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1.
J Med Chem ; 56(9): 3710-24, 2013 May 09.
Article in English | MEDLINE | ID: mdl-23631755

ABSTRACT

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 µM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.


Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Animals , Behavior, Animal/drug effects , Binding, Competitive , Catalytic Domain , D-Amino-Acid Oxidase/chemistry , D-Amino-Acid Oxidase/metabolism , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Glycine/metabolism , Humans , Kinetics , Male , Molecular Docking Simulation , Neuroglia/drug effects , Neuroglia/metabolism , Rats , Rats, Sprague-Dawley , Serine/biosynthesis , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacokinetics
2.
J Pharmacol Exp Ther ; 345(3): 502-11, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23520265

ABSTRACT

Inhibition of d-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury. In addition, SUN was efficacious against complete Freund's adjuvant-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates of increase in brain and plasma d-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically evoked responses of central spinal cord dorsal horn neurons and compared these with spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. After intravenous administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.


Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Neuralgia/drug therapy , Spinal Cord/drug effects , Amines/pharmacology , Analgesics/pharmacology , Anesthesia , Animals , Behavior, Animal/drug effects , Constriction, Pathologic/pathology , Cyclohexanecarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Freund's Adjuvant , Furans/pharmacology , Gabapentin , Hot Temperature , Hyperalgesia/drug therapy , Hyperalgesia/psychology , Ligation , Male , Physical Stimulation , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Serine/pharmacokinetics , Spinal Nerves/physiology , gamma-Aminobutyric Acid/pharmacology
3.
Neuropsychopharmacology ; 29(5): 929-42, 2004 May.
Article in English | MEDLINE | ID: mdl-14735136

ABSTRACT

Both sex and gonadal steroid hormones may influence the abuse-related behavioral effects of cocaine under some conditions, but there is considerable inconsistency in the literature. In the present study, rats were trained under a fixed ratio (FR) 5 schedule of food presentation and were then allowed to self-administer cocaine (1.0 mg/kg/injection) until behavior stabilized. Subsequently, complete dose-effect functions for cocaine self-administration (0.032-3.2 mg/kg/injection) were determined in female and male rats before and after gonadectomy, and in gonadectomized female and male rats before and during chronic treatment with estradiol or testosterone, respectively. Sex, gonadectomy, and gonadal hormones did not alter the shape or position of dose-effect functions for cocaine self-administration. These results suggest that sex, estrogen, and testosterone levels are not critical determinants of cocaine's reinforcing effects in rats under these conditions. This study differed from earlier studies in that complete dose-effect functions for cocaine were determined. These findings suggest that the behavioral training history, the unit dose of cocaine, and the schedule of reinforcement are important variables in studies of sex and gonadal hormone effects on cocaine self-administration.


Subject(s)
Cocaine-Related Disorders/psychology , Estradiol/pharmacology , Orchiectomy , Ovariectomy , Testosterone/pharmacology , Animals , Conditioning, Operant/drug effects , Dose-Response Relationship, Drug , Estradiol/blood , Female , Food , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Reinforcement Schedule , Reinforcement, Psychology , Sex Characteristics , Testosterone/blood , Vagina/cytology , Vagina/drug effects
4.
Neuropsychopharmacology ; 28(6): 1125-39, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12637953

ABSTRACT

kappa-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed kappa/mu receptor activity is unclear. The effects of three mixed kappa/mu agonists (MCL-101, (-)cyclorphan, and Mr2034) and one kappa-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all kappa agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (-)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration dose-effect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (-)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed kappa/mu agonists produced fewer side effects (some salivation) than the kappa-selective agonist (sedation, salivation, emesis). However, none of these kappa agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, kappa and mixed kappa/mu-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed kappa/mu agonists appear to offer some advantages over selective kappa agonists as potential treatments for cocaine abuse.


