RESUMEN
Because the validity of the use of preaccumulated isotopic excitatory amino acids (EAAs) to index the depolarization-evoked release of endogenous EAAs has been questioned, we compared the K(+)-evoked efflux of preaccumulated D-[3H]aspartate from rat cerebrocortical minislices with that of endogenous L-aspartate and L-glutamate. Release of all EAAs increased with the rate of superfusion. Using the most rapid rate (1.6 ml/min), transient elevations in [K+] caused a concentration-dependent increase, with 50 mM K+ evoking a 33-, 23- and 93-fold increase in the efflux of D-[3H]aspartate, L-aspartate and L-glutamate, respectively; this efflux was Ca(2+)-dependent and tetrodotoxin insensitive. Under polarized conditions (5 mM K+), 1 mM kainic acid increased the efflux of preaccumulated and endogenous EAAs. These elevations were not blocked by the competitive kainate receptor antagonist 6,7-dinitroquinoxaline-2-3-dione (DNQX) and were not affected by removing Ca2+ ions. We conclude that in superfused cortical minislices, the efflux of preaccumulated D-[3H]aspartate provides a robust and reliable index of the release of endogenous L-aspartate and L-glutamate.
Asunto(s)
Ácido Aspártico/metabolismo , Corteza Cerebral/metabolismo , Ácido Glutámico/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Técnicas In Vitro , Ácido Kaínico/farmacología , Masculino , Potasio/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Tetrodotoxina/farmacologíaRESUMEN
This study used [3H]dizocilpine (MK-801) binding to the N-methyl-D-aspartate (NMDA) receptor to examine glycine, redox and zinc modulatory sites in membranes derived from the frontal and parietal cortex of control subjects (n = 8) and suicide victims (n = 6). [3H]dizocilpine binding in the presence of glutamate and glutamate plus glycine was similar in control and suicide subjects. The sulphydryl redox site was assessed using the oxidizing agent 5,5'-dithio-bis (2-nitrobenzoic acid), which inhibited binding in a dose-dependent fashion. Both redox and zinc sites were unaffected in the frontal and parietal cortex of suicide victims. These data indicate that the NMDA receptor and its glycine, redox and zinc subsites are preserved in the neocortex of suicide victims.
Asunto(s)
Química Encefálica , Maleato de Dizocilpina/metabolismo , Glicina/farmacología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Suicidio , Zinc/farmacología , Adulto , Femenino , Lóbulo Frontal/química , Ácido Glutámico/farmacología , Humanos , Canales Iónicos/efectos de los fármacos , Masculino , Oxidación-Reducción , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The integrity of dopaminergic, noradrenergic and serotonergic neurons in normal aging and Alzheimer's disease is reviewed. Loss of dopaminergic innervation of the neostriatum is a prominent age-related change, which corresponds with the age-related loss of dopaminergic cell bodies from the substantia nigra. This change is regionally specific, since dopaminergic innervation of the neocortex and the neostriatum are not affected. Although there is an age-related loss of noradrenergic cell bodies from the locus coeruleus, most studies indicate normal concentrations of noradrenaline in target areas. There is also evidence for reduced serotonergic innervation of the neocortex and, less convincingly, the neostriatum. Alzheimer's disease is associated with more pronounced noradrenergic and serotonergic denervation but, unlike normal aging, dopaminergic innervation of neostriatum is intact; although dopamine neurons are probably dysfunctional in this region. Studies relating neuronal markers to the symptomatology of Alzheimer's disease indicate that dysfunction of monoamine neurons is more closely linked to non-cognitive than to cognitive changes in behavior. In addition, monoaminergic therapies have been successful in ameliorating affective and psychotic behaviors along with sleep disturbances in both Alzheimer's disease and senescence. It seems likely that monoaminergic therapies (developed as we learn more about alterations in dopamine, noradrenaline and serotonin) will continue to be necessary to treat such behavioral disturbances.