Abstract: Direct intrastriatal injection of N ‐methyl‐D‐aspartate (NMDA; 100 μg/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 ED 50 values of 6 and 1 mg/kg, i.p., respectively. CPP antagonized the harmaline‐induced increases in cGMP levels with an ED 50 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.
BMY-14802 [alpha-(4-flurophenyl)-4-(5-fluoro-pyramidinyl)-1-piperazine butanol], a potent sigma ligand with poor affinity for dopamine and phencyclidine receptors in vitro, attenuated parenteral harmaline- and direct intracerebellar D-serine-induced increases in mouse cerebellar cGMP. Intracerebroventricularly injected BMY-14802 also antagonized the effects of intracerebellar D-serine, indicating a central mechanism. However, direct co-injection of BMY-14802 into the cerebellum failed to antagonize the D-serine-induced increases in cGMP, indicating a locus of action outside the cerebellum. In contrast, quisqualate-induced cGMP increases were not attenuated by BMY-14802. These results indicate a functional modulation of the N-methyl-D-aspartate/glycine/phencyclidine/ion channel complex-mediated events by BMY-14802, possibly through a transsynaptic mechanism, thus representing the first in vivo demonstration of a sigma ligand modulation of a response mediated through the N-methyl-D-aspartate receptor complex.
Abstract: Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N ‐methyl‐D‐aspartate (NMDA)‐coupled and ‐uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [ 3 H]1‐(2‐thienyl)cyclohexylpiperidine with an IC 50 of 79 n M without affecting σ ‐ , glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA‐coupled PCP recognition sites, tiletamine decreased basal, harmaline‐, and D‐serine‐mediated increases in cyclic cGMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3‐hydroxy[ 3 H]PCP to its high‐affinity NMDA‐uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK‐801), ketamine, PCP, dexoxadrol, and 1‐(2‐thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA‐uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK‐801‐induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA‐uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100–500 μg/rat), tiletamine increased pyriform cortical DA metabolism with a bell‐shaped dose‐response curve. These data indicate a differential interaction of tiletamine with the NMDA‐coupled and ‐uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology.
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