Topologically protected magnetoelectric switching in a multiferroic.

Electric control of magnetism and magnetic control of ferroelectricity can improve the energy efficiency of magnetic memory and data-processing devices1. However, the necessary magnetoelectric switching is hard to achieve, and requires more than just a coupling between the spin and the charge degrees of freedom2-5. Here we show that an application and subsequent removal of a magnetic field reverses the electric polarization of the multiferroic GdMn2O5, thus requiring two cycles to bring the system back to the original configuration. During this unusual hysteresis loop, four states with different magnetic configurations are visited by the system, with one half of all spins undergoing unidirectional full-circle rotation in increments of about 90 degrees. Therefore, GdMn2O5 acts as a magnetic crankshaft that converts the back-and-forth variations of the magnetic field into a circular spin motion. This peculiar four-state magnetoelectric switching emerges as a topologically protected boundary between different two-state switching regimes. Our findings establish a paradigm of topologically protected switching phenomena in ferroic materials.

A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators.

BACKGROUND AND PURPOSE: Altered glutamatergic neurotransmission is linked to several neurological and psychiatric disorders. Metabotropic glutamate receptor 2 (mGlu2) plays an important role on the presynaptic control of glutamate release and negative allosteric modulators (NAMs) acting on mGlu2/3 receptors are under assessment for their potential as antidepressants, neurogenics and cognitive enhancers. Two new potent mGlu2/3 NAMs, RO4988546 and RO5488608, are described in this study and the allosteric binding site in the transmembrane (TM) domain of mGlu2 is characterized. EXPERIMENTAL APPROACH: Site directed mutagenesis, functional measurements and ß2-adrenoceptor-based modelling of mGlu2 were employed to identify important molecular determinants of two new potent mGlu2/3 NAMs. KEY RESULTS: RO4988546 and RO5488608 affected both [³H]-LY354740 agonist binding at the orthosteric site and the binding of a tritiated positive allosteric modulator (³H-PAM), indicating that NAMs and PAMs could have overlapping binding sites in the mGlu2 TM domain. We identified eight residues in the allosteric binding pocket that are crucial for non-competitive antagonism of agonist-dependent activation of mGlu2 and directly interact with the NAMs: Arg³·²8, Arg³·²9, Phe³·³6, His(E2.52) , Leu5·4³, Trp6·48, Phe6·55 and Val7·4³. The mGlu2 specific residue His(E2.52) is likely to be involved in selectivity and residues located in the outer part of the binding pocket are more important for [³H]-LY354740 agonist binding inhibition, which is independent of the highly conserved Trp6·48 residue. CONCLUSIONS AND IMPLICATIONS: This is the first complete molecular investigation of the allosteric binding pocket of mGlu2 and Group II mGluRs and provides new information on what determines mGlu2 NAMs selective interactions and effects.

Characterization of RO4583298 as a novel potent, dual antagonist with in vivo activity at tachykinin NK1 and NK3 receptors.

BACKGROUND AND PURPOSE: Clinical results of osanetant and talnetant (selective-NK3 antagonists) indicate that blocking the NK3 receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize the in vitro and in vivo properties of a novel dual NK1/NK3 antagonist, RO4583298 (2-phenyl-N-(pyridin-3-yl)-N-methylisobutyramide derivative). EXPERIMENTAL APPROACH: RO4583298 in vitro pharmacology was investigated using radioligand binding ([³H]-SP, [³H]-osanetant, [³H]-senktide), [³H]-inositol-phosphate accumulation Schild analysis (SP- or [MePhe7]-NKB-induced) and electrophysiological studies in guinea-pig substantia nigra pars compacta (SNpc). The in vivo activity of RO4583298 was assessed using reversal of GR73632-induced foot tapping in gerbils (GFT; NK1) and senktide-induced tail whips in mice (MTW; NK3). KEY RESULTS: RO4583298 has a high-affinity for NK1 (human and gerbil) and NK3 (human, cynomolgus monkey, gerbil and guinea-pig) receptors and behaves as a pseudo-irreversible antagonist. Unusually it binds with high-affinity to mouse and rat NK3, yet with a partial non-competitive mode of antagonism. In guinea-pig SNpc, RO4583298 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non-competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW. CONCLUSIONS AND IMPLICATIONS: RO4583298 is a high-affinity, non-competitive, long-acting in vivo NK1/NK3 antagonist; hence providing a useful in vitro and in vivo pharmacological tool to investigate the roles of NK1 and NK3 receptors in psychiatric disorders.

Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor.

