The scopolamine model as a pharmacodynamic marker in early drug development.

Abstract:

RATIONALE:Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process. OBJECTIVE:Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration. METHODS/RESULTS:In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory. CONCLUSIONS:These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.

journal_title

Psychopharmacology

authors

Lenz RA,Baker JD,Locke C,Rueter LE,Mohler EG,Wesnes K,Abi-Saab W,Saltarelli MD

doi

10.1007/s00213-011-2456-4

subject

Has Abstract

pub_date

2012-03-01 00:00:00

pages

97-107

issue

1

eissn

0033-3158

issn

1432-2072

journal_volume

220

pub_type

杂志文章,随机对照试验
  • An automated method for studying exploratory and stereotyped behaviour in rats.

    abstract::A technique is described for studying exploratory as well as stereotyped behaviour in rats using an automated hole-board. Both visual and automated recordings can be employed using the technique. Hole dipping is monitored automatically using an infra-red detector system. Repetitive patterns of hole-dipping are used as...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00426711

    authors: Makanjuola RO,Hill G,Maben I,Dow RC,Ashcroft GW

    更新日期:1977-05-09 00:00:00

  • Effect of 5,7-dihydroxytryptamine on the development of tolerance to ethanol.

    abstract::5,7-Dihydroxytryptamine (5,7-DHT) or the vehicle was administered once into both lateral ventricles of the rat. Desmethylimipramine (DMI) was administered IP prior to the intraventricular injection of 5,7-DHT to prevent the destruction of norepinephrine (NE) terminals. Following recovery from surgery, ethanol (5 g/kg,...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00431969

    authors: Lê AD,Khanna JM,Kalant H,LeBlanc AE

    更新日期:1980-02-01 00:00:00

  • Cocaine enhances memory storage in mice.

    abstract::Mice were trained on a one-trial inhibitory avoidance task and given immediate post-training intraperitoneal injections of cocaine (0.03-1.00 mg/kg). On a retention test 24 h later, the retention latencies of mice given the 0.10 mg/kg dose were significantly higher than those of the controls. The effect of cocaine on ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00589905

    authors: Introini-Collison IB,McGaugh JL

    更新日期:1989-01-01 00:00:00

  • Functional consequences of acute cocaine treatment depend on route of administration.

    abstract::The 2-[14C]deoxyglucose method was used to compare the effects of the acute administration of cocaine by two different routes, intravenous and intraperitoneal, on rates of local cerebral glucose utilization in freely moving rats. Doses were initially chosen on the basis of their ability to elicit equivalent increases ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02244931

    authors: Porrino LJ

    更新日期:1993-01-01 00:00:00

  • Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization.

    abstract:OBJECTIVES:Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely c...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-012-2847-1

    authors: Doherty JM,Frantz KJ

    更新日期:2013-02-01 00:00:00

  • N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.

    abstract:RATIONALE:Dysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid...

    journal_title:Psychopharmacology

    pub_type: 信件

    doi:10.1007/s00213-005-0246-6

    authors: Lafleur DL,Pittenger C,Kelmendi B,Gardner T,Wasylink S,Malison RT,Sanacora G,Krystal JH,Coric V

    更新日期:2006-01-01 00:00:00

  • Differential effects of the serotonin1A agonist, 8-OH-DPAT, on masculine and feminine sexual behavior of the ferret.

    abstract::Administration of the serotonin (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) facilitates the expression of masculine sexual behavior in male and female rats as well as in male rhesus monkeys and inhibits lordosis behavior in female rats. In the present study the effects of 8-OH-DPAT on ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02244989

    authors: Paredes RG,Kica E,Baum MJ

    更新日期:1994-05-01 00:00:00

  • Lack of reinforcement enhancing effects of nicotine in non-dependent smokers.

    abstract:RATIONALE:Recent animal research has shown that, aside from its primary and secondary reinforcing effects, nicotine may enhance reinforcement from stimuli unrelated to nicotine intake. Little human research has directly examined this potentially important influence of nicotine. OBJECTIVES:We report two virtually ident...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-009-1574-8

    authors: Perkins KA,Grottenthaler A,Wilson AS

    更新日期:2009-09-01 00:00:00

  • Context-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests: evidence of associative tolerance without conditioned compensatory responding.

