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Cited by 7Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchSchizophrenia research and treatment

Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine

Open access
Jian-min, Chen, Zhi-yuan, Wang, Shi-xuan, Wu, Rui, Song, Ning, Wu, Jin, Li·2022·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2022.885574PMC PMC9086831
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Abstract

D-amphetamine has been used to enhance cognitive performance over the last few decades. Due to the rapid absorption after administration, d-amphetamine shows narrow effective window and severe abuse potential. Lisdexamfetamine, a prodrug of d-amphetamine, reduces the magnitude of plasma d-amphetamine concentration and prolongs the action duration when compared with immediate-release d-amphetamine at equimolar doses. However, the differences of these two drugs, which produce distinct pharmacokinetic characteristics, in cognition improvement still unclear. In present study, we compared the effects of d-amphetamine (i.p) and lisdexamfetamine (p.o) at equimolar doses (0.2, 0.5, 1.5, 4.5, and 13.5 mg/kg of d-amphetamine base) on locomotion, spatial working memory and recognition memory in rats. Given the crucial involvement of dopamine neurotransmitter system within the medial prefrontal cortex (mPFC) in cognitive processing, microdialysis was conducted to profile the difference in neurochemical characteristics between the two drugs. In our results, d-amphetamine ranges from 0.5 to 1.5 mg/kg significantly increased locomotor activity. However, d-amphetamine ranges from 0.2 to 13.5 mg/kg failed to improve spatial working memory and recognition memory in Y-maze-based spontaneous alternation and two-trial delayed alternation tasks of rats, respectively. In contrast, lisdexamfetamine with 4.5 mg/kg significantly increased the locomotion and improved both spatial working and recognition memory. Further, microdialysis showed that lisdexamfetamine induced lower magnitude and longer duration of extracellular dopamine increase than that of d-amphetamine. These results suggest that lisdexamfetamine was more effective than d-amphetamine in improving spatial cognitive performance, which was attributed to the steady and lasting dopamine release pattern within the mPFC.

AI snapshot

Written from the paper’s full text.

TL;DR

Lisdexamfetamine, a d-amphetamine prodrug, improved spatial working and recognition memory and increased locomotion at 4.5 mg/kg, whereas immediate-release d-amphetamine did not improve memory and impaired it at 13.5 mg/kg. Microdialysis showed lisdexamfetamine produced a lower-magnitude but longer-lasting increase in medial prefrontal cortex dopamine than d-amphetamine.

Key findings

  • Locomotion: d-amphetamine 0.5 and 1.5 mg/kg significantly increased total 180-min locomotor activity vs control (Kruskal-Wallis: P = 0.018 and P < 0.001, respectively), while 4.5–13.5 mg/kg decreased locomotion. Lisdexamfetamine 4.5 mg/kg significantly increased locomotion within 180 min (P = 0.016 vs control), and 13.5 mg/kg increased activity at 60 min (P = 0.027 vs control).
  • Spatial working memory: d-amphetamine 0.2–13.5 mg/kg failed to improve Y-maze spontaneous alternation; 13.5 mg/kg significantly reduced alternations vs control (P = 0.004). Lisdexamfetamine 4.5 mg/kg significantly increased spontaneous alternations vs control (P = 0.032).
  • Spatial recognition memory: d-amphetamine 13.5 mg/kg significantly reduced novel-arm retention vs control (P = 0.001). Lisdexamfetamine 4.5 mg/kg significantly increased novel-arm visits (P = 0.047) and novel-arm retention (P = 0.043) vs control.
  • Microdialysis: d-amphetamine increased mPFC DA to 222.49 ± 84.42% of baseline at 30 min and returned toward baseline by 90 min (108.25 ± 16.28%); lisdexamfetamine peaked at 177.35 ± 37.94% at 60 min and remained elevated from 90–180 min (e.g., 151.31 ± 13.27% at 180 min). DOPAC reached lowest levels at 120 min for d-amphetamine (87.52 ± 12.04%) and at 180 min for lisdexamfetamine (68.95 ± 16.61%); HVA decreased similarly for both.