BACKGROUND AND PURPOSE: The OX(2) receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX(2) receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). EXPERIMENTAL APPROACH: The affinity of [(3)H]EMPA was assessed in membranes from HEK293-hOX(2)-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A- or orexin-B-induced accumulation of [(3)H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX(2) receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats. KEY RESULTS: [(3)H]EMPA bound to human and rat OX(2)-HEK293 membranes with K(D) values of 1.1 and 1.4 nmol x L(-1) respectively. EMPA competitively antagonized orexin-A- and orexin-B-evoked accumulation of [(3)H]IP at hOX(2) receptors with pA(2) values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [(3)H]EMPA for OX(2) receptors. EMPA significantly reversed [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. CONCLUSIONS AND IMPLICATIONS: EMPA is a high-affinity, reversible and selective OX(2) receptor antagonist, active in vivo, which should prove useful for analysis of OX(2) receptor function.

Characterization of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors.

BACKGROUND AND PURPOSE: As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) as enhancers of GABAB receptors. EXPERIMENTAL APPROACH: Enhancing properties of rac-BHFF were assessed in the Chinese hamster ovary (CHO)-Galpha16-hGABA(B1a,2a) cells by Fluorometric Imaging Plate Reader and GTPgamma[35S]-binding assays, and in rat hippocampal slices by population spike (PS) recordings. In vivo activities of rac-BHFF were assessed using the loss of righting reflex (LRR) and stress-induced hyperthermia (SIH) models. KEY RESULTS: In GTPgamma[35S]-binding assays, 0.3 microM rac-BHFF or its pure enantiomer (+)-BHFF shifted the GABA concentration-response curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3- and 87.3-fold) and efficacy (149% and 181%), respectively. In hippocampal slices, rac-BHFF enhanced baclofen-induced inhibition of PS of CA1 pyramidal cells. In an in vivo mechanism-based model in mice, rac-BHFF increased dose-dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg(-1) p.o. rac-BHFF (100 mg kg(-1) p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic-like activity in the SIH model in mice. CONCLUSIONS AND IMPLICATIONS: rac-BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABAB receptors in the central and peripheral nervous systems.

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety.

RATIONALE: The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. OBJECTIVES: This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed. RESULTS: Current data show that animal and human mGlu(5) binding can be directly compared in experiments using the PET ligand (11)C-ABP688. Testing of the mGlu(2/3) receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. CONCLUSIONS: Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs.

Nitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogenesis during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's sensitivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly basis for at least five weeks. Haloperidol failed to significantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to significantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential sensitivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more sensitive to atypical antipsychotics rather than haloperidol.

Elements of cerebral microvascular ischaemia.

Although neuronal cells have long been thought to be the prime target of ischaemic insults, events which occur at the blood-vascular-parenchymal interface are necessary for the initiation of ischaemic tissue injury. This cascade of microvascular events includes fibrin accumulation, endothelium expression of leukocyte adhesion receptors, breakdown of the basal laminae with loss of astrocyte and endothelial cell contacts leading to blood-brain barrier disruption and consequently oedema formation and haemorrhagic transformation. Potential stroke treatments have been studied in the clinic and many have not been particularly successful, probably due to the delicate balance between improved outcome and adverse reactions as well as the window of opportunity for drug treatment after symptom onset. The only acute intervention trial demonstrating any benefit in patients was that of intravenous tissue plasminogen activator (tPA), administered within 3 h of the onset of symptoms of ischaemic stroke. Such treatment improved clinical outcome at 3 months, although there was an increased incidence of symptomatic haemorrhage [New Engl. J. Med. 333 (1995) 1581]. The recent progress made in defining the mechanisms involved in the initiation of ischaemic events, as described in this review, may lead to the identification of new strategies for intervention in the ischaemic cascade.

Effect of AMPA receptor modulators on hippocampal and cortical function.

Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

White matter ischaemia.

Brain and spinal cord white matter are vulnerable to the effects of ischaemia. Reduction of the energy supply leads to a cascade of events including depolarization, influx of Na(+) and the subsequent reverse operation of the membrane protein the Na(+)/Ca(2+) exchanger which ultimately terminates in intracellular Ca(2+) overload and irreversible axonal injury. Various points along the white matter damage cascade could be specifically targeted as a potential means of inhibiting the development of axonal irreversible injury.

On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia.

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine 1-100 mg/kg s.c.) daily on post-natal days 3-5. L-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.

Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI).