    abstract:RATIONALE:Demonstrations of associative tolerance to the analgesic effects of morphine, not confounded by practice or novelty effects, have been restricted to the tail-flick and flinch-jump tests. OBJECTIVES:Experiment 1 investigated whether associative tolerance would be found on two other nociceptive assessment meth...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s002130051077

    authors: Cepeda-Benito A,Tiffany ST,Cox LS

    更新日期:1999-08-01 00:00:00

  • Serotonin-induced platelet intracellular calcium mobilization in depressed patients.

    abstract::Serotonin(5-HT)-stimulated intracellular calcium(Ca) mobilization was measured in the platelets of depressed patients to assess 5-HT2 receptor function. The 5-HT-induced Ca response was significantly higher in unmedicated patients with bipolar depression and melancholic major depression than in those with non-melancho...

    journal_title:Psychopharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF02245204

    authors: Kusumi I,Koyama T,Yamashita I

    更新日期:1994-01-01 00:00:00

  • Plasma levels and estimated dopamine D2 receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia: a 3-year follow-up study.

    abstract:INTRODUCTION:Dopamine D2 receptor occupancy levels needed for the maintenance treatment of schizophrenia remain to be elucidated. We examined 3-year clinical outcomes of patients with schizophrenia who received long-acting injectable risperidone (LAI risperidone) at baseline and investigated their dopamine D2 receptor ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-016-4428-1

    authors: Ikai S,Suzuki T,Mimura M,Uchida H

    更新日期:2016-12-01 00:00:00

  • Caffeine enhances the stimulant effect of methamphetamine, but may not affect induction of methamphetamine sensitization of ambulation in mice.

    abstract::Methamphetamine (MAP: 1 and 2 mg/kg SC) and caffeine (CAF: 1, 3, 10 and 30 mg/kg SC) dose-dependently increased ambulation in mice. Repeated administration (5 times at 3 to 4-day intervals) of MAP, but not CAF, induced sensitization to its effect. Furthermore, the mice repeatedly receiving CAF showed no significant ch...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02245053

    authors: Kuribara H

    更新日期:1994-10-01 00:00:00

  • Non-competitive inhibition of clomipramine N-demethylation by fluvoxamine.

    abstract::The selective serotonin reuptake inhibitor fluvoxamine interferes with the metabolism of tricyclic antidepressants. The present investigation was set out to characterize these interactions in vitro using rat liver microsomes and in vivo by analysing levels of clomipramine and metabolites in sera of depressed patients ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02245180

    authors: Härtter S,Arand M,Oesch F,Hiemke C

    更新日期:1995-01-01 00:00:00

  • Effects of nicotine and mecamylamine on cognition in rhesus monkeys.

    abstract:RATIONALE:Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therap...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-004-1804-z

    authors: Katner SN,Davis SA,Kirsten AJ,Taffe MA

    更新日期:2004-09-01 00:00:00

  • Lack of effect of high-dose cocaine on monoamine uptake sites in rat brain measured by quantitative autoradiography.

    abstract::There have been a number of claims that high-dose administration of cocaine to rats leads to neurotoxic effects on dopamine neurons. In this study possible neurotoxic effects on monoamine neurons were examined by measuring the effects of cocaine (35 mg/kg daily for 10 days) on the binding of radioligands to uptake sit...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02244815

    authors: Benmansour S,Tejani-Butt SM,Hauptmann M,Brunswick DJ

    更新日期:1992-01-01 00:00:00

  • The relationship between level of cigarette consumption and latency to the onset of retrospectively reported withdrawal symptoms.