Methods

  • Male Sprague-Dawley rats (220–240 g) were assigned to control, d-amphetamine (i.p.), or lisdexamfetamine (p.o.) groups at equimolar doses of 0.2, 0.5, 1.5, 4.5, and 13.5 mg/kg d-amphetamine base.
  • Behavioral testing included locomotor activity over 180 min in 15-min bins, Y-maze spontaneous alternation for spatial working memory, and two-trial Y-maze delayed alternation with a 60-min inter-trial interval for spatial recognition memory; d-amphetamine was given 30 min before testing/acquisition and lisdexamfetamine 60 min before.
  • In vivo microdialysis sampled mPFC extracellular DA, DOPAC, and HVA using HPLC-ECD in freely moving rats; guide cannula placement was verified by Nissl staining. Statistical analyses used ANOVA with Dunnett’s or Bonferroni tests, or Kruskal-Wallis tests, with P < 0.05.

Limitations

  • The paper does not include a dedicated limitations section.
  • Evident from the text: only male Sprague-Dawley rats were studied, so sex and strain effects are not addressed.
  • Evident from the text: microdialysis groups had n = 5 per group, and the study did not report plasma d-amphetamine pharmacokinetics; the pharmacokinetic comparison relies on prior literature rather than direct measurement here.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2022.885574

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

15 of 46 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A dramatic increase in DA in the nucleus accumbens is related to severe abuse and addiction.

    “In addition, the dramatic increase in DA in the nucleus accumbens (NAc), a key brain region responding to reward (13, 14), is also related to severe abuse and addiction.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [13] Bisagno, 2016, Cognitive enhancers versus addictive psychostimulants: the good and bad side of dopamine on prefrontal cortical circuits., Pharmacol Res. source

      Section 4, “Dopamine and motivational salience” (page unavailable), describes increased dopamine release in the nucleus accumbens and says addictive drugs can enhance dopamine transmission and act as reinforcers. Section 5 links dopamine-system responses to the development of addiction. Neither passage specifically links a dramatic increase in nucleus accumbens dopamine to severe abuse or addiction. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [14] Dolder, 2018, Acute effects of lisdexamfetamine and D-amphetamine on social cognition and cognitive performance in a placebo-controlled study in healthy subjects., Psychopharmacology (Berl). source
  • Premisecitation

    Lisdexamfetamine shows lower inter- and intra-individual variability in exposure compared with an equivalent dose of immediate-release d-amphetamine.

    “Such pharmacokinetic profile of lisdexamfetamine shows lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release d-amphetamine (22).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Ermer, 2016, Lisdexamfetamine dimesylate: prodrug delivery, amphetamine exposure and duration of efficacy., Clin Drug Investig. source
  • Premisecitation

    Psychostimulants (i.e., d-amphetamine) action on the DA system exerts bidirectional effects, improving or decreasing working memory performance depending on the dosage (inverted U-shaped curve).

    “In fact, psychostimulants (i.e., d-amphetamine) action on the DA system exerts bidirectional effects, improving or decreasing working memory performance depending on the dosage (inverted U-shaped curve) (39, 40).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [39] Lapish, 2015, Amphetamine exerts dose-dependent changes in prefrontal cortex attractor dynamics during working memory., J Neurosci. source
    • cites [40] Tipper, 2005, Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation., Psychopharmacology (Berl). source
  • Premisecitation

    Chronic administration and withdrawal of amphetamine and morphine have been shown to cause severe spatial recognition memory and executive impairment in rodents and humans.

    “Chronic administration and withdrawal of amphetamine and morphine have been shown to cause severe spatial recognition memory and executive impairment in rodents and humans (49–51).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [49] Ma, 2007, Effects of morphine and its withdrawal on Y-maze spatial recognition memory in mice., Neuroscience. source
    • cites [50] Ersche, 2006, Profile of executive and memory function associated with amphetamine and opiate dependence., Neuropsychopharmacology. source

      The Discussion (page unavailable) reports marked spatial-planning, paired-associates-learning, and visual-pattern-recognition impairments in human amphetamine and opiate users, including former users. It does not establish that administration or withdrawal caused those impairments, test rodents, or demonstrate spatial recognition memory impairment specifically; the study concerns dependence on opiates rather than morphine specifically. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [51] Marszalek-Grabska, 2016, Memantine improves memory impairment and depressive-like behavior induced by amphetamine withdrawal in rats., Brain Res. source
  • Findingcitation

    In our animal results and other studies of healthy non-sleep-deprived individuals, d-amphetamine failed to improve spatial working memory.

