Cortical neurons, generation

Two possible pathways for the biosynthesis of 2-AG have been proposed (1) a phospholipase C (PLC) hydrolysis of membrane phospholipids followed by a second hydrolysis of the resulting 1,2-diacylglycerol by diacylglycerol lipase or (2) a phospholipase Ai (PLA,) activity that generates a lysophospholipid, which in turn is hydrolyzed to 2-AG by lysophospholipase C (Fig. 5) (Piomelli, 1998). Alternative pathways may also exist from either triacylglycerols by a neutral lipase activity or lysophosphatidic acid by a dephosphorylase. The fact that PLC and diacylglycerol lipase inhibitors inhibit 2-AG formation in cortical neurons supports the contention that 2-AG is, at least predominantly, biosynthesized by the PLC pathway (Stella, 1997). However, a mixed pathway may also be plausible. 

The amino acid glutamate is the most widely used excitatory neurotransmitter in the central nervous system of mammals. Glutamate is the primary neurotransmitter used by the vast majority of reticular formation, thalamic and cortical neurons, which play a crucial role in the generation of the characteristic electrical activity as recorded in the electroencephalogram (for details see Steriade McCarley (2005)). The activity of these neurons is tightly regulated by the other neurotransmitters described in this chapter. 

A recent study showed THC to be toxic to hippocampal neurons, while sparing cortical neurons in concentrations likely to be reached in normal human doses (0.5 pM) (Chan et al. 1998). Apoptotic changes were noted in the hippocampus such as shrinkage of neuronal cell bodies and nuclei as well as DNA strand breaks. THC stimulates release of arachidonic acid, and it was hypothesized that this neurotoxic effect is mediated by cyclooxygenase pathways and free radical generation. In support of this, the toxicity is inhibited by nonsteroidal anti-inflammatory drugs, such as aspirin, and antioxidants such as vitamin E. 

The above examples point out at the direct stimulation of apoptosis by nitric oxide. At the same time, the exclusively rapid reaction of NO with superoxide always suggests the possibility of peroxynitrite participation in this process [141] correspondingly, the role peroxynitrite in the stimulation of apoptosis has been considered. Bonfoco et al. [144] has found that the producers of low peroxynitrite concentrations during the exposure of cortical neurons to the low level of NMDA or the use of peroxynitrite donors resulted in an apoptosis in neurons, while the high concentrations of peroxynitrite induced necrotic cell damage. The formation of peroxynitrite is apparently responsible for NO-stimulated apoptosis in superoxide-generating transformed fibroblasts because nontransformed cells, which do not produce superoxide, were not affected by nitric oxide [145]. It is of interest that proapoptotic effect of peroxynitrite may depend on the cell type. Thus, the formation of peroxynitrite enhanced the NO-induced apoptosis in glomerular endothelial cells, while superoxide inhibited the formation of ceramide and apoptosis in these cells exposed to nitric oxide probably due to peroxynitrite formation... 

Apoptosis is induced by various intra- and extracellular stimuli, and recently nitric oxide was reported to induce apoptosis in cultured cerebellar granule cells and cultured cortical neurons. The toxicity of nitric oxide is mainly ascribed to peroxynitrite, a reaction product of nitric oxide with superoxide (Figure 13.8). Cells producing an increased amount of SOD (superoxide, superoxide oxidoreductase EC 1.15.1.1) are resistant to nitric oxide-mediated apoptosis. In contrast, superoxide levels that have been increased by downregulation of Cu,Zn-SOD lead to apoptotic cell death in PC 12 cells, which required the reaction with nitric oxide to generate peroxynitrite. Peroxynitrite itself was found to induce apoptosis in PC12 cells and in cultured cortical neurons. 

The minicolumns can be demonstrated physiologically by experiments in which a microelectrode is inserted into the cortex in an essentially horizontal direction. When this is done, it is found that there are changes in the receptive properties of the cortical neurons every 50 p.m or so, as the electrode passes from one minicolumn into the next one, and that groups of these microcolumns are activated by peripheral stimuli to generate larger units, the macrocolumns, or functional columns. The question that has produced debate is what is the anatomical equivalent... 

The action of lobeline (237) as a nicotinic receptor agonist has continued to generate considerable interest. (-)-Lobeline demonstrated a potent hyperalgesic effect, similar to that of nicotine, when tested in the low intensity thermally evoked tail avoidance response assay [514]. It improved cognition and retention in rats comparably to nicotine [515]. Both 237 and nicotine exhibited anxiolytic effects in mice [516] and partially inhibited iV-methyl-D-aspartate-induced responses in rat cortical neurons in vitro [517]. It was a potent inhibitor of nicotine-induced prostration in rats (ED50 = 10 nM) and antagonized additional actions of nicotine including systolic blood pressure increases, seizure, and death [518]. 

The slow (deep sleep) -waves probably originate in the eortex beeause they survive separation from, or lesions of, the thalamus. However, the rhythm and appearanee of spindles in earlier phases of the sleep eyele do depend on links with the thalamus (see Steriade 1999). Unlike stimulation of the specific sensory relay nuclei in the thalamus, which only affects neurons in the appropriate sensory areas of the cortex, the nonspecific nuclei can produce responses throughout the cortex and may not only control, but also generate, cortical activity. Certainly, in vitro studies show that neurons of the non-specific reticular thalamic nucleus (NspRTN) can fire spontaneously at about 8-12 Hz (equivalent to EEG a-rhythm) or lower, and that low-frequency stimulation of this area can induce sleep. 

In addition, the brainstem contains a diffuse network of neurons known as the reticular formation. This network is best known for its role in cortical alertness, ability to direct attention, and sleep. It is also involved with coordination of orofacial motor activities, in particular those involved with eating and the generation of emotional facial expressions. Other functions include coordination of eating and breathing, blood pressure regulation, and response to pain. 

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