    abstract:RATIONALE:Subthreshold smokers (who smoke < or =5 cigarettes/day) experience withdrawal symptoms, yet they smoke less than is required to maintain serum nicotine levels. OBJECTIVES:For study 1, our aim was to determine (1) if adult subthreshold smokers report withdrawal symptoms; (2) how they rate symptom severity; (3...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-006-0497-x

    authors: Fernando WW,Wellman RJ,Difranza JR

    更新日期:2006-10-01 00:00:00

  • Opposite environmental regulation of heroin and amphetamine self-administration in the rat.

    abstract:RATIONALE:The circumstances of drug taking are thought to play a role in drug abuse but the evidence of it is anecdotal. Previous studies have shown that the intravenous self-administration of cocaine is facilitated in rats non-residing in the test chambers relative to rats that live in the test chambers at all times. ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-008-1154-3

    authors: Caprioli D,Celentano M,Paolone G,Lucantonio F,Bari A,Nencini P,Badiani A

    更新日期:2008-06-01 00:00:00

  • Tolerance and selective cross-tolerance to the motivational effects of opioids.

    abstract::The issue of whether tolerance develops to the motivational effects of opioids was addressed by use of an unbiased place preference conditioning procedure. Administration of the mu-opioid agonists morphine or fentanyl produced dose-related preferences for the drug-associated place in control rats. In contrast, the kap...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02431542

    authors: Shippenberg TS,Emmett-Oglesby MW,Ayesta FJ,Herz A

    更新日期:1988-01-01 00:00:00

  • Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial.

    abstract:RATIONALE:Schizophrenia is a disorder with cognitive deficits that could stem from cholinergic dysfunction. OBJECTIVES:Our aim was to examine if donepezil administered to stable, medicated outpatients with schizophrenia improves cognition and psychopathology. METHODS:We conducted a double-blind placebo-controlled tri...

    journal_title:Psychopharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1007/s00213-005-2235-1

    authors: Freudenreich O,Herz L,Deckersbach T,Evins AE,Henderson DC,Cather C,Goff DC

    更新日期:2005-09-01 00:00:00

  • Effect of topiramate treatment on ethanol consumption in rats.

    abstract:RATIONALE:Results from clinical studies have shown that topiramate effectively reduces alcohol consumption in a population of heavy-drinking alcohol-dependent humans. OBJECTIVES:We undertook this preclinical study in order to establish topiramate's efficacy in a rodent model and to determine whether topiramate's effic...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-009-1683-4

    authors: Breslin FJ,Johnson BA,Lynch WJ

    更新日期:2010-01-01 00:00:00

  • Effects of cocaine rewards on neural representations of cognitive demand in nonhuman primates.

    abstract:RATIONALE:Investigations of the neural consequences of the effects of cocaine on cognition have centered on specific brain circuits including prefrontal cortex, medial temporal lobe and striatum and their roles in controlling drug dependent behavior and addiction. These regions are critical to many aspects of drug abus...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-010-2017-2

    authors: Hampson RE,Porrino LJ,Opris I,Stanford T,Deadwyler SA

    更新日期:2011-01-01 00:00:00

  • Relationship between ecstasy use and depression: a study controlling for poly-drug use.

    abstract:RATIONALE:3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") causes serotonin neuron damage in laboratory animals. The serotonin system is known to be important in the regulation of mood. Previous research has shown that MDMA users score higher on self-report ratings of depression than controls. However, MDMA users ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-003-1705-6

    authors: Roiser JP,Sahakian BJ

    更新日期:2004-05-01 00:00:00

  • The delta opioid receptor antagonist naltrindole attenuates both alcohol and saccharin intake in rats selectively bred for alcohol preference.

    abstract::This study demonstrates that the selective delta receptor antagonists ICI 174864 and naltrindole (NTI) attenuate alcohol intake in a dose-dependent manner, without altering water intake, in rats selectively bred for alcohol preference. ICI 174864 had a very limited duration of action, as evidenced by the fact that sup...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/BF02246191

    authors: Krishnan-Sarin S,Jing SL,Kurtz DL,Zweifel M,Portoghese PS,Li TK,Froehlich JC

    更新日期:1995-07-01 00:00:00

  • Subchronic hydrocortisone treatment alters auditory evoked potentials in normal subjects.