    “In our animal results and other studies of healthy non-sleep-deprived individuals, d-amphetamine failed to improve spatial working memory (46).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] Roberts, 2020, How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine., Eur Neuropsychopharmacol. source
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 20

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    D-amphetamine has been used to enhance cognitive performance in healthy individuals.

    “In addition, another application of these drugs is to enhance cognition in healthy individuals who are engaging in certain vocations, referred to as cognitive enhancers (5).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Husain, 2011, Cognitive enhancement by drugs in health and disease., Trends Cogn Sci. source

      The “Uses of cognitive enhancement” section says that drugs including methylphenidate and modafinil are used by healthy people, including students and military personnel, to maintain or improve performance. The “Effects of genotype on response to drugs” section reports improved performance after a dose of amphetamine in one genotype group, but deterioration in another; it does not identify the drug as D-amphetamine or establish its use for enhancement in healthy people in particular vocations. Page numbers are unavailable in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    D-amphetamine and methamphetamine rapidly enter the brain and increase synaptic DA by competitively inhibiting DAT and reversing DAT direction.

    “D-amphetamine and methamphetamine enter brain rapidly after administration. They competitively inhibit dopamine transporter (DAT) clearing dopamine (DA), and also release DA via reversing DAT direction, ultimately causing excessive DA accumulation in synaptic cleft ultimately (11).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Goodwin, 2009, Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo., J Biol Chem. source

      The Abstract states that D-amphetamine and methamphetamine competitively inhibit DAT-mediated dopamine uptake and release dopamine through reverse transport; the Discussion also describes excess dopamine in synaptic clefts. Our copy does not establish that both drugs enter the brain rapidly after administration, so that part of the attributed claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Both cognitive enhancement and drug addiction are highly associated with pharmacokinetic properties.

    “Several studies have revealed that both cognitive enhancement and drug addiction are highly associated with pharmacokinetic properties (9, 10).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Allain, 2015, How fast and how often: the pharmacokinetics of drug use are decisive in addiction., Neurosci Biobehav Rev. source

      Section 3 states that pharmacokinetic variables strongly influence drug effects relevant to addiction, supporting the addiction portion of the claim. The passages from our copy do not address cognitive enhancement, so this source does not support that portion. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [10] Wood, 2014, Psychostimulants and cognition: a continuum of behavioral and cognitive activation., Pharmacol Rev. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lisdexamfetamine is a prodrug approved for ADHD and binge eating disorder treatment.

    “Lisdexamfetamine, the first prodrug approved for ADHD (16, 17) and binge eating disorder (18) treatment, is synthesized by covalently linking d-amphetamine to the amino acid l-lysine (19).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [16] Frampton, 2016, Lisdexamfetamine: a review in ADHD in adults., CNS Drugs. source
    • cites [17] Coghill, 2017, Long-term safety and efficacy of lisdexamfetamine dimesylate in children and adolescents with ADHD: a phase IV, 2-year, open-label study in Europe., CNS Drugs. source

      The Introduction identifies lisdexamfetamine as an amphetamine-based prodrug, and the paper studies its use for ADHD. Our copy does not establish that it was the first prodrug approved for ADHD or address approval for binge eating disorder. In the citing sentence, a separate citation is attached to the binge-eating-disorder clause. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] Ward, 2018, Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder., Expert Opin Drug Metab Toxicol. source

  • May combine two claims.

    Premisecitation

    DA acts as an inverted U-shaped pattern on cognitive performance; too low or too high DA levels elicited by clinically inappropriate doses of d-amphetamine impair cognition.

    “DA acts as an inverted U-shaped pattern to cognitive performance. As is reported, too lower or higher DA level elicited by clinically-inappropriate doses of d-amphetamine impairs cognition (12).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Spencer, 2015, The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex., Biol Psychiatry. source

      The ‘Receptor Mechanisms in the PFC’ section states that dopamine has an inverted-U-shaped effect on prefrontal-cortex-dependent working memory. ‘Summary and Implications’ contrasts cognitive improvement at clinically relevant psychostimulant doses with impairment at higher doses. The copy does not establish that clinically inappropriate doses of d-amphetamine produce both the low and high dopamine levels described in the claim, and it does not extend the inverted-U relationship to all cognitive performance. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    It is widely accepted that clinically relevant doses improve and supra-clinical doses impair working memory.

