Neurohypophyseal hormones, analogs, and fragments: their effect on puromycin-induced amnesia.

Walter, Roderich; Hoffman, Paula L.; Flexner, Josefa B.; Flexner, Louis B.

doi:10.1073/pnas.72.10.4180

Cited by 100 publications

(20 citation statements)

References 53 publications

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“…Another possible mechanism by which peripherally administered oxytocin and vasopressin may affect the CNS is through the formation of active fragments that may cross the BBB. Fragments of both oxytocin and vasopressin have been shown to cross the BBB and affect memory processes (de Wied et al, 1972(de Wied et al, , 1987de Wied, 1976;de Wied and Versteeg, 1979;Walter et al, 1975;Burbach et al, 1983a,b;Tanabe et al, 1997;Rainbow et al, 1979). One promising strategy for peptide delivery to the brain is through chemical modification resulting in a peptide or fragment with favorable BBB permeability, which has important implications for the development of clinically relevant treatments.…”

Section: Discussionmentioning

confidence: 99%

Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger's Disorders

Hollander

Novotny

Hanratty

et al. 2003

Neuropsychopharmacol

624

403

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Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral domains: repetitive behaviors, social deficits, and language abnormalities. There is evidence that abnormalities exist in peptide systems, particularly the oxytocin system, in autism spectrum patients. Furthermore, oxytocin and the closely related peptide vasopressin are known to play a role in social and repetitive behaviors. This study examined the impact of oxytocin on repetitive behaviors in 15 adults with autism or Asperger's disorder via randomized double-blind oxytocin and placebo challenges. The primary outcome measure was an instrument rating six repetitive behaviors: need to know, repeating, ordering, need to tell/ask, self-injury, and touching. Patients with autism spectrum disorders showed a significant reduction in repetitive behaviors following oxytocin infusion in comparison to placebo infusion. Repetitive behavior in autism spectrum disorders may be related to abnormalities in the oxytocin system, and may be partially ameliorated by synthetic oxytocin infusion.

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Section: Discussionmentioning

confidence: 99%

Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger's Disorders

Hollander

Novotny

Hanratty

et al. 2003

Neuropsychopharmacol

624

403

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“…Several of these peptides, notably vasopressin and its analogs, can modify various aspects of behavior including acquisition and extinction of conditioned responses in lower species as well as of memory in man (4-10). In addition, non-disulfide-containing linear hormone fragments, such as Pro-Leu-Gly-NH2 (melanotropin-release inhibiting factor) (11), Z-Pro-Leu-Gly-NH2 (7), the enzymatically stable cyclo(LeuGly) (12), and Pro-Arg-Gly-NH2 (13) also exhibit these effects (7,8,13).Recently, in comparing the relative potencies of these peptides in facilitating the development of physical dependence on and tolerance to morphine, van Ree and de Wied (3) found not only that oxytocin and 8-arginine vasotocin are more effective than 8-arginine vasopressin but, moreover, that ProLeu-Gly-NH2 and cyclo(Leu-Gly) are as effective as oxytocin in these tests.Replacement of an L residue in a peptide hormone or agonistic analog by the D isomer has been reported to produce, in certain instances, a competitive inhibitor or partial agonist-findings that might be explained by steric misplacement of an "active element" (14) from its preferred orientation in the "active site" (15) such that intrinsic activity is decreased or even lost with retention of receptor affinity (14, 16).On the basis of this background it was decided, as a first step in a series of studies, to evaluate the effect of Z-Pro-D-Leu on the development of physical dependence on and tolerance to morphine. …”

