cyclic-gmp and 3-methoxytyramine

In vitro microdialysis was used to investigate the mechanism of nitric oxide (NO) donor-induced changes in dopamine (DA) secretion from PC12 cells. Infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP, 1.0 mm) induced a long-lasting increase in DA and 3-methoxytyramine (3-MT) dialysate concentrations. SNAP-induced increases were inhibited either by pre-infusion of the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazolo[4,3]quinoxalin-1-one (ODQ, 0.1 mm) or by Ca2+ omission. Ca2+ re-introduction restored SNAP effects. SNAP-induced increases in DA + 3-MT were unaffected by co-infusion of the l-type Ca2+ channel inhibitor nifedipine. The NO-donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3, 1.0 mm) induced a short-lasting decrease in dialysate DA + 3-MT. Ascorbic acid (0.2 mm) co-infusion allowed NOR-3 to increase dialysate DA + 3-MT. ODQ pre-infusion inhibited NOR-3 + ascorbic acid-induced DA + 3-MT increases. Infusion of high K+ (75 mm) induced a 2.5-fold increase in dialysate DA + 3-MT. The increase was abolished by NOR-3 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mm) with NOR-3 + high K+ restored high K+ effects. Co-infusion of nifedipine inhibited high K+-induced DA + 3-MT increases. These results suggest that activation of the NO/sGC/cyclic GMP pathway may be the underlying mechanism of extracellular Ca2+-dependent effects of exogenous NO on DA secretion from PC12 cells. Extracellular Ca2+ entry may occur through nifedipine-insensitive channels. NO effects and DA concentrations in dialysates largely depend on both the timing of NO generation and the extracellular environment in which NO is generated.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Ascorbic Acid; Calcium; Calcium Channel Blockers; Cell Survival; Cyclic GMP; Dopamine; Enzyme Inhibitors; Extracellular Space; Homovanillic Acid; Microdialysis; Nitric Oxide; Nitric Oxide Donors; Nitro Compounds; PC12 Cells; Pheochromocytoma; Potassium; Rats; S-Nitroso-N-Acetylpenicillamine

We showed previously, using in vitro microdialysis, that activation of the nitric oxide (NO)/cyclic GMP pathway was the underlying mechanism of exogenous NO-induced dopamine (DA) secretion from PC12 cells. In this study, infusion of the potential peroxynitrite generator 3-morpholinosydnonimine (SIN-1, 1.0 mM for 60 min) induced a long-lasting decrease in dialysate DA+3-methoxytyramine (3-MT) in dialysates from PC12 cell suspensions. Ascorbic acid (0.2 mM) co-infusion allowed SIN-1 to increase dialysate DA+3-MT. SIN-1+ascorbic acid effects were abolished by Ca(2+) omission. Infusion of high K(+) (75 mM) induced a 2.5-fold increase in dialysate DA+3-MT. The increase was inhibited by SIN-1 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mM) with SIN-1+high K(+) resulted in a 3.5 fold increase in dialysate DA+3-MT. The L-type Ca(2+) channel inhibitor nifedipine selectively inhibited the DA+3-MT increase pertaining to high K(+), while the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]-oxadiazolo[4,3]quinoxalin-1-one selectively inhibited the increase pertaining to SIN-1 effects. These results suggest that activation of the NO/sGC/cyclic GMP pathway is the underlying mechanism of extracellular Ca(2+)-dependent effects of SIN-1 on DA secretion from PC12 cells. Extracellular Ca(2+) entry occurs through nifedipine-insensitive channels. Ascorbic acid is a key determinant in modulating the distinct profiles of SIN-1 effects.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium; Calcium Channel Blockers; Cyclic GMP; Dialysis; Dopamine; Drug Interactions; In Vitro Techniques; Molsidomine; Nifedipine; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; PC12 Cells; Potassium; Rats; Signal Transduction; Time Factors