    “It is widely accepted that clinically relevant doses improve and supra-clinical doses impair working memory (41).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Berridge, 2016, Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex., Brain Res. source

  • May combine two claims.

    Premisecitation

    Working memory serves as the basis of other higher order cognitive processes including recognition memory, which is mediated by mPFC function.

    “Among numerous cognitive domains, working memory serves as the basis of other higher order cognitive processes including but not limited to recognition memory (27–29), which is mediated by mPFC function.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [27] Riley, 2015, Role of prefrontal persistent activity in working memory., Front Syst Neurosci. source

      The Introduction says working memory is a core component of other cognitive functions, including language, problem solving, reasoning, and abstract thought. The paper discusses prefrontal cortex involvement in working memory, but the passages do not identify recognition memory as one of those functions or establish that recognition memory is mediated by mPFC. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [28] Thiele, 2018, Neuromodulation of attention., Neuron. source

      The Main Text describes working memory as holding goals that guide attention, supporting a relationship between working memory and another cognitive process. It does not say that working memory underlies recognition memory. The passages on prefrontal function concern working memory or attentional control, not mPFC mediation of recognition memory (pages unavailable in our copy). (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [29] Salmon, 2015, Recognition memory span in autopsy-confirmed Dementia with Lewy bodies and Alzheimer’s disease., Neuropsychologia. source

      The Discussion says the recognition memory span task requires working-memory processes interacting with secondary memory, supporting a link between working memory and recognition memory. It describes fronto-striatal and medial temporal lobe systems, but does not say recognition memory is mediated by mPFC function or that working memory is the basis of higher-order cognitive processes generally. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DA within the mPFC plays a crucial role in mediating several cognitive domains, such as working memory and attention.

    “DA within the mPFC plays a crucial role in mediating several cognitive domains, such as working memory (52) and attention (53).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [52] Cools, 2011, Inverted-U-shaped dopamine actions on human working memory and cognitive control., Biol Psychiatry. source
    • cites [53] Xing, 2016, Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex., Brain Res. source

  • May combine two claims.

    Findingown data

    Lisdexamfetamine at 4.5 mg/kg significantly increased novel arm visits and retention relative to start and other arms.

    “Bonferroni test for post hoc test: 0.5 mg/kg: P = 0.032 in novel arm vs. the other arm, 4.5 mg/kg: P < 0.001 in novel arm vs. start arm and other arm”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lisdexamfetamine at 0.5 mg/kg significantly increased novel arm visits and retention relative to the other arm.

    “Bonferroni test for post hoc test: 0.5 mg/kg: P = 0.032 in novel arm vs. the other arm, 4.5 mg/kg: P < 0.001 in novel arm vs. start arm and other arm”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no difference between d-amphetamine and lisdexamfetamine on HVA; both led to a gradual decrease in HVA concentration.

    “For HVA, there was no difference between d-amphetamine and lisdexamfetamine, which both led to a gradual decrease in HVA concentration (Figure 5D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Acute treatment with 4.5 and 13.5 mg/kg d-amphetamine significantly damaged recognition memory acquisition and showed similar effects on spatial working memory.

    “Our results showed that acute treatment with 4.5 and 13.5 mg/kg d-amphetamine significantly damaged recognition memory acquisition and showed similar effects on spatial working memory.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lisdexamfetamine is synthesized by covalently linking d-amphetamine to the amino acid l-lysine.

    “Lisdexamfetamine, the first prodrug approved for ADHD (16, 17) and binge eating disorder (18) treatment, is synthesized by covalently linking d-amphetamine to the amino acid l-lysine (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Biederman, 2007, Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study., Clin Ther. source

  • May combine two claims.

    Premisecitation

    Compared with immediate-release d-amphetamine at equimolar doses, lisdexamfetamine produces an identical AUC for plasma d-amphetamine but a 50% lower Cmax and significantly delayed tmax.

    “In comparison with immediate-release d-amphetamine, lisdexamfetamine produced an identical AUC for plasma d -amphetamine, but a 50% lower Cmax and significantly delayed tmax at equimolar doses (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Rowley, 2012, Lisdexamfetamine and immediate release d-amfetamine – differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity., Neuropharmacology. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Severe addiction to amphetamine and its analogs is a worldwide public health problem that extensively limits their applications.

    “However, severe addiction to amphetamine and its analogs (called amphetamine-type stimulants, such as methamphetamine) has become a worldwide public health problem, extensively limiting their applications (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Cao, 2016, Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction., Eur J Pharmacol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    D-amphetamine improves spatial working memory and language production in healthy volunteers.

    “In the last decades, d-amphetamine has been reported to improve spatial working memory and language production in healthy volunteers (6), as well as increasing vigilance both in boys and adult men (7).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Barch, 2005, Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers., Schizophr Res. source
    • cites [7] Rapoport, 1980, Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men., Arch Gen Psychiatry. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The pharmacodynamic effects of lisdexamfetamine are independent of the route of administration.

    “Hutson et al. reported that the pharmacodynamic effects of lisdexamfetamine are independent of the route of administration (20), which is enzymatically hydrolyzed by an erythrocyte peptidase (the rate-limiting step) to yield d-amphetamine, the actual pharmacological active metabolite.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Hutson, 2014, Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug., Neuropharmacology. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Locomotor activity measurement is a method used to evaluate the behavioral stimulant properties of drugs.

    “Locomotor activity measurement is a method used to evaluate the behavioral stimulant properties of drugs (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Antoniou, 1998, D-amphetamine, cocaine and caffeine: a comparative study of acute effects on locomotor activity and behavioural patterns in rats., Neurosci Biobehav Rev. source

  • May combine two claims.

    Premisereasoning

    Lisdexamfetamine, based on its sustained-release pharmacokinetic profile with lower magnitude plasma d-amphetamine concentration, is reasonably believed to produce a wider efficient window and less individual variability in enhancing cognitive performance.

    “Lisdexamfetamine, based on the sustained-released pharmacokinetic profile with lower magnitude of plasma d-amphetamine concentration, is reasonably believed to produce wider efficient and less individual variability to enhance cognitive performance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antoniou et al. concluded that amphetamine had a complex effect on locomotion, characterized mainly by motor activation at lower doses and stereotypy at high doses.

    “Antoniou et al. concluded that amphetamine had a complex effect on locomotion, characterized mainly by motor activation at lower doses and stereotypy at high doses (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Antoniou, 1998, D-amphetamine, cocaine and caffeine: a comparative study of acute effects on locomotor activity and behavioural patterns in rats., Neurosci Biobehav Rev. source

  • May combine two claims.

    Premisecitation

    Due to its unique pharmacokinetics, lisdexamfetamine shows a lower reward property and a larger therapeutic window than d-amphetamine.

    “Due to the unique pharmacokinetics, lisdexamfetamine shows a lower reward property and larger therapeutic window than d-amphetamine (21, 38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Rowley, 2012, Lisdexamfetamine and immediate release d-amfetamine – differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity., Neuropharmacology. source
    • cites [38] Rowley, 2014, Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats., J Psychopharmacol. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Using appropriate cognitive paradigms in rodents is effective for exploring pharmacological action, underlying mechanisms, and anticipating side effects.

    “In preclinical study, using appropriate cognitive paradigms in rodents are effective for pharmacological action and the underlying mechanisms exploration, as well as side effects anticipation (23).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Wallace, 2015, Animal paradigms to assess cognition with translation to humans., Handb Exp Pharmacol. source

  • May combine two claims.

    Premisecitation

    Namara et al. found that 0.2 mg/kg d-amphetamine (i.p.) failed to increase locomotor activity, while doses of 5 and 10 mg/kg caused prominent stereotypy.

    “Namara et al. found 0.2 mg/kg d-amphetamine (i.p.) failed to increase locomotor activity, while doses of 5 and 10 mg/kg d-amphetamine caused prominent stereotypy (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] McNamara, 2006, Dose-response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine., Synapse. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Guide cannula placements not in the mPFC were excluded based on Nissl staining.

    “The injection site of the guide cannula, which was not in the mPFC, was deleted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Brut et al. found that acute treatment with low doses of d-amphetamine (1.0 mg/kg) eliminated the alternation tendency, while higher doses (5.0-7.0 mg/kg) produced marked stimulus perseveration in a radial maze.

    “Brut et al. found that acute treatment with low doses of d-amphetamine (1.0 mg/kg) eliminated the alternation tendency, while higher doses (5.0- 7.0 mg/kg) also produced marked stimulus perseveration in a radial maze (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bruto, 1983, Acute and chronic amphetamine treatment: differential modification of exploratory behavior in a radial maze., Pharmacol Biochem Behav. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several lines of evidence have shown that d-amphetamine causes significantly perseverative patterns (i.e., repetition of location rather than direction) in exploration in the Y-maze.

    “In addition, several lines of evidence have shown that d-amphetamine causes significantly perseverative patterns (i.e., repetition of location rather than direction) in exploration in the Y-maze (43, 44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Kokkinidis, 1987, Amphetamine-elicited perseverative and rotational behavior: evaluation of directional preference., Pharmacol Biochem Behav. source
    • cites [44] Kokkinidis, 1977, Perseveration and rotational behavior elicited by d-amphetamine in a Y-maze exploratory task: differential effects of intraperitoneal and unilateral intraventricular administration., Psychopharmacology (Berl). source

  • May combine two claims.

    Interpretationown data

    As a prodrug of d-amphetamine, lisdexamfetamine displays pharmacokinetical sustained and lower magnitude plasma amphetamine base concentration, as well as its eliciting DA level in mPFC.

    “Taken together, as a prodrug of d-amphetamine, lisdexamfetamine displays pharmacokinetical sustained and lower magnitude plasma amphetamine base concentration, as well as its eliciting DA level in mPFC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    D-amphetamine has been proven to decrease MAO activity in striatal tissue, contributing to a reduction in DOPAC and final metabolite HVA reduction.

    “D-amphetamine has been proven to decrease MAO activity in striatal tissue (56), contributing to a reduction in DOPAC and final metabolite HVA reduction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Wallace, 2012, Effects of amphetamine on subcellular distribution of dopamine and DOPAC., Synapse. source
    • Rests on an assumption: DOPAC is a major metabolite of DA, catalyzed by monoamine oxidase (MAO), and further forms HVA under the action of catechol-o-methyl-transferase (COMT).

  • May combine two claims.

    Premisecitation

    D-amphetamine selectively improved working memory in poor and intermediate performers at low doses, whereas it impaired good performers at a higher dose.

    “D-amphetamine selectively improved working memory in poor and intermediate performers at low doses, whereas it was impaired good performers at a higher dose (14, 45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Dolder, 2018, Acute effects of lisdexamfetamine and D-amphetamine on social cognition and cognitive performance in a placebo-controlled study in healthy subjects., Psychopharmacology (Berl). source
    • cites [45] Grégoire, 2012, The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences., Neurobiol Learn Mem. source
29 of 29

  • The paper relies on this without support.

    The difference in route of administration (i.p. for d-amphetamine, p.o. for lisdexamfetamine) does not account for the observed differences in cognitive effects.

    “D-amphetamine were injected at a volume of 1 ml/kg (intraperitoneal [i.p.]), and lisdexamfetamine was infused at a volume of 2 ml/kg (per os [p.o.]).”

  • The paper relies on this without support.

    The timing of drug administration (30 min for d-amphetamine, 60 min for lisdexamfetamine before tests) is appropriate to compare their cognitive effects.

    “For the Y-maze spontaneous alternation task, d-amphetamine (i.p.) and lisdexamfetamine (p.o.) were treated 30 and 60 min before the test, respectively.”

  • The paper relies on this without support.

    Increasing neuronal excitability appropriately with a certain dose of stimulant drugs is beneficial for enhancing cognitive activity.

    “Increasing neuronal excitability appropriately with a certain dose of stimulant drugs is beneficial for enhancing cognitive activity.”

  • The paper relies on this without support.

    Baseline working memory capacity is another key factor affecting cognitive performance.

    “Except for dosage, baseline working memory capacity is another key factor affecting cognitive performance.”

  • The paper relies on this without support.

    The effects of both drugs on cognitive performance remain unknown.

    “However, the effects of both drugs on cognitive performance remain unknown.”

  • The paper relies on this without support.

    Whether acute administration of amphetamine influences spatial recognition memory and whether there is a difference between amphetamine and lisdexamfetamine remain unknown.

    “However, whether acute administration of amphetamine influences this cognitive domain and whether there is a difference between amphetamine and lisdexamfetamine remain unknown.”

  • The paper relies on this without support.

