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Snyder Et Al 81 P REGIONAL AUTORADIOGRAPHIC LOCALISATION OF NITRIC OXIDE SYNTHASE IN THE RAT BRAIN USING [3H]NITROARGININE EJ Kidd, AD Michel & I'l'A Humphrey. Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QJ. Nitric oxide synthase (NOS) is the enzyme responsible for the production of nitric oxide, a putative neurotransmitter. The distribution of this enzyme in rat brain (Vincent & Kamura, 1992) and spinal cord (Valtschanoff et al., 1992) neurones has previously been studied using the NADPH-diaphorase technique. However, this method may not be specific for NOS and therefore a more selective tool would be valuable. Nitroarginine is an inhibitor of NOS which has recently become available in a tritiated form. We have shown that the binding of this radioligand to the soluble enzyme can be prevented by L-arginine (Michel et al., 1993) and have now examined the regional distribution of its binding in the rat cenitral nervous system (CNS) using autoradiography. Frozen sections (20 gin) of unfixed brain and spinal cord, on coated slides, were preincubated in 50 mM Tris.HCI, 3 mM CaCl2 and 0.025% Triton X100 butter, pH 7.4 for 30 min at 25°C, then incubated for 60 min at 4°C with -7 nM [3H]nitroarginine (Michel et al., 1993) with or without 1 jM nitroarginine for non-specific binding, washed for 3 x 10 min and dipped for 10 sec in ice-cold distilled water. The dried slides were apposed to X-ray film for 3 months and the images were quantified using suitable standards. The highest levels of specific binding (grey values, mean ± s. e. mean, n 2 19) were found in the tenia tecta (0.155 ± 0.009), throughout the amygdaloid complex, in particular in the anterior (0.107 ± 0.007) and medial (0.125 ± 0.006) nuclei, the amygdalopiriform transition (0.134 ± 0.005) and in the anterior cerebellum (0.087 ± 0.002). There was also binding in the thalamic bed nucleus of the stria terminalis (0.067 ± 0.005), the dentate gyrus (0.033 ± 0.001), the ventral hippocampal CA3 area (0.051 ± 0.002), layers 1 and 2 of the frontal cortex (0.064 ± 0.003) and the superior gray layer of the superior colliculus (0.053 ± 0.002). The paraventricular nucleus of the hypothalamus and the superficial layers of the dorsal hom of the thoracic and lumbar spinal cord were also labelled but this was not quantifiable at this time point. Binding in the striatum and the rest of the cortex was diffuse and therefore not quantified. There appeared to be few or no specific binding sites in the pons and medulla. The regional distr-ibution of binding sites for [3H]itroargiine in the rat CNS was, in general, similar to that seen with the diaphorase method. There were, however, differences in the cortex and the hindbrain which may be due to the existence of more than one isoform of NOS in the CNS. Thus, [3H]nitroarginine appears to be a very useful ligand for studying the distribution of NOS in the CNS and may also be capable of distinguishing between potential isoforms. More studies are plamned using dual labelling techniques to determine whether [3H]nitroarginine binds to cells, labelled either with the diaphorase method or a specific antibody to the cloned braini isoform of NOS. Valtschanoff, J.G., Weinberg, R.J. & Rustionii, A. (1992). J. Comp. Neurol., 321, 209-222. Vinicenit, S.R. & Kimura, H. (1992). Neuroscience, 46, 755-784. Michel, A.D., Phul, R., Stewart, T. & Humphi-ey, P.P.A. (1993). Br. J. Pharmacol., 109, 287-288. 82P HIGH-AFFINITY UPTAKE OF L-ARGININE BY CEREBELLAR AND CORTICAL SYNAPTOSOMES Christian R. Aldridge & Keith J. Collard, Department of Physiology, University of Wales College of Cardiff, P.O. Box 902, Cardiff CF1 lSS. There is good evidence that nitric oxide (NO) may have transmitter-like functions in the peripheral nervous system (Belvisi et al. 1992), but little is known about such a role in the CNS. In order to function in a transmitter-like manner, NO must be formed locally within nerve endings. NO synthase is present in synaptosomal fractions (Knowles et al. 1990), but the precursor amino acid is formed mainly in glial cells (Aoki et al. 1991). Consequently, a transcellular transport of L-arginine has been suggested to operate in which L-arginine released by glial cells is taken up by neurones and used for the production of NO (Hansel et al. 1992). In this preliminary study, we have re-examined the transport of L-arginine in synaptosomes prepared from rat cerebellum and cortex. Standard procedures routinely used in our laboratory to study synaptosomal amino acid transport were adapted for this study (Wilkinson & Collard 1984). The kinetics of the uptake of L-arginine at 370C revealed that uptake could be