Comparison of the kappa-opioid receptor antagonist DIPPA in tests of anxiety-like behavior between Wistar Kyoto and Sprague Dawley rats

Rationale  

Recent evidence suggests a role for the dynorphin/kappa-opioid receptor (KOR) system in the expression of stress-induced behaviors. Wistar Kyoto (WKY) rats exhibit increased depression-like and anxiety-like responses in behavioral tests compared to other strains and may be a model of comorbid depression and anxiety characterized by increased activity within the dynorphin/KOR system. Though KOR antagonists produce antidepressant-like effects in WKY rats, their effects in tests of anxiety-like behavior have not been examined in the WKY strain.     

Noise benefit in prepulse inhibition of the acoustic startle reflex

Rationale  

Under some conditions, external sensory noise enhances cognitive functions, a phenomenon possibly involving stochastic resonance and/or enhanced central dopamine transmission. Prepulse inhibition (PPI) of the startle reflex is a robust measure of sensorimotor gating and can be modulated by activity in the cortex and basal ganglia, including the central dopamine pathways.     

Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens

Rationale  

Kappa opioid receptors (KORs) have been implicated in depressive-like states associated with chronic administration of drugs of abuse and stress. Although KOR agonists decrease dopamine in the nucleus accumbens (NAc), KOR modulation of phasic dopamine release in the core and shell subregions of the NAc—which have distinct roles in reward processing—remains poorly understood.     

Effectiveness of analogs of the kappa opioid receptor antagonist (3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) to reduce U50,488-induced diuresis and stress-induced cocaine reinstatement in rats

Rationale  

The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects.     

The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats

Rationale  

The biological underpinnings of schizophrenic polydipsia are poorly understood.     

SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine

Rationale

Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-d-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor-stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity.

Objectives

Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex.

Methods

Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI.

Results

When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg—a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg—that was insufficient to enhance PPI when administered alone—SSR504734 even exacerbated the deleterious effect of apomorphine on PPI.

Conclusions

The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition.     

Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner

Rationale

Mechanisms that mediate age differences during nicotine withdrawal are unclear.

Objective

This study compared kappa-opioid receptor (KOR) activation in na?ve and nicotine-treated adolescent and adult rats using behavioral and neurochemical approaches to study withdrawal.

Methods

The behavioral models used to assess withdrawal included conditioned place and elevated plus maze procedures. Deficits in dopamine transmission in the nucleus accumbens (NAcc) were examined using microdialysis procedures. Lastly, the effects of KOR stimulation and blockade on physical signs produced upon removal of nicotine were examined in adults.

Results

Nicotine-treated adults displayed a robust aversion to an environment paired with a KOR agonist versus na?ve adults. Neither of the adolescent groups displayed a place aversion. KOR activation produced an increase in anxiety-like behavior that was highest in nicotine-treated adults versus all other groups. KOR activation produced a decrease in NAcc dopamine that was largest in nicotine-treated adults versus all other groups. Lastly, KOR activation facilitated physical signs of withdrawal upon removal of nicotine and KOR blockade reduced this effect.

Conclusion

Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine. Given that chronic nicotine facilitated the neurochemical effects of KOR agonists in adults but not in adolescents, it is suggested that KOR regulation of mesolimbic dopamine may contribute to age differences in nicotine withdrawal.     

Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration

Rationale  

Exposure to inescapable stressors increases both the rewarding properties and self-administration of cocaine through the signaling of the kappa-opioid receptor (KOR), but the effect of this signaling on other reinforcing agents remains unclear.     

Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice

Rationale  

Muscarinic cholinergic M₁ and M₄ receptors may participate in schizophrenia’s etiology and have been proposed as targets for antipsychotic medications.     

Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse

Rationale  

Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking.     

Kinase cascades and ligand-directed signaling at the kappa opioid receptor

Background and Rationale  

The dynorphin/kappa opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well known to produce analgesia, and more recently, it has been implicated as a mediator of stress-induced responses including anxiety, depression, and reinstatement of drug seeking.     

Role of kappa-opioid receptors in stress and anxiety-related behavior

Rationale

Accumulating evidence indicates that brain kappa-opioid receptors (KORs) and dynorphin, the endogenous ligand that binds at these receptors, are involved in regulating states of motivation and emotion. These findings have stimulated interest in the development of KOR-targeted ligands as therapeutic agents. As one example, it has been suggested that KOR antagonists might have a wide range of indications, including the treatment of depressive, anxiety, and addictive disorders, as well as conditions characterized by co-morbidity of these disorders (e.g., post-traumatic stress disorder) A general effect of reducing the impact of stress may explain how KOR antagonists can have efficacy in such a variety of animal models that would appear to represent different disease states.

Objective

Here, we review evidence that disruption of KOR function attenuates prominent effects of stress. We will describe behavioral and molecular endpoints including those from studies that characterize the effects of KOR antagonists and KOR ablation on the effects of stress itself, as well as on the effects of exogenously delivered corticotropin-releasing factor, a brain peptide that mediates key effects of stress.

Conclusion

Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled.     

Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists

Rationale  

H₃-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.     

The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice

Rationale  

Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-d-aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia.     

Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents

Rationale

Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.

Objectives

This study represents a systematic examination of this hypothesis.

Methods

Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB₁ receptor radioligand and [³⁵S]GTPγS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.

Results

Salvinorin A did not bind to nor activate CB₁ receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB₁ receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [³⁵S]GTPγS assay. Salvinorin A did not substitute for Δ⁹-tetrahydrocannabinol (THC) in mice trained to discriminate THC.

Conclusions

These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.     

Serotonin1A receptor deletion does not interact with maternal separation-induced increases in startle reactivity and prepulse inhibition deficits

Rationale  

Early life stress is a risk factor for the development of psychopathology in later life. Consequences of adverse life events, however, may depend on the genetic makeup of an individual. Reduced serotonin_1A receptor function may predispose to the development of anxiety disorders.     

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers

Rationale

Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects.

Objectives

The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli.

Methods

A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R _MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES₅₀) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity.

Results

Dexamphetamine increased the threshold and ES₅₀ of the response to pulse-alone trials in both sexes and reduced R _MAX exclusively in females. Dexamphetamine modestly increased PPI of the R _MAX across both attention conditions. PPI of R _MAX was reduced during the ATTEND condition compared to the IGNORE condition.

Conclusions

Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.     

Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice

Background and purpose

Galantamine, a weak acetylcholine esterase (AChE) inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves apomorphine-induced deficits in prepulse inhibition (PPI), sensory information-processing deficits, via a nAChR-independent mechanism. The present study examined the role of muscarinic ACh receptors (mAChRs) in the effect of galantamine, and studied the mechanism of galantamine-induced increases in prefrontal ACh levels in mice.

Experimental approach

Apomorphine (1 mg kg⁻¹) was administered to male ddY mice (9–10 weeks old) to create a PPI deficit model. Extracellular ACh concentrations in the prefrontal cortex were measured by in vivo microdialysis.

Key results

Galantamine- and donepezil-mediated improvements in apomorphine-induced PPI deficits were blocked by the preferential M₁ mAChR antagonist telenzepine. The mAChR agonist oxotremorine also improved apomorphine-induced PPI deficits. Galantamine, like donepezil, increased extracellular ACh concentrations in the prefrontal cortex. Galantamine-induced increases in prefrontal ACh levels were partially blocked by the dopamine D₁ receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, but not by antagonists of mAChRs (telenzepine) and nAChRs (mecamylamine). Galantamine increased dopamine, but not 5-HT, release in the prefrontal cortex.

Conclusions and implications

Galantamine improves apomorphine-induced PPI deficits by stimulating mAChRs through increasing brain ACh levels via a dopamine D₁ receptor-dependent mechanism and AChE inhibition.     

Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats

Rationale

Blockade of N-methyl-d-asparate (NMDA) receptors has been shown to produce some of the abnormal behaviors related to symptoms of schizophrenia in rodents and human. Neonatal treatment of rats with non-competitive NMDA antagonists has been shown to induce behavioral abnormality in a later period.

Objectives

The aim of this study was to determine whether brief disruption of NMDA receptor function during a critical stage of development is sufficient to produce sensorimotor-gating deficits in the late adolescence or early adulthood in the rat.

Methods

Male pups received the NMDA receptor blocker MK-801 (0.13 or 0.20 mg/kg), or an equal volume of saline on postnatal day (PD) 7 through 10. The animals were tested twice for prepulse inhibition (PPI) and locomotor activity in pre- (PD 35-38) and post- (PD 56-59) puberty.

Results

Neonatal exposure to both doses MK-801 disrupted PPI in the adolescence and early adulthood. Low-dose MK-801 elicited long-term effects on startle amplitudes, whereas high-dose MK-801 did not. Neither dose of MK-801 showed a significant effect on spontaneous locomotor activity, whereas the high dose attenuated rearing.

Conclusions

The results of this study suggest neonatal exposure to MK-801 disrupted sensorimotor gating in the adolescence and early adulthood stages. These findings indicate that rats transiently exposed to NMDA blockers in neonatal periods are useful for the study of the pathophysiology and treatment of schizophrenia.     

The effects of d-amphetamine, methylphenidate, sydnocarb, and caffeine on prepulse inhibition of the startle reflex in DBA/2 mice

Rationale  

Dopamine (DA) agonists decrease prepulse inhibition (PPI) and are widely used in translational models for the sensorimotor gating deficits in schizophrenia. Reductions in PPI induced by DA agonists are routinely reversed by antipsychotics in these translational models. Nevertheless, under conditions of low-baseline PPI, DA agonists may increase PPI in humans and experimental animals. DBA/2 mice have naturally low-baseline PPI, which as in the drug-induced translational models, is increased by antipsychotics.