Direct intrastriatal injection of N-methyl-D-aspartate (NMDA; 100 micrograms/rat) increased striatal dopamine (DA) release in vivo. However, parenteral administration of (+/-)-3-(2-carboxypiperizin-4-yl)propyl-1-phosphonic acid (CPP) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) did not alter DA metabolism and release in several brain regions in the rat and mouse. Intracerebroventricular administration of the competitive NMDA antagonists CPP, CGS-19755, 2-amino-5-phosphonopentanoate, and 2-amino-7-phosphonoheptanoate did not alter rat striatal DA metabolism and release but profoundly reduced cerebellar cyclic GMP (cGMP) levels in the same animals. CPP and CGS-19755 decreased basal cerebellar cGMP levels in the mouse with ED50 values of 6 and 1 mg/kg, i.p., respectively. CPP antagonized the harmaline-induced increases in cGMP levels with an ED50 value of 5.0 mg/kg, i.p. CPP (25 mg/kg, i.p.) also decreased basal cGMP levels in mouse cerebellum for up to 3 h, a result suggesting brain bioavailability and a long duration of NMDA receptor antagonism in vivo. These contrasting patterns suggest that NMDA receptors exert a tonic excitatory tone on the guanine nucleotide signal transduction pathway in the cerebellum while exerting a phasic control over nigrostriatal dopaminergic neurotransmission. These results also indicate that competitive NMDA antagonists, unlike phencyclidine receptor agonists, may not mediate biochemical and behavioral effects via dopaminergic mechanisms.

Topics: Animals; Cerebellum; Corpus Striatum; Cyclic GMP; Dopamine; Glutamine; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Rats; Rats, Inbred Strains; Substantia Nigra; Synaptic Transmission

The stable analogues of adenosine, N-ethylcarboxamidoadenosine (NECA), R-phenylisopropyladenosine (R-PIA) and cyclohexyladenosine (CHA), dose-dependently decreased levels of 3-methoxytyramine (3-MT) in the striatum and antagonized pargyline-dependent accumulation of 3-methoxytyramine. These agents were equipotent with ED25 values of approximately 1 mg/kg, (p.o.) in inhibiting pargyline-dependent accumulation of 3-methoxytyramine. Since CHA and R-PIA are relatively selective for A1 receptors and NECA is almost equipotent at A1 and A2 sites, the data of undifferentiated potency for these 3 agents on release of dopamine (levels of 3-MT) would argue in favor of mediation of A1 receptors in this phenomenon. This conclusion was further supported by experiments with the A1-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDX), which antagonized the actions of CHA. Similar antagonism of CHA-dependent decreases in levels of cyclic GMP in the cerebellum, an action known to be mediated by A1 receptors, was also observed. These data support previous studies which indicated an adenosine receptor-mediated modulation of nigrostriatal release of dopamine. In addition, the present data indicate that this is an action on A1 receptors.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Brain; Cerebellum; Corpus Striatum; Cyclic GMP; Dopamine; Dopamine Antagonists; Male; Phenylisopropyladenosine; Proteins; Rats; Rats, Inbred Strains; Receptors, Purinergic

The dibutyryl analogues of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were administered into the lateral ventricles and catecholamine metabolites were determined in brain 40 min later. Dibutyryl cAMP elevated the level of homovanillic acid in whole brain and dihydroxyphenyl acetic acid levels in striatum, the dopamine-rich part of the limbic system and hemispheres but neither affected the accumulation of 3-methoxytyramine following inhibition of MAO with pargyline nor dopamine and noradrenaline levels. Normetanephrine accumulating after MAO inhibition was elevated markedly by dibutyryl cAMP. Dibutyryl cGMP was without effect on the catecholamine metabolites investigated. Dibutyryl cAMP appears to stimulate dopamine metabolism within dopaminergic nerve endings but does not stimulate dopamine release. Dibutyryl cAMP-induced activation of noradrenaline metabolism, however, appears to coincide with a stimulation of noradrenaline release.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain; Brain Chemistry; Bucladesine; Catecholamines; Cyclic GMP; Dibutyryl Cyclic GMP; Dopamine; Homovanillic Acid; Male; Normetanephrine; Phenylethyl Alcohol; Rats; Rats, Inbred Strains