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confidence: 99%

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confidence: 99%

Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

Walter¹,

Ritzmann²,

Bhargava³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

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The peptide Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.Certain neurohypophyseal hormones, their analogs, and disulfide-containing cyclic fragments of these hormones facilitate development of physical dependence on and tolerance to actions of morphine (1-3). Several of these peptides, notably vasopressin and its analogs, can modify various aspects of behavior including acquisition and extinction of conditioned responses in lower species as well as of memory in man (4-10). In addition, non-disulfide-containing linear hormone fragments, such as Pro-Leu-Gly-NH2 (melanotropin-release inhibiting factor) (11), Z-Pro-Leu-Gly-NH2 (7), the enzymatically stable cyclo(LeuGly) (12), and Pro-Arg-Gly-NH2 (13) also exhibit these effects (7,8,13).Recently, in comparing the relative potencies of these peptides in facilitating the development of physical dependence on and tolerance to morphine, van Ree and de Wied (3) found not only that oxytocin and 8-arginine vasotocin are more effective than 8-arginine vasopressin but, moreover, that ProLeu-Gly-NH2 and cyclo(Leu-Gly) are as effective as oxytocin in these tests.Replacement of an L residue in a peptide hormone or agonistic analog by the D isomer has been reported to produce, in certain instances, a competitive inhibitor or partial agonist-findings that might be explained by steric misplacement of an "active element" (14) from its preferred orientation in the "active site" (15) such that intrinsic activity is decreased or even lost with retention of receptor affinity (14, 16).On the basis of this background it was decided, as a first step in a series of studies, to evaluate the effect of Z-Pro-D-Leu on the development of physical dependence on and tolerance to morphine. MATERIALS AND METHODSThe Z-Pro-D-Leu (17) used was prepared in these laboratories (18). Male C57BL/6J, Swiss Webster, and ICR mice weighing 26 ± 4 g (±SD) were used in these studies.Mice were randomly divided into two groups. One group received subcutaneous injections of water (vehicle); the other group received Z-Pro-D-Leu (50 ,jg per mouse on day 1). Two hours later, the mice were then further subdivided and each subgroup was implanted with placebo or morphine pellets. The injections of vehicle and Z-Pro-D-Leu were repe...

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“…Among the few tested, cyclo(Leu-Gly) and cyclo(Pro-Phe) showed activity. This group of cyclic dipeptides is of particular interest because a substantial amount of research with cyclo(Leu-Gly) has revealed it not only to be active behaviorally (7)(8)(9) and to be able to cross the blood-brain barrier (10) as well as intestinal tissue (11) intact but also to be stable to enzymatic degradation in brain for at least 96 hr (12). Dose-response experiments revealed MIF and cyclo(LeuGly) to be the most potent peptides tested to date in blocking physical dependence to morphine (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Walter¹,

Ritzmann²,

Bhargava³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50jsg doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Doseresponse studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, or 0.005 ,ug per mouse revealed MIF and cyclo(Leu-ly) to be the most potent peptides and to be effective In lockng physical dependence to morphine at a dose as low as 0.5 and 0.05 ,g per mouse, respectively. The benzyloxycarbonyl derivative of MIF, Pro-Leu, and Pro--Leu exhibited significant activities down to a dose of 5 1Ag of peptide per mouse.Recent evidence (1) indicates that the dipeptide benzyloxycarbonyl-Pro-D-Leu is capable of blocking the development of tolerance to and physical dependence on morphine in mice; these effects were achieved without altering the analgesic potency of morphine.In light of the potential clinical importance of these observations and their significance for the study of the mechanism of action of central nervous system-active peptides, it was decided to investigate whether more potent inhibitors could be found. The inhibitory properties of a selected number of peptides was evaluated over a broader dose range. Because, in our original studies, Z-Pro-D-Leu was equally effective in blocking tolerance, abrupt withdrawal, or naloxone-precipitated withdrawal (1), it was decided to use naloxone-precipitated withdrawal in mice as the bioassay in the current investigation for an evaluation of structure-function and dose-response relationships.MATERIAL AND METHODS A double-blind procedure was used for all experiments, and each peptide was tested in at least two independent experiments. Male Swiss Webster mice (Scientific Small Animal Farm, Inc., Melrose Park, IL) weighing 24 ± 2 g (mean E SD) were used. The mice were housed five or six per cage in temperature (23 ± 1"C) and light (light 0600-1800 hr) controlled rooms and were kept in our laboratory for a minimum of 7 days prior to the initiation of experiments. Food (Purina Laboratory Chow) and water were available ad lib.Mice were randomly divided into two groups. One group received subcutaneous injections of 0.1 ml of water (vehicle). The other group received peptide dissolved in 0.1 ml of water; in the case of the structure-activity studies, a single dose of 50 ,ug of peptide per mouse was given on day 1, and in the doseresponse studies 50, 5, 0.5, or 0.005 tig of peptide was administered to the respective groups of mice. Two hours later the mice were implanted with morphine pellets. The injections ofThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 518 vehicle and respective peptides were repeated 24 and 48 hr after the first injection in their respective groups. Morphine pellets, containing 75 mg of mo...

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Neurohypophyseal hormones, analogs, and fragments: their effect on puromycin-induced amnesia.

Cited by 100 publications

References 53 publications

Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger's Disorders

Oxytocin Infusion Reduces Repetitive Behaviors in Adults with Autistic and Asperger's Disorders

Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

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