2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

To evaluate the possibility of pharmacologically distinct N-methyl-D-aspartate (NMDA) receptor subtypes, quantitative autoradiography was used to determine the potency of several compounds as inhibitors of L-[3H]glutamate or [3H]MK-801 binding to rat brain NMDA receptors in 10 brain regions. Competitive NMDA receptor antagonists displayed differing pharmacological profiles in the forebrain, cerebellum, and medial regions of the thalamus (midline nuclei). For example, compared with other competitive antagonists, 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP) and LY-233536 were especially weak displacers of L-[3H]glutamate binding in the cerebellum. In the the medial thalamus, CPP and D-2-amino-5-phosphonopentanoate displayed relatively low affinities, whereas LY-233536 was relatively potent. The noncompetitive NMDA receptor antagonists also displayed regional variations in their pharmacological profiles. Relative to other regions, [3H]MK-801 binding in the cerebellum was weakly displaced by MK-801 and potently displaced by dextromethorphan and SKF-10047. In the medial thalamus, 1-[1-(2-thienyl)-cyclohexyl]piperidine was relatively potent and SKF-10047 was relatively weak. These results confirm previous suggestions that the cerebellum contains a distinct NMDA receptor subtype and indicate that nuclei of the medial thalamus contain a novel NMDA receptor subtype that is distinct from both those found in the cerebellum and in the forebrain.

Topics: Animals; Autoradiography; Cerebellum; Dizocilpine Maleate; Glutamates; Phenazocine; Piperazines; Prosencephalon; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Thalamus

The present report investigates the modulation of the hypothalamic-pituitary-adrenal (HPA) axis in the rat by sigma receptors, using a selective ligand, (+) pentazocine, and comparing the effects with (+) SKF 10, 047. Both compounds stimulate ACTH release potently after central and peripheral administration. These effects are centrally mediated, since they did not release ACTH from anterior pituitary primary cultures. The effects are not blocked by naloxone, but are blocked by the NMDA antagonist, CPP, indicating a centrally mediated functional interaction between NMDA and sigma receptors, in vivo.

Topics: Adrenocorticotropic Hormone; Animals; Aspartic Acid; Cells, Cultured; Hypothalamo-Hypophyseal System; Male; N-Methylaspartate; Pentazocine; Phenazocine; Piperazines; Pituitary-Adrenal System; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, sigma

Competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists and other central nervous system depressants were assessed for their ability to antagonize the discriminative stimulus effects of NMDA in rats trained under a standard two-lever fixed ratio schedule of food reinforcement. The competitive NMDA antagonists, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate and NPC 12626 [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate], dose-dependently antagonized NMDA-lever selection at doses that did not affect rates of responding. Conversely, the noncompetitive NMDA antagonists, phencyclidine, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] and (+)-N-allylnormetazocine, as well as pentobarbital and diazepa, all reduced response rates dose-dependently without antagonism of NMDA-lever responding. In stimulus generalization tests, NPC 12626 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate at doses higher than those required to antagonize NMDA, often elicited NMDA-lever responding. The mechanisms underlying the similarities in the interoceptive stimuli produced by NMDA and its competitive antagonists remain to be determined. These results indicate that although competitive NMDA antagonists antagonize effects of NMDA without concomitant behavioral disruption, noncompetitive NMDA antagonists and central nervous system depressants are behaviorally disruptive at doses that do not antagonize NMDA. The results provide further evidence for differences in the behavioral profiles of competitive and noncompetitive NMDA antagonists.

Topics: Amino Acids; Animals; Aspartic Acid; Dibenzocycloheptenes; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; N-Methylaspartate; Phenazocine; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The behavioral effects of phencyclidine (PCP) were compared with those of several compounds known to antagonize the actions of N-methyl-D-aspartate using two patterns of schedule-controlled responding in rats. Rates of variable interval responding suppressed by punishment were increased greatly by the benzodiazepine chlorodiazepoxide and showed small increases after MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] . However, no consistent increases in response rates were produced by PCP, by the stereoisomers of N-allylnormetazocine (NANM: SKF 10,047) or by the anti-ischemic drug, ifenprodil. Small doses of PCP did increase rates of unpublished variable interval responding, as did a low dose of MK-801. Timing behavior maintained by a differential reinforcement of low rate schedule was disrupted by all the compounds studied. Response rates were increased by at least one dose of PCP, MK-801, (+)-NANM and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. The effect of MK-801, however, was considerably greater than that of the other compounds. Ifenprodil and (-)-NANM did not increase rates of responding but, at high doses, produced decreases in reinforcement frequency indicating that efficient timing behavior had been disrupted. These results show that although PCP, MK-801 and (+)-NANM produce generally similar behavioral effects, there may also be some differences between the compounds, notably a more consistent effect of MK-801 on punished responding. These behavioral effects may be related to antagonism of N-methyl-D-aspartate but ifenprodil, which is also an N-methyl-D-aspartate antagonist, does not show a similar behavioral profile.

Topics: Animals; Aspartic Acid; Conditioning, Psychological; Dibenzocycloheptenes; Dizocilpine Maleate; Male; N-Methylaspartate; Phenazocine; Phencyclidine; Piperazines; Piperidines; Punishment; Rats; Rats, Inbred Strains; Reinforcement Schedule; Stereoisomerism