Dr Tyra Zetterström

Job: Reader of Neuropharmacology

Faculty: Health and Life Sciences

School/department: Leicester School of Pharmacy

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

T: +44 (0)116 250 6477

E: tscz@dmu.ac.uk

W: www.dmu.ac.uk/pharmacy

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Personal profile

Dr Zetterström graduated in Pharmacy (Apotekarexamen) at the University of Uppsala, Sweden in 1979 with Honours in Pharmacology and Toxicology. Following a brief period as a practising pharmacist, she established her interest in the neuropharmacology of CNS transmitters in the Department of Pharmacology at the Karolinska Institute, Stockholm, Sweden and obtained her PhD in 1986. Together with her supervisor Professor Urban Ungerstedt she pioneered the method of microdialysis for the in vivo pharmacological analysis of the CNS neurotransmitter dopamine.

Dr Zetterström spent the next three years in the Department of Physiology in Oxford as a Wellcome Trust Swedish-British Fellow. In 1989 she joined the newly established Smith Kline Beecham Centre for Applied Neuropsychobiology in the Department of Clinical Pharmacology in Oxford and was appointed to Research Lecturer in 1997.

She joined the Leicester School of Pharmacy at the start of the new millennium. Throughout her time at DMU, Dr Zetterström’s research has focused on the pharmacology and physiology of monoamine transmitters, particularly in relation to their influence on expression of brain derived neurotrophic factor (BDNF), a key protein for neuronal development and adaptation. Highlights of Dr Zetterström’s research are findings of drug induced BDNF mRNA expression, including therapeutics for the treatment of depression and attention deficit hyperactivity disorders (ADHD).

Research group affiliations

Pharmacology

Publications and outputs

Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum
Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum Zetterstrom, T. S. C.; Quansah, Emmanuel; Zette The psychostimulant methylphenidate (MPH) is the primary drug treatment for attention deficit hyperactivity disorder (ADHD) in children. MPH is well known to acutely block the dopamine (DAT) and noradrenaline (NET) transporters. Its effect on additional catecholamine targets is however less known. This study was aimed at comparing the effects of acute (2 mg/kg, i.p.) and chronic (2 mg/kg twice daily for 2 weeks) MPH treatment to young rats on key catecholamine protein targets in brain regions implicated in the symptoms and treatment of ADHD. For this purpose, the density of DAT, NET, the vesicular monoamine transporter 2 (VMAT2), the rate limiting enzyme for catecholamine synthesis tyrosine hydroxylase (TH) and the dopamine D1 receptor were measured in frontal (FC), parietal cortex (PCx) and the dorsal (DS) and ventral (VS) striatum. The data demonstrate that the effects of MPH depend on duration of treatment and brain region investigated. With the exception of DAT in the VS our results indicate that chronic but not acute administration of MPH increases levels of DAT, NET, TH, VMAT2 and D1. These effects were further more prominent in the VS over DS and in the PCx compared to the FC. In addition, chronic MPH enhanced DAT levels in the left DS but not in right side. To summarize, this study shows new evidence that chronic MPH to young rats preferentially alters catecholamine targets in PCx and VS over DS and FC. The effect of chronic MPH to increase levels of DAT, NET and VMAT2 suggests that the drug might long-term loose some of its acute action to increase extracellular levels of dopamine and noradrenaline. In conclusion, these findings provide novel insights into the mechanism of action by MPH in the treatment of ADHD and further suggest that the long-term effectiveness of the stimulant drug could be limited. 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.
Methylphenidate alters monoaminergic and metabolic pathways in the cerebellum of adolescent rats
Methylphenidate alters monoaminergic and metabolic pathways in the cerebellum of adolescent rats Quansah, Emmanuel; Ruiz-Rodado, Victor; Grootveld, M.; Zetterstrom, T. S. C. Abnormalities in the cerebellar circuitry have been suggested to contribute to some of the symptoms associated with attention deficit hyperactivity disorder (ADHD). The psychostimulant methylphenidate (MPH) is the major drug for treating this condition. Here, the effects of acute (2.0 mg/kg and 5.0 mg/kg) and chronic (2.0 mg/kg, twice daily for 15 days) MPH treatments were investigated in adolescent (35-40 days old) rats on monoaminergic and metabolic markers in the cerebellum. Data acquired indicates that acute MPH treatment (2.0 mg/kg) decreased cerebellar vesicular monoamine transporter (VMAT2) density, while chronic treatment caused an increase. In contrast, protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor were not significantly altered by neither acute nor chronic MPH treatment. In addition, while chronic but not acute MPH treatment significantly enhanced dopamine turnover (DOPAC/dopamine) in the cerebellum, levels of dopamine and homovanillic acid (HVA) were not altered. Acute MPH (5.0 mg/kg) significantly modified levels of a range of cerebellar metabolites with similar trends also detected for the lower dose (2.0 mg/kg). In this regard, acute MPH tended to decrease cerebellar metabolites associated with energy consumption and excitatory neurotransmission including glutamate, glutamine, N-acetyl aspartate, and inosine. Conversely, levels of some metabolites associated with inhibitory neurotransmission, including GABA and glycine were reduced by acute (5.0 mg/kg) MPH, together with acetate, aspartate and hypoxanthine. In conclusion, this study demonstrated that MPH alters cerebellar biochemistry, and that this effect depends on both dose and duration of treatment. The therapeutic significance of these results 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
Chronic methylphenidate regulates genes and proteins mediating neuroplasticity in the juvenile brain
Chronic methylphenidate regulates genes and proteins mediating neuroplasticity in the juvenile brain Quansah, Emmanuel; Sgamma, Tiziana; Jaddoa, Estabraq; Zetterstrom, T. S. C. Methylphenidate (MPH) is the front-line psychostimulant medication prescribed for alleviating the symptoms associated with attention deficit hyperactivity disorder (ADHD) in children. Here, we investigated the effects of chronic MPH (2.0 mg/kg, twice daily for 15 days) exposure to young rats (20-25 days old at start of treatment) on the expression of genes and proteins associated with neuroplasticity, such as activity regulated cytoskeleton-associated protein (Arc), insulin receptor substrate protein 53 (IRSp53), cell division control protein 42 (Cdc42), and actin-related protein 2 (Arp2). Chronic MPH increased Arc expression in areas of the cerebrum including, the striatum, nucleus accumbens and hippocampus. In addition, chronic MPH also increased the expression of IRSp53 in the striatum, while Cdc42 and Arp2 were specifically increased in the nucleus accumbens. Conversely, chronic MPH decreased Arc and IRSp53 protein expression in the cerebellum, indicating differential effects of the drug in cerebral areas relative to the cerebellum. Overall, our results indicate that chronic MPH treatment increases expression of genes and proteins associated with dendritic spine formation and neuronal plasticity in target areas of the cerebrum while it decreases the expression in the cerebellum. 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
1H NMR-based metabolomics reveals neurochemical alterations in the brain of adolescent rats following acute methylphenidate administration
1H NMR-based metabolomics reveals neurochemical alterations in the brain of adolescent rats following acute methylphenidate administration Quansah, Emmanuel; Ruiz-Rodado, Victor; Grootveld, M.; Probert, Fay; Zetterstrom, T. S. C. The psychostimulant methylphenidate (MPH) is increasingly used in the treatment of attention deficit hyperactivity disorder (ADHD). While there is little evidence for common brain pathology in ADHD, some studies suggest a right hemisphere dysfunction among people diagnosed with the condition. However, in spite of the high usage of MPH in children and adolescents, its mechanism of action is poorly understood. Given that MPH blocks the neuronal