Subject(s)
Cocaine/administration & dosage , Discrimination Learning/drug effects , Narcotics/pharmacology , Receptors, Opioid, kappa/agonists , Receptors, Opioid, mu/agonists , Analgesics, Non-Narcotic/pharmacology , Animals , Discrimination Learning/physiology , Dose-Response Relationship, Drug , Macaca mulatta , Male , Receptors, Opioid, kappa/physiology , Receptors, Opioid, mu/physiology , Self Administration/methods , Self Administration/psychology
5.
Psychopharmacology (Berl) ; 164(1): 19-26, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12373415

ABSTRACT

RATIONALE: Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys. OBJECTIVES: To compare the effects of repeated injections of the same dose of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) on plasma cocaine concentrations, cocaine pharmacokinetics and behavioral responses in male and female rhesus monkeys. METHODS: Four injections of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) were administered at 30-min intervals to five or six male and five or six female rhesus monkeys. Samples for plasma cocaine analysis were collected at 2, 4, 8, 16 and 24 min after the first three injections. After the fourth cocaine injection, additional samples were collected at 10-min intervals over 150 min. RESULTS: Plasma cocaine peaks and nadirs increased monotonically after successive cocaine injections ( P<0.0001). Peak plasma cocaine levels measured at 2 min after cocaine administration were higher after 0.8 mg/kg cocaine than after 0.4 mg/kg cocaine ( P<0.006). There were no significant gender differences in time to peak plasma cocaine levels (t(max)), peak cocaine concentrations (C(max)) or half-life (t(1/2); min) at either dose of cocaine. Group average behavioral ratings were similar in males and females after each dose of cocaine. CONCLUSIONS: Peak plasma cocaine concentrations increased progressively during low and high dose cocaine binge episodes, and there were no significant gender differences in cocaine pharmacokinetics. These findings demonstrate the feasibility of simulating "binge" patterns of cocaine administration in rhesus monkeys.


Subject(s)
Cocaine/administration & dosage , Cocaine/blood , Animals , Cocaine/pharmacokinetics , Female , Injections, Intravenous , Macaca mulatta , Male
6.
J Pharmacol Exp Ther ; 302(1): 264-73, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12065726

ABSTRACT

It has been suggested that heroin and morphine may act on different opioid receptor populations in rodents. In support of this hypothesis, the opioid antagonist 3-methoxynaltrexone was reported to be more potent as an antagonist of the antinociceptive effects of heroin than of morphine in mice and rats. To assess the generality of this finding across species and experimental endpoints, the present study compared the potencies of naltrexone and 3-methoxynaltrexone as antagonists of heroin and morphine in two behavioral assays in rhesus monkeys. In the thermal nociception study, tail-withdrawal latencies were measured from water heated to 50 degrees C. In the heroin discrimination study, monkeys were trained to discriminate 0.1 mg/kg heroin from saline in a two-key, food-reinforced drug discrimination procedure, and percentage of heroin-appropriate responding and response rates were measured. Both heroin and morphine produced dose-dependent antinociception, increases in percentage of heroin-appropriate responding, and decreases in response rates. Heroin was approximately 20-fold more potent than morphine. Naltrexone (0.032-0.1 mg/kg) was equipotent in antagonizing all effects of heroin and morphine (pA(2) values = 7.90-8.22). 3-Methoxynaltrexone (0.1-3.2 mg/kg) was also equipotent in antagonizing the antinociceptive, discriminative stimulus, and rate-suppressant effects of heroin and morphine; however, 3-methoxynaltrexone was approximately 100-fold less potent than naltrexone (pA(2)/pK(B) values = 5.96-6.36). These results suggest that heroin and morphine act on pharmacologically similar populations of opioid receptors in rhesus monkeys, and also indicate that 3-methoxynaltrexone does not differentially antagonize the effects of heroin and morphine in rhesus monkeys.


Subject(s)
Analgesics, Opioid/antagonists & inhibitors , Analgesics/antagonists & inhibitors , Discrimination, Psychological/drug effects , Heroin/agonists , Heroin/antagonists & inhibitors , Morphine/antagonists & inhibitors , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Analgesics, Opioid/pharmacology , Animals , Cues , Discrimination Learning/drug effects , Dose-Response Relationship, Drug , Heroin/pharmacology , Hot Temperature , Kinetics , Macaca mulatta , Male , Morphine/pharmacology , Pain Measurement/drug effects , Substance-Related Disorders/psychology
7.
Psychoneuroendocrinology ; 27(3): 319-36, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11818169

ABSTRACT

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01-0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032-1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys.


Subject(s)
Heroin/pharmacology , Narcotic Antagonists/pharmacology , Narcotics/pharmacology , Pituitary Gland, Anterior/drug effects , Receptors, Opioid, mu/drug effects , Animals , Azocines/pharmacology , Dose-Response Relationship, Drug , Heroin/antagonists & inhibitors , Injections, Intravenous , Macaca mulatta , Male
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