HIV-1 Envelope Protein gp120 Potentiates NMDA-evoked Noradrenaline Release by a Direct Action at Rat Hippocampal and Cortical Noradrenergic Nerve Endings

Exposure of rat or human neocortical or hippocampal tissue to glutamate receptor agonists elicits a Ca²⁺-dependent, exocytotic-like release of previously accumulated [³H]noradrenaline through activation of both N -methyl- d -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors colocalized on the noradrenergic axon terminals. Here we show that the NMDA (100 μM)-evoked release of [³H]noradrenaline from superfused thin layers of isolated rat hippocampal or cortical nerve endings was potentiated when the human immunodeficiency virus type 1 coat protein gp120 was added to the superfusion medium concomitantly with NMDA. The effect of gp120 (10 pM to 3 nM) on the 100 μM NMDA-evoked release of [³H]noradrenaline was concentration-dependent; the maximal effect (-140% potentiation) was reached at 100 pM of gp120. The protein was inactive on its own. The [³H]noradrenaline release evoked by NMDA (100 μM) + gp120 (100 μM) was prevented by classical NMDA receptor antagonists, as well as by 10 μM memantine. Neither the release evoked by NMDA nor that elicited by NMDA + gp120 was sensitive to the nitric oxide synthase inhibitor N ^G -nitro- l -arginine, suggesting no involvement of nitric oxide. The [³H]noradrenaline release elicited by 100 nM AMPA was unaffected by gp120. The protein potentiated the release evoked by 100 nM glutamate; the effect of 100 pM gp120 was quantitatively identical to that of 1 μM glycine, with no apparent additivity between gp120 and glycine. The antagonism by 1 μM 7-chloro-kynurenic acid of the NMDA-induced [³H]noradrenaline release was reversed by glycine or gp120. The data are compatible with gp120 acting directly as a powerful positive allosteric modulator at a neuronal NMDA receptor.     

Retinal ganglion cell loss produced by intraocular kainic acid in cats: variation with somal size and eccentricity

Eight eyes of adult cats were injected with different doses of kainic acid (KA) and examined following survival times of either 5 or 12 days. At a survival time of 12 days, a dose of 76 nmol produced an 18% lossof ganglion cells in the center of the area centralis (AC), 70% loss at a location 2 mm from the AC, and 95% loss at a location 6 mm from the AC. Larger doses (240, 760 and 2400 nmol) produced losses comparable to that observed for 76 nmol. For example, 2400 nmol produced a 35% loss in the AC, 81% at 2 mm, and 88% at 6 mm. At a survival time of 5 days, doses of 240 and 760 nmol produced a loss of ganglion cells comparable to that seen at 12 days. In one eye, a large dose of KA (7600 nmol) produced total loss of ganglion cells at a survival time of 5 days. By comparing loss of cells in restricted somal diameter ranges at different retinal eccentricities, it was possible to distinguish two significant correlations that were largely independent of survival time and dose: (1) at 2 mm, loss of cells with somal diameters larger than 21 μm significantly exceeded loss of cells with smaller somata. In particular, alpha cells were totally eliminated in 6 of the 8 KA-treated eyes. (2) The mean loss of ganglion cells with somal diameters less than 21 μm was significantly greater at 2 mm and 6 mm than in the AC. Together, these results show that loss of ganglion cells produced by KA varies somal size and retinal eccentricity.