice (NCI 1980). However, this study did not include tests for neurological impairment or histopathological examinations of tissues in the nervous system other than the brain. 

Reiativeiy recentiy, the gases nitric oxide (NO) and carbon monoxide (CO) have been found to act as neurotransmitters in the nervous system. Nitric oxide is synthesized from L-arginine via nitric oxide synthase, requiring NADPH as a co-enzyme and tetrahydrobiopterin as a cofactor. Unlike other neurotransmitters, NO is a smaii, very soiubie moiecuie and cannot be stored in synaptic vesicles. Rather, it is synthesized on demand and freeiy diffuses through membranes. It is not broken down enzymaticaiiy because it is unstabie and degrades rapidiy. NO may have several actions, one of which is to increase the production of cGMP by guanyiyi... 

Although ubiquitin was used as a marker for brain pathology, no physiological or pathological role for ubiquitin in the nervous system was found until about a decade ago. The first discovery of ubiquitin—proteasome-mediated degradation of a physiologically relevant substrate in the nervous system was that of R subunits of PKA. Since then several substrates of the ubiquitin—proteasome pathway in the nervous system have been identified (Table 6). 

It may come as a surprise that CO is synthesized by the human body and has roles in human metabolism. Specifically, an enzyme that degrades heme, a constituent of hemoglobin, our oxygen-transporting protein, makes CO, which is a neurotransmitter. Much more about neurotransmitters follows in chapter 21 when we talk about the central nervous system. For the present, just understand that specialized cells known as neurons are the conduits for communication in the nervous system. Neurotransmitters are small molecules that relay information from one neuron to another. Neurotransmitter CO is made, functions, and is quickly destroyed. Personally, I find it surprising that CO has such a critical role in the nervous system. Surprised or not, there it is and there is no doubt about it. 

Her case is one of a great many in which some decline in optimal mental function compromises life. These compromises fall into two general categories, whose distinction may be less real than apparent. On the one hand, there are neurological diseases in which there is some detectable, definable lesion in the nervous system. In the last chapter, we met one notable example Alzheimer s disease. As mentioned then, Alzheimer s disease is characterized by amyloid plaques external to neurons and fibrillary tangles within them—clear lesions. On the other hand, there are psychiatric diseases in which the pathology is clear but for which we can detect no lesion in the nervous system. Depression and schizophrenia provide two important examples. 

Increased response to tactile stimuli and hyperactivity occurred in male mice at initiation of daily dermal exposures for 1 week to 0.1 mL kerosene (Upreti et al. 1989). Females were not tested in this study. No histopathological changes were noted in the nervous system of mice exposed to 2,000-8,000 mg/kg/day JP-5 for 13 weeks or mice chronically exposed to 250 or 500 mg/kg/day of either marine diesel fuel or JP-5 (NTP/NIH 1986). 

No studies were located regarding neurological effects in humans after oral exposure to 2,3-benzofuran. No abnormalities in the nervous systems were detected by histopathologic examination of rats and mice exposed to... 

Stimulation of N-methyl-D-aspartate (NMDA) receptors (see Chapter 16) in the nervous system is linked to activation of NO synthase and creation of an intracellular NO signal (Yun et al., 1998). NO can directly activate Ras protein redox modification of Ras protein is assumed to take place in this process. 

The genes for all three a-LTX receptors have been knocked out in mice, and these mutations are not lethal. NRX la knockout mice show no obvious behavioral phenotype (Geppert et al. 1998). LPH1 knockout causes social problems in mice (Tobaben et al. 2002), consistent with LPH1 involvement in schizophrenia (Chen and Chen 2005). PTPo knockout leads to developmental abnormalities in the nervous system and outside it (Meathrel et al. 2002 Batt et al. 2002). 

The various components of the nervous system can be further differentiated into three basic cellular elements (1) neurons, (2) interstitial cells, and (3) connective tissue, blood vessels, and microglia. The neuron is the only cell type in the nervous system involved in information processing. Each neuron is, in its own right, a receiver, an integrator, and a transmitter of information. Neurons are always in contact with other neurons so that they create simple or complex channels through which many different responses can be transmitted. All behavior, no matter how complex, results from the interactive function of the billions of neurons. 

---