Dr Benjamin Gronier

Job: Senior Lecturer

Faculty: Health and Life Sciences

School/department: Leicester School of Pharmacy

Address: De Montfort University, The Gateway, Leicester, LE1 9BH.

T: +44 (0)116 207 8418

E: bgronier@dmu.ac.uk

W: http://www.dmu.ac.uk/hls

 

Personal profile

Ben's main interests lie in the following areas:

  • Psychopharmacology of dopamine and other central monoamines
  • Pharmacology of antipsychotic drugs and pathology of schizophrenia
  • Pharmacology and neuropathophysiology of attention deficit hyperactivity disorders (ADHD)
  • Neurochemical and electrophysiological action of psychostimulants and cognition enhancers
  • Function of brain glutamate and dopamine receptors and role in cognition and in brain disorders
  • Brain mechanism involved in the pathophysiology of obesity.

Research group affiliations

Pharmacology

Publications and outputs 

  • In silico Hierarchical Clustering of Neuronal Populations in the Rat Ventral Tegmental Area Based on Extracellular Electrophysiological Properties
    In silico Hierarchical Clustering of Neuronal Populations in the Rat Ventral Tegmental Area Based on Extracellular Electrophysiological Properties Di Miceli, Mathieu; Husson, Zoe; Ruel, Philippe; Laye, Sophie; Cota, Daniela; Fioramonti, Xavier; Bosh-Bouju, Clementine; Gronier, Ben The ventral tegmental area (VTA) is a heterogeneous brain region, containing different neuronal populations. During in vivo recordings, electrophysiological characteristics are classically used to distinguish the different populations. However, the VTA is also considered as a region harboring neurons with heterogeneous properties. In the present study, we aimed to classify VTA neurons using in silico approaches, in an attempt to determine if homogeneous populations could be extracted. Thus, we recorded 291 VTA neurons during in vivo extracellular recordings in anesthetized rats. Initially, 22 neurons with high firing rates (>10 Hz) and short-lasting action potentials (AP) were considered as a separate subpopulation, in light of previous studies. To segregate the remaining 269 neurons, presumably dopaminergic (DA), we performed in silico analyses, using a combination of different electrophysiological parameters. These parameters included: (1) firing rate; (2) firing rate coefficient of variation (CV); (3) percentage of spikes in a burst; (4) AP duration; (5) Dt1 duration (i.e., time from initiation of depolarization until end of repolarization); and (6) presence of a notched AP waveform. Unsupervised hierarchical clustering revealed two neuronal populations that differed in their bursting activities. The largest population presented low bursting activities (<17.5% of total spikes in burst), while the remaining neurons presented higher bursting activities (>17.5%). Within nonhigh- firing neurons, a large heterogeneity was noted concerning AP characteristics. In conclusion, this analysis based on conventional electrophysiological criteria clustered two subpopulations of putative DA VTA neurons that are distinguishable by their firing patterns (firing rates and bursting activities) but not their AP properties. open access article
  • Ad libitum administration of sucrose during adolescence causes changes in dopamine neurotransmission which are partially reversed by glucagon-like peptide
    Ad libitum administration of sucrose during adolescence causes changes in dopamine neurotransmission which are partially reversed by glucagon-like peptide Omoloye, Adesina; Gronier, Ben Ad libitum administration of sucrose during adolescence causes changes in dopamine neurotransmission which are partially reversed by glucagon-like peptide. Background: Overconsumption of sugar in children, associated with erratic eating behaviour, is linked to poor health and a higher risk to develop psychological problems [1]. It can cause abnormal fluctuation of metabolic hormones and the production of metabolites that can affect central neuronal activity. We asked the question whether prolonged continuous consumption of sucrose solution (5%) was sufficient to trigger alterations in dopaminergic neurotransmission and examined whether this could be modulated by glucagon-like peptide, a gut metabolic hormone which is known to interfere with food and drug rewarding systems [2]. Methods: Adolescent rats (PND 23-26) were administered sucrose 5% and water ad libitum, or water for 2 weeks, with or without the stable glucagon-like peptide agonist analogue exendin-4 (0.005 mg/kg/day, ip). After one week washout, rats were examined for their behavioural response to dopamine drugs and the electrophysiological characteristics of their ventral tegmental area (VTA) dopamine neurons, using single unit recording method under terminal anaesthesia. Statistical significance was ascertained by t-tests, or repeated measures ANOVA, as appropriate. Results: Rats displayed a strong preference for sucrose that was not prevented by the administration of