resolved into a single saturable carrier-mediated process with minimal diffusion. Linear transformation of the data provided values for Km and Vmax as follows: Cortical synaptosomes, Km 26.3 uM, Vmax 357.1 pmol/mg protein/min; cerebellar synaptosomes, Km 45.45 uM, Vmax 512.8 pmol/mg protein/min. Using an incubation concentration of 10 uM, L-arginine uptake (pmol/mg protein/min) in Na+-rich Krebs in cortical and cerebellar synaptosomes was 94.02 ± 3.9 and 94.13 ± 9.76 respectively. In the absence of extracellular Na4 it was 225.21 ± 11.06 and 234.33 ± 15.7 (n=5). The difference between uptake in Na+-rich and Na+- free conditions was significant (P<0.001 Student's t test). The results of this study have revealed the presence of a high-affinity L-arginine uptake system which differs kinetically and in its Na+-dependency from the low-affinity carrier previously described (Snyder et al. 1973). The relationship between this carrier and the production of NO in nerve endings has yet to be investigated. However, the high-affinity nature of the carrier and its inhibition by Na suggests that it is a carrier which may be involved in the production of neurally active material and which may be regulated by changes in ion distribution across the plasma membrane. Aoki, E., Semba, R., Mikoshiba, K. & Kashiwamata, S. (1991) Brain Res. 547 190-192. Belvisi, M.G., Stretton, C.D., Yacoub, M. & Barnes, P.J. (1992) Eur. J. Pharmacol. 210 221-222. Hansel, C., Batchelor, A., Cuenod, M., Garthwaite, J., Knupfel, T. & Do, K.Q. (1992) Neurosci. Lett. 142 211-214. Knowles, R.G., Palacios, M., Palmer, R.M.J. & Moncada, S. (1990) Biochem. J. 269 207-210. Snyder, S.H., Young, A.B., Bennett, J.P. & Mulder, A.H. (1973) Fed. Proc. 32 2039-2047. Wilkinson, L.S. & Collard, K.J. (1984) J. Neurochem. 43 274-275. 83P BEHAVIOURAL RECOVERY FOLLOWING INTRASTRIATAL LESIONS WITH QUINOLINIC ACID IS NOT RELATED TO SURVIVAL OF NITRIC OXIDE SYNTHASE-POSITIVE NEURONES L. M. Tucker, P. C. Emson' & A. J. Morton (introduced by J.M.Edwardson), Department of Pharmacology, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QJ, aK and 1 Cambridge Research Station, Babraham, Cambridge CB2 4AT, MX. Intrastriatal injections of quinolinic acid (QA) are said to induce pathology which is similar to that of Huntington's disease, including the relative sparing of neurones containing NADPH-diaphorase (Beal et al., 1986). However, using high QA concentrations we find extensive loss of these neurones. With the discovery that NADPH- diaphorase is the neuronal form of nitric oxide synthase (NOS; Hope et al., 1991) there has been speculation about the role which neurones containing this enzyme may play in the pathogenesis of excitotoxic neuronal damage. We examined the effect of unilateral, intrastriatal injections of QA (10, 30, 50 and 100 nmol) on the survival of NOS-positive neurones in rat striatum for periods up to three months. We used methamphetamine-induced rotation as a measure of the striatal damage induced by QA, and looked to see if there was a correlation between the level of drug-induced rotation and the sparing of NOS-containing neurones. Methamphetamine (5 mg/kg i.p.) was administered to rats lesioned with QA up to 3 months previously. Rotations were counted over the next 60 minutes in an automated rotometer. After testing, the rats were perfusion-fixed with 2% paraformaldehyde in 0.1M PBS and cryostat sections (30jm) of brain were cut and stained immunocytochemically for NOS using a rabbit antiserum (gift of Dr. A. Davenport). NOS-positive cells in the lesioned and contralateral unlesioned striata were counted in 6 serial sections (1501±m apart) from each rat (3 rats per group). Rotation (mean turns/hour ± SEM for each group) increased over the first two weeks following lesioning with 50 nmol QA (from 24±80 at 1 day to 531±170 at 9 days) suggesting that striatal damage was progressive over this period. The increase seen after 100 nmol QA (from 266±202 at 1 day to 653±153 at 9 days) was not significant. (Vehicle-lesioned control rotation was 23±10 at 9 days). By 23 days post-lesion, rotation was significantly reduced in rats with 50 nmol, but not 100 nmol QA lesions (control, 31±49; 50 nmol QA, 124±161; 100 nmol QA, 523±150). After 30 nmol QA, there was some rotation at two weeks (53±18 turns/hour) but by three months rotation was no longer seen. Rats with 10 nmol QA lesions did not rotate. The size of the lesions as determined by the extent of reactive gliosis was directly proportional to the amount of QA injected. There was extensive loss of NOS-positive neurones from all lesions but not from regions immediately beyond the lesion.
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