1. There has been considerable research in the field of schizophrenia over the past few years with emphasis on the discovery of better drugs, particularly those with 5-HT2 antagonist activity. 2. In an effort to enhance identification of such compounds and to further understand the contribution of 5-HT2 activity to the effects of antipsychotic drugs, a series of conventional, atypical and purported antipsychotic compounds were assessed as antagonists of DOI-induced behaviors in rats. 3. DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) is an hallucinogen having high affinity and selectivity as an agonist at 5-HT2A/2C receptors. Over a 30-min period after injection, DOI (0.3-10.0 mg/kg; i.p.) produced dose-related behavioral effects including head-and-body shakes, forepaw tapping and skin-jerks. Effects of the antipsychotic drugs and other compounds (30 min pretreatment; i.p.) were examined against a fixed dose of DOI (3.0 mg/kg). 4. In a dose-dependent manner, M100907 (MDL 100,907), risperidone, haloperidol, clozapine, iloperidone, olanzapine, amperozide, remoxipride, ritanserin and the neurotensin agonist NT1 (N alpha MeArg-Lys-Pro-Trp-Tle-Leu) antagonized each of the three behavioral effects of DOI. Drugs attenuating the head-and-body shakes were equally effective in blocking both forepaw tapping and skin-jerks indicating that these behaviors are mediated by similar mechanisms. The following compounds had either inconsistent or no effect on the DOI-induced behaviors: SB 200646A, citalopram, imipramine, fluoxetine, morphine, CP 99994, diazepam, ondansetron and SKF 97541. 5. The data show that antipsychotic agents, as a drug class, effectively block the effects of DOI. These actions are selective, as a series of nine non-antipsychotic and centrally-acting drugs were generally inactive in the procedure.

The discriminative stimulus properties of U50,488 and morphine are not shared by fedotozine.

Fedotozine is a kappa opioid receptor agonist having antinociceptive properties but devoid of diuretic effects. The aim of the study was to evaluate the discriminative stimulus effects of fedotozine at doses previously reported to produce maximal effects in in vivo assays measuring kappa-mediated analgesia. By using a two-lever drug discrimination task, two groups of rats were trained to discriminate either a 3 mg/kg i.p. dose of the kappa opioid agonist, U50,488, or a 5 mg/kg i.p. dose of the mu opioid agonist, morphine, from saline. Once trained, rats were used to conduct tests of stimulus generalization with morphine, U50,488 and fedotozine along with another kappa agonist, CI-977, and another mu agonist, fentanyl. The stimulus effect of U50,488 was shared by CI-977 but not by morphine. Conversely, the stimulus effect of morphine was shared by fentanyl but not by U50,488. Fedotozine (1-10 mg/kg) failed to substitute to either U50,488 or morphine. These results indicate that, when administered at doses fully effective in producing antinociception, the interoceptive stimulus effects of fedotozine, if any, can be distinguished from those produced by U50,488 and morphine.

Disruption of latent inhibition in the rat by the 5-HT2 agonist DOI: effects of MDL 100,907, clozapine, risperidone and haloperidol.

Latent inhibition (LI), a measure of the ability to learn to ignore irrelevant stimuli, is disrupted in acute schizophrenics and in rats treated with amphetamine; antipsychotics prevent amphetamine disruption of LI in rats. The 5-HT2A/C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has hallucinogenic properties in humans, and evidence suggests that 5-HT2 antagonism is an important component of atypical antipsychotic activity. Therefore, the ability of DOI to disrupt LI in rats was tested, and the ability of clinically-used and putative antipsychotics to reverse DOI disruption of LI was assessed. The method consisted of four phases. After habituation to the apparatus, thirsty rats underwent preexposure to a tone stimulus 24 h prior to two tone-shock conditioning trials. LI was demonstrated at testing (an additional 24 h later) by reduced lick suppression during tone presentation. When administered at the preexposure phase only, DOI disrupted LI. However, when administered at both preexposure and conditioning phases, DOI did not disrupt LI except at the highest dose, where lick suppression itself was also disrupted. Therefore, disruptive effects of DOI on LI are not easily dissociated from state-dependent learning effects. Additional experiments demonstrated that haloperidol, clozapine, risperidone, and the selective 5-HT2A antagonist MDL 100,907 prevented the disruptive effects of DOI on LI when administered at preexposure only. These results agree with findings that these compounds can also prevent other behavioral effects of DOI. Further experiments will be required to explore the possible involvement of state-dependent learning effects in the present results. However, if the disruptive effects of DOI on LI are due to an influence on attentional processes rather than state-dependent learning, this procedure may have potential as a method for detection of antipsychotic activity.

Comparative antipsychotic profiles of neurotensin and a related systemically active peptide agonist.