    Exploration between two given arms is crucial to guide free exploration after a 60-min ITI.

    “Exploration between two given arms is crucial to guide free exploration after a 60-min ITI.”

  • The paper relies on this without support.

    DOPAC is a major metabolite of DA, catalyzed by monoamine oxidase (MAO), and further forms HVA under the action of catechol-o-methyl-transferase (COMT).

    “DOPAC is a major metabolite of DA, catalyzed by monoamine oxidase (MAO), and further forms HVA under the action of catechol-o-methyl-transferase (COMT).”
8 of 8

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(11, 38) = 25.818reported p < .001 · recomputed p < .001

    “F(11,38) = 25.818, p < .001”

  • ConsistentF(5, 48) = 10.391reported p < .001 · recomputed p < .001

    “F(5,48) = 10.391, p < .001”

  • ConsistentF(55, 210) = 1.519reported p = .019 · recomputed p = .019

    “F(55,210) = 1.519, p = .019”

  • ConsistentF(11, 38) = 21.488reported p < .001 · recomputed p < .001

    “F(11,38) = 21.488, p < .001”

  • ConsistentF(5, 48) = 4.899reported p = .001 · recomputed p = .001

    “F(5,48) = 4.899, p = .001”

  • ConsistentF(55, 210) = 1.594reported p = .01 · recomputed p = .010

    “F(55,210) = 1.594, p = .01”

  • ConsistentF(5, 54) = 8.995reported p < .001 · recomputed p < .001

    “F(5,54) = 8.995, p < .001”

  • ConsistentF(2, 53) = 9.489reported p < .001 · recomputed p < .001

    “F(2,53) = 9.489, p < .001”

  • ConsistentF(10, 108) = 2.543reported p = .011 · recomputed p = .009

    “F(10,108) = 2.543, p = .011”

    The paper states a correction for multiple tests

  • ConsistentF(5, 54) = 0.991reported p = .432 · recomputed p = .432

    “F(5,54) = 0.991, p = .432”

  • ConsistentF(2, 53) = 0.714reported p = .494 · recomputed p = .494

    “F(2,53) = 0.714, p = .494”

  • ConsistentF(10, 108) = 4.347reported p < .001 · recomputed p < .001

    “F(10,108) = 4.347, p < .001”

  • ConsistentF(5, 54) = 1.413reported p = .234 · recomputed p = .234

    “F(5,54) = 1.413, p = .234”

  • ConsistentF(2, 53) = 13.995reported p < .001 · recomputed p < .001

    “F(2,53) = 13.995, p < .001”

  • ConsistentF(10, 108) = 1.489reported p = .153 · recomputed p = .153

    “F(10,108) = 1.489, p = .153”

  • ConsistentF(6, 63) = 0.849reported p = .537 · recomputed p = .537

    “F(6,63) = 0.849, p = .537”

  • ConsistentF(2, 53) = 16.257reported p < .001 · recomputed p < .001

    “F(2,53) = 16.257, p < .001”

  • ConsistentF(10, 108) = 1.421reported p = .181 · recomputed p = .181

    “F(10,108) = 1.421, p = .181”

18 of 18

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Doses described as equimolar have different reported molar amounts

    Major

    The abstract describes the two drugs as given at equimolar doses, but the methods report different μmol/kg values at every corresponding dose. For example, the first pair is 1.17 versus 1.48 μmol/kg.

  • Claim of impairment at 4.5 mg/kg contradicts delayed-alternation results

    Major

    The discussion says 4.5 mg/kg d-amphetamine significantly damaged recognition memory acquisition. The results report a significant reduction versus control only at 13.5 mg/kg; at 4.5 mg/kg, rats instead made more novel-arm than start-arm visits.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Jian-min, C., Zhi-yuan, W., Shi-xuan, W., Rui, S., Ning, W., & Jin, L.
Corresponding author
Ning, Wu
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2022-04-26
Volume
13
Pages
885574-885574
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2022.885574
PMC
PMC9086831
OpenAlex
W4224854609
Cited by
7
References
56
Citations by year
2025: 2 · 2024: 3 · 2023: 2
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
lisdexamfetamine, d-amphetamine, prodrugs, locomotor activity, spatial working memory, recognition memory, medial prefrontal cortex, dopamine release, microdialysis, cognitive enhancement

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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