Kappa opioid antagonist effects of the novel kappa antagonist 5?-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys

Negus, S. Stevens; Mello, Nancy K.; Linsenmayer, David; Jones, Robert M.; Portoghese, Philip S.

doi:10.1007/s00213-002-1038-x

Cited by 60 publications

(70 citation statements)

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“…treatment with GNTI, a structurally dissimilar -antagonist, had antidepressant-like effects. GNTI was more potent than norBNI, consistent with previous reports in which the effects of these agents were compared Jewett et al, 2001;Negus et al, 2002). The fact that structurally dissimilar -antagonists have similar actions in the FST suggests that the antidepressant-like effects of norBNI are attributable to a specific blockade of -receptors rather than nonspecific side effects.…”

Section: Discussionsupporting

confidence: 87%

“…At the dosages used, a single treatment with these agents has extended efficacy: norBNI produces a -receptor-specific blockade in rats (Jones and Holtzman, 1992) for Ͼ3 weeks (Spanagel and Shippenberg, 1993). GNTI has detectable -receptor-specific effects in monkeys for ϳ10 days (Negus et al, 2002), although its effects in rats do not seem to endure as long as than those of norBNI (Jewett et al, 2001). (ANTI was not tested in i.c.v.…”

Section: Ratsmentioning

confidence: 99%

“…A goal of the present studies was to extend this work by examining the effects of norBNI over a more complete range of doses, while using a more stringent and widely accepted method of scoring the FST (behavioral sampling; Detke et al, 1995). Furthermore, to examine whether the antidepressant-like effects of norBNI are associated with specific actions at -receptors, we conducted similar studies using two novel and structurally dissimilar -antagonists: 5Ј-guanidinonaltrindole (GNTI) Jewett et al, 2001;Negus et al, 2002) and 5Ј-acetamidinoethylnaltrindole (ANTI) (Stevens et al, 2000). We also explored the possibility that the -agonist [5␣, 7␣,8␤]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) would have the opposite (prodepressantlike) effects on behavior in the FST.…”

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confidence: 99%

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Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Mague

Pliakas

Todtenkopf

et al. 2003

J Pharmacol Exp Ther

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443

418

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We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at -opioid receptors) in NAc neurons, these findings raised the possibility that -receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the -antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at -receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar -antagonists: 5Ј-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5Ј-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the -antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the -agonist) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the -ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective -antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that -antagonists may have efficacy as antidepressants, but lack stimulant or rewardrelated effects.The neurobiology of depression is not understood. Because most antidepressants with clinical efficacy act upon monoamines [primarily norepinephrine (NE) and serotonin (5HT)], much research on depression has focused upon interactions between these neurotransmitters and their reuptake transporters and receptor proteins. However, recent research has become progressively focused upon the intracellular mechanisms of depression and antidepressant treatments (Manji et al., 2001;Duman, 2002;Nestler et al., 2002), with the goal of developing novel therapeutics that act faster, are more efficacious, and have fewer side effects. This approach has led to the study of brain circuits typically associated with reward-related processes, including the mesolimbic dopamine (DA) system Newton et al., 2002).The mesolimbic DA system projects from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc) of the basal forebrain, and is modulated directly and indirectly by noradrenergic and serotonergic inputs (Pasquier et al., 1977). This circuitry contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (Carlezon and Wise, 1996b;Kreek and Koob, 1998;Wise, 1998...

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Section: Discussionsupporting

confidence: 87%

Section: Ratsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Mague

Pliakas

Todtenkopf

et al. 2003

J Pharmacol Exp Ther

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443

418

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“…However, development of clinically useful -antagonists has been slow, partly because the initially synthesized -opioid antagonists that demonstrated a high de-gree of selectivity [e.g., norbinaltorphimine (nor-BNI) and JDTic] showed remarkably long durations of action in vivo (lasting more than 21 day after a single administration), despite having receptor interactions that are freely reversible in vitro (Portoghese et al, 1987;Horan et al, 1992;Butelman et al, 1993;Broadbear et al, 1994;Negus et al, 2002;Carroll et al, 2004). The basis for this long in vivo duration of action was not initially clear and might have been a consequence of slow clearance from the brain (pharmacokinetic), of metabolic conversion in vivo to a product that covalently bound to the receptor (metabolic), or through a long-lasting inactivation of the receptor signaling complex through an undefined mechanism.…”

Section: Introductionmentioning

confidence: 99%

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

et al. 2011

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The -opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective -opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel -opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: , and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the -opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule -opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the -receptor does not require sustained JNK activation.

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“…For kappa opioid receptors however, highly selective ligands are rather limited. GNTI is a selective kappa opioid receptor antagonist, as it displays several hundred-fold selectivity over mu and delta opioid receptors [15][16][17] . This was the selective kappa antagonist of choice for the present study.…”

Section: Introductionmentioning

confidence: 99%

Effect of GNTI, a kappa opioid receptor antagonist, on MK-801 -induced hyperlocomotion and stereotypy in mice

Zou

Zhang

et al. 2006

Acta Pharmacologica Sinica

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Aim: To examine the effect of , a selective antagonist for the kappa opioid receptor, in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia. Methods: Two doses of MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis. Results: GNTI inhibited MK-801-induced hyperlocomotion and stereotypy. In particular, GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg vs 0.6 mg/kg MK-801. Conclusion: Antagonism of kappa opioid receptors attenuates MK-801-induced behavior, suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia. GNTI appears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

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Kappa opioid antagonist effects of the novel kappa antagonist 5?-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys

Cited by 60 publications

References 14 publications

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

Effect of GNTI, a kappa opioid receptor antagonist, on MK-801 -induced hyperlocomotion and stereotypy in mice

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