exendin-4. However, rats on sucrose treatment tend to consume slightly more food that the naïve/control rats and the exendin-4 treated animals. After 1 week washout, rats that were treated with sucrose-only displayed a stronger motor response than naïve rats to the administration of D-amphetamine (1 mg/kg), as shown by a larger increase in rearing activity (p<0.05, two-way ANOVA). Sucrose-treated rats also displayed a larger response than naïve animals to the D3 preferential agonist pramipexole (0.05 mg/kg, ip) on yawning and pica eating activities (p<0.01, two-way ANOVA). Interestingly, these behavioural changes were not observed in rats that were co-administered exendin-4 with sucrose. There were no significant changes in the electrophysiological characteristics of dopamine neurons (firing, burst and population activities) in sucrose treated and naïve/control animals. We then tested the effects of these chronic treatments on the ability of the preferential dopamine D3 receptor agonist pramipexole (cumulative doses 0.020-0.1 mg/kg, iv) to reduce the firing activity of VTA dopamine neurons (to test dopamine auto-receptor sensitivity). Animals treated with sucrose-only displayed a partial decrease in their responses to pramipexole (p<0.05, two-way ANOVA) which was more pronounced in VTA dopamine neurons from rats that were co-administered sucrose with exendin-4 (p<0.01, two-way ANOVA). Conclusion: In conclusion, our data show that prolonged ad libitum access to sucrose to adolescent rats may alter brain circuits related to dopamine neurotransmission. It increases the behavioural effects of dopamine agonists, and is possibly associated with hypersensitivity of some postsynaptic dopamine receptors. These effects were partially prevented by exendin-4, which may elicit some protective effects on dopamine receptor function. On the other hand, we noticed that sucrose treatment induced a partial but significant decrease in the sensitivity of dopamine auto-receptors which was surprisingly exacerbated by exendin-4 co-administration, indicating that exendin-4 may exert differential effects on pre- and post-synaptic dopamine receptors. It will be of particular interest to find out how long these differential effects will persist. References [1] M.D. Kendig Cognitive and behavioural effects of sugar consumption in rodents. A review Appetite, 80 (2014), pp. 41-54 [2] E. Jerlhag GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence Neuropharmacology, 136 (2018), pp. 343-349 Research showing that a sucrose-enriched diet in adolescent can cause change in behaviour and brain neuronal activity
  • Chronic methylphenidate treatment during adolescence has long-term effects on monoaminergic function.
    Chronic methylphenidate treatment during adolescence has long-term effects on monoaminergic function. Di Miceli, Mathieu; Omoloye, Adesina; Gronier, Ben Background: Psychostimulants like methylphenidate or D-amphetamine are often prescribed for attention deficit and hyperactivity disorders in children. Whether such drugs can be administered into a developing brain without consequences in adulthood is still an open question. Methods: Here, using in vivo extracellular electrophysiology in anesthetised preparations, combined with behavioural assays, we have examined the long-term consequences in adulthood of a chronic methylphenidate oral administration (5 mg/kg/day, 15 days) in early adolescent (post-natal day 28) and late adolescent (post-natal day 42) rats, by evaluating body weight change, sucrose preference (indicator of anhedonia), locomotor sensitivity to D-amphetamine and electrical activities of ventral tegmental area dopamine and dorsal raphe nucleus serotonin neurons. Results: Chronic methylphenidate treatment during early or late adolescence did not induce weight deficiencies and anhedonia-like behaviours at adulthood. However, it increased bursting activities of dorsal raphe nucleus serotonin neurons. Furthermore, chronic methylphenidate treatment during early but not during late adolescence enhanced D-amphetamine-induced rearing activity, as well as ventral tegmental area dopamine cell excitability (firing, burst and population activity), associated with a partial desensitisation of dopamine D2 auto-receptors. Conclusions: We have demonstrated here that early, but not late, adolescent exposure to oral methylphenidate may induce long-lasting effects on monoamine neurotransmission. The possible clinical implication of these data will be discussed. Original investigation showing potential long-term consequences of chronic psychostimulant administration in adolescence. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine
    Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine Di Miceli, Mathieu; Gronier, Ben Abstract: Background: Metadoxine is composed of pyroglutamic acid and vitamin B6. Administrations of metadoxine are indicated in cases of acute alcohol intoxication or in chronic alcoholism. Objectives: To reference all available clinical trials investigating the effects of metadoxine on humans. A focus was put on alcohol intoxication and chronic alcoholism, alcohol abstinence and survival rates. Adverse events were also taken into consideration. Finally, potential roles of metadoxine in treating disorders of the central nervous system will be assessed. Methods: PRISMA guidelines were followed. Computerised literature searches were performed in July 2017 to retrieve all clinical trials investigating metadoxine from the MEDLINE®, the European Union Clinical Trials Register and the ClinicalTrials.gov databases, using the following equation: “metadoxine”. Inclusion criteria were all published clinical trials investigating metadoxine in humans, regardless of outcome measures. Exclusion criteria were articles not abstracted, in vitro studies, studies in rodents, retrospective studies and reviews. Results: Sixteen studies were included. Evidence suggests that metadoxine appears safe to use, as it rarely induced adverse events (reported in 7 out of the 7 studies measuring safety/tolerability). Moreover, metadoxine seems efficient in treating acute alcohol intoxication (2/2 studies) as well as improving liver functions following chronic alcoholism (4/5 studies). Finally, currently on-going clinical trials will reveal if metadoxine could be indicated in attention deficit and hyperactivity disorders as well as fragile X syndrome. Conclusion: Metadoxine appears safe to use and seems efficient to improve liver functions following alcohol-related diseases. Further clinical trials will be necessary to determine if metadoxine can be promising for treating brain disorders. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion.
    Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion. Gronier, Ben; Savignac, H. M.; Di Miceli, Mathieu; Idris, S. M.; Tzortzis, G.; Anthony, D.; Burnet, P.W.J. We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors.
    Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors. Di Miceli, Mathieu; Gronier, Ben RATIONALE: Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. Currently available ADHD drugs include the psychostimulants methylphenidate (MPH) and D-amphetamine (D-AMP), acting on norepinephrine and dopamine transporters/release, and atomoxetine (ATX), a selective norepinephrine uptake inhibitor. Recent evidence suggests an involvement of glutamate neurotransmission in the pathology and treatment of ADHD, via mechanisms to be clarified. OBJECTIVE: We have investigated how ADHD drugs could modulate, through interaction with catecholamine receptors, basal and glutamate-induced excitability of pyramidal neurons in the prefrontal cortex (PFC), a region which plays a major role in control of attention and impulsivity. METHODS: We have used the technique of extracellular single-unit recording in anaesthetised rats coupled with microiontophoresis. RESULTS: Both MPH (1-3 mg/kg) and D-AMP (1-9 mg/kg) increased the firing activity of PFC neurons in a dopamine D1 receptor-dependent manner. ATX administration (1-6 mg/kg) also increased the firing of neurons, but this effect is not significantly reversed by D1 (SCH 23390) or alpha1 (prazosin) receptor antagonists but potentiated by alpha2 antagonist (yohimbine). All drugs induced a clear potentiation of the excitatory response of PFC neurons to the microiontophoretic application of the glutamate agonist N-methyl-D-aspartate (NMDA), but not to the glutamate agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). The potentiating effect of D-AMP on NMDA-induced activation of PFC neurons was partially reversed or prevented by dopamine D1 receptor blockade. CONCLUSION: Our data shows that increase in excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs.
  • The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex
    The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex Gronier, Ben; Waters, S.; Ponten, Henrik The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2–3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington’s disease for which pridopidine is currently in development.
  • Pharmacological mechanisms involved in the electrophysiological effects of methylphenidate on prefrontal cortex neurons.
    Pharmacological mechanisms involved in the electrophysiological effects of methylphenidate on prefrontal cortex neurons. Gronier, Ben; Blanc, E.
  • Age-dependent effects of methylphenidate in the prefrontal cortex: Evidence from electrophysiological and Arc gene expression measurements.
    Age-dependent effects of methylphenidate in the prefrontal cortex: Evidence from electrophysiological and Arc gene expression measurements. Gronier, Ben; Aston, James; Liauzun, Claire; Zetterstrom, T. S. C.
  • In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: Involvement of dopamine D1 and alpha 2 adrenergic receptors.
    In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: Involvement of dopamine D1 and alpha 2 adrenergic receptors. Gronier, Ben