Several lines of evidence have shown that neurotensin can modulate dopamine neurotransmission. It has been suggested that neurotensin has potential antipsychotic activity because it reduces dopaminergic activity preferentially in the nucleus accumbens. In the present study, the effects of neurotensin and NT1 (N alpha Me-Arg-Lys-Pro-Trp-TIe-Leu or Eisai hexapeptide), a metabolically stable and systemically active neurotensin agonist, were examined in several models of antipsychotic activity and side effect liability in mice; analgesic and hypothermic effects of both compounds also were determined. Up to high doses, neurotensin (5.0 and 10.0 micrograms, i.c.v.) and NT1 (10.0 and 20.0 mg/kg, i.p.) did not produce catalepsy. A much lower dose of neurotensin (0.03 microgram, i.c.v.) significantly reduced amphetamine- and phencyclidine-stimulated locomotor activity; NT1 also diminished amphetamine- and phencyclidine-stimulated locomotion with ED50 values of 0.3 and 0.4 mg/kg, i.p., respectively. Neurotensin (0.01-0.3 microgram, i.c.v.) and NT1 (0.1-1.0 mg/kg, s.c.) also produced dose-dependent analgesia in the paw pressure test and decreased body temperature; these effects were insensitive to pretreatment with naloxone (10.0 mg/kg, i.p.). Together, the results support the hypothesis that neurotensin agonists have antipsychotic and analgesic activity. Moreover, the data suggest that such compounds may not produce extrapyramidal side effects.

Antinociceptive effects of neuropeptide Y and related peptides in mice.

This study compares the antinociceptive and orexigenic activities of NPY and analogs after intracerebroventricular administration in mice. NPY had an antinociceptive action in the mouse writhing test which was not affected by prior treatment with naltrexone, yohimbine, idazoxan or reserpine. A detailed examination revealed that NPY (0.023-0.7 nmol), PYY (0.007-0.07 nmol), NPY2-36 (0.023-0.23 nmol) and the Y1 agonist [Leu31, Pro34]-NPY (0.07-0.7 nmol) all produced a dose-dependent and complete suppression of acetic acid-induced writhing. In contrast, the Y2 agonist, NPY13-36, had little or no antinociceptive effect. As shown by their ED50 values, the relative potency of the peptides was PYY > NPY2-36 > or = NPY > [Leu31, Pro34]-NPY > > NPY13-36, suggesting that a Y1 rather than a Y2 or Y3 receptor subtype was implicated in the antinociceptive action. Thereafter, all peptides were assessed for their effects on food intake. With respect to dose and peptide specificity, the hyperphagic effects of NPY and related peptides paralleled those on nociception, suggesting a common receptor mechanism. However, a purported NPY antagonist, [D-Trp32]-NPY, attenuated NPY's effect on feeding yet this same peptide elicited a dose-dependent inhibition of acetic acid-induced writhing, suggesting some molecular distinction between antinociception and stimulation of food intake.

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay.

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.

Behavioral effects of neuropeptide Y receptor agonists in the elevated plus-maze and fear-potentiated startle procedures.

Evidence from animal studies has led to the proposal that neuropeptide Y (NPY) has anxiolytic-like effects in rats after intracerebroventricular (i.c.v.) administration. The purpose of the present study was to extend these observations by examining the behavioral effects of a series of NPY receptor agonists including NPY, peptide YY (PYY), the NPY fragment 2-36 (NPY(2-36)), the Y(1) agonist [Leu(31), Pro(34)]-NPY and the Y(2) agonist NPY fragment 13-36 (NPY(13-36)), in two established anxiety models in rats: the elevated plus-maze and the fear-potentiated startle procedures. In the elevated plus-maze procedure, i.c.v. PYY (0.07-2.3nmol), NPY (0.07-2.3nmol), NPY(2-36) (0.07-2.3nmol). [Leu(31), Pro(34)]-NPY (0.7-7nmol), but not NPY(13-36) (0.7-7nmol), increased preference for the open arms of the plus-maze in a dose-dependent manner. In an acoustic startle paradigm, NPY, PYY and NPY(2-36) inhibited fear-potentiated startle over the dose-range of 0.23-2.3nmol. [Leu(31), Pro(34)]-NPY (2.3-13.2nmol) also attenuated fear-potentiated startle, whereas NPY(13-36) (up to 13.2nmol) had no effect. Taken together, these findings demonstrate that NPY, PYY and NPY(2-36) have anxiolytic-like effects that are likely mediated by Y(1) receptors.

Central nervous system pharmacology of neuropeptide Y.

Neuropeptide Y (NPY) is a 36-amino acid peptide belonging to the pancreatic polypeptide family that has marked and diverse biological activity across species. NPY originally was isolated from mammalian brain tissue somewhat more than 10 years ago and, since that time, has been the subject of numerous scientific publications. NPY and its proposed three receptors (Y1, Y2 and Y3) are relatively abundant in and uniquely distributed throughout the brain and spinal cord. This review will highlight the results from a number of research-oriented studies that have examined how NPY is involved in CNS function and behavior, and how these studies may relate to the possible development of medicines, either NPY-like agonists or antagonists, directed towards the treatment of disorders such as anxiety, pain, hypertension, schizophrenia, memory dysfunction, abnormal eating behavior and depression.