    abstract:RATIONALE:Abnormalities of cortical evoked potentials and background electroencephalographic (EEG) frequencies occur in several psychiatric disorders, some of which, especially depression, are associated with hypercortisolaemia. However, there have been few investigations of the effects of exogenously administered cort...

    journal_title:Psychopharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/s002130000528

    authors: Ashton CH,Lunn B,Marsh VR,Young AH

    更新日期:2000-09-01 00:00:00

  • Psychostimulants and forced swim stress interaction: how activation of the hypothalamic-pituitary-adrenal axis and stress-induced hyperglycemia are affected.

    abstract:RATIONALE:We recently reported that simultaneous exposure to amphetamine and various stressors resulted in reduced hypothalamic-pituitary-adrenal (HPA) and glycemic responses to the stressors. Since this is a new and relevant phenomenon, we wanted to further explore this interaction. OBJECTIVES:This study aims (i) to ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-017-4675-9

    authors: Gagliano H,Ortega-Sanchez JA,Nadal R,Armario A

    更新日期:2017-10-01 00:00:00

  • Attenuating the alcohol allure: attentional broadening reduces rapid motivational response to alcohol pictures.

    abstract:RATIONALE:Past research has found that exposure to alcohol cues causes a narrowing of attentional scope and enhances the neural responses associated with approach motivation. OBJECTIVE:The current research sought to determine if a manipulated broadened (global) attentional scope would reduce approach-motivated neural ...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-017-4557-1

    authors: Ryerson NC,Neal LB,Gable PA

    更新日期:2017-04-01 00:00:00

  • The interactive effects of ketamine and nicotine on human cerebral blood flow.

    abstract:AIM:The purpose of this study was to determine if acute nicotine attenuated ketamine-induced regional cerebral blood flow (rCBF). METHOD:Following 2-4 h of nicotine abstinence, healthy chronic smokers participated in four sets of rCBF studies, H2(15)O positron emission tomography, during a simple sensory motor control...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-009-1758-2

    authors: Rowland LM,Beason-Held L,Tamminga CA,Holcomb HH

    更新日期:2010-03-01 00:00:00

  • A comparison of the effect of lorazepam on memory in heavy and low social drinkers.

    abstract::The cognitive deficits, particularly memory impairment, observed in association with organic brain damage caused by chronic alcohol ingestion, are consistent with the profile of benzodiazepine-induced amnesia. This study examined the cognitive capabilities of a group of heavy social drinkers (n = 11) and a group of lo...

    journal_title:Psychopharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF02244897

    authors: Nichols JM,Martin F,Kirkby KC

    更新日期:1993-01-01 00:00:00

  • Impact of modulation of the α7 nicotinic acetylcholine receptor on nicotine reward in the mouse conditioned place preference test.

    abstract:RATIONALE:The α7 nicotinic acetylcholine receptor (nAChR) has been implicated as a target in modulating nicotine reward. However, the effect of pharmacological agents that have been shown to alter the channel properties of the α7 nAChR is not well understood in nicotine reward. OBJECTIVES:This study aimed to investiga...

    journal_title:Psychopharmacology

    pub_type: 杂志文章

    doi:10.1007/s00213-019-05331-y

    authors: Jackson A,Alkhlaif Y,Papke RL,Brunzell DH,Damaj MI

    更新日期:2019-12-01 00:00:00

  • The relationships between clinical response, psychophysiological variables and plasma levels of amitriptyline and diazepam in neurotic outpatients.

    abstract::In a 4 week study of the response of neurotic outpatients to treatment with amitriptyline, diazepam, amitriptyline and diazepam, or placebo clinical and psychophysiological variables and plasma levels of the drug were assessed. Clinical improvements were substantial in all treatment groups but clear relationships betw...

    journal_title:Psychopharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF00431822

    authors: Johnstone EC,Bourne RC,Crow TJ,Frith CD,Gamble S,Lofthouse R,Owen F,Owens DG,Robinson J,Stevens M

    更新日期:1981-01-01 00:00:00