Click here for a full listing of Benjamin Gronier‘s publications and outputs.

Research interests/expertise

  • Neuropsychopharmacology
  • Psychiatry
  • Neuro-electrophysiology
  • Cognition Neurodevelopment disorders
  • Attention deficit hyperactivity disorders
  • Schizophrenia
  • Antipsychotics
  • Psychostimulants.

Areas of teaching

  • Pharmacology
  • Endocrinology
  • Central Nervous System
  • Nutrition
  • Pharmacokinetics.

Qualifications

PhD

Courses taught

  • Pharmacy (year 1-4)
  • Pharmaceutical and Cosmetic Sciences (year 2)
  • Biomedical Sciences (year 2)
  • Speech and Language Therapy (year 1)
  • Psychiatry trainees.

Honours and awards

  • Ben was nominated for the Vice Chancellor Teaching of Excellence (2006)
  • Ben was part of the group that obtained the Curriculum development and Innovation award (2006).

Membership of professional associations and societies

  • European college of Neuropsychopharmacology
  • Society for Neuroscience.

Professional licences and certificates

  • Home office animal licence (modules 1-4)
  • Radioprotection supervisor.

Forthcoming events

European College of Neuropsychopharmacology, October 2012, Vienna, Austria

Conference attendance

European College on Neuropsychopharmacology meeting, Istanbul, September 2009. Ben was invited to present and organize a session entitled: 'Age dependent effects of methylphenidate in animal studies; does it matter?'

Key research outputs

  • Electrophysiological and neurochemical studies ADHD drugs in the adult and developing brain
  • Modulation of glutamate NMDA receptor function by psychotropic drugs
  • Control of the neuronal activity in the mesocorticolimbic dopaminergic systems by psychotropic drugs and environmental factors

Current research students

  • Ahmed Alsabi, PhD student, 2nd supervisor
  • Komal Siddiqi, PhD student, 2nd supervisor
  • Adele Bousquet, MSC Pharmacology (France), 1st supervisor
  • Razane El Bizre, MSC Pharmaceutical Technology, 1st supervisor
  • Maryam Meriki, MSC/Pharmacy Student (France), 1st supervisor

Externally funded research grants information

Successful applications:

  • Biotechnology and Biological Sciences Research Council co-application grant (Dr P Burnet, Department of Psychiatry, Oxford University) :
    The effect of D-alanine and a prebiotic on rat brain N-methyl-D-aspartate (NMDA) receptors and executive function. £ 345,000.
  • Industrial collaboration with Neurosearch (H Ponteck, Sweden). £ 29,900

 Pending:

  • NARSAD (long term effect of methylpenidate on mesocortical dopamine neurones) $ 56,000.
  • Industrial collaboration with Eli Lilly (Indianapolis, US) Long term effect of atomoxetine on prefrontal cortex neurones and cognitive functions. £ 42,000.

Internally funded research project information

  • Higher Education Innovation Funding (£10000). A multidisciplinary investigation on the use of intranasal administration of dopamine as an alternative treatment for ADHD. (In collaboration with Prof J Taylor).
  • DMU PhD studentship to start in October 2012: Impact of psychostimulant administration during development on adult brain functions controlling motivation, impulsivity and cognition.

Search Who's Who

 
< Target area section ends />
[option one heading]

[option one text]

< Footer section begins />
[option two heading]

[option two text]

< Footer section ends />
[option three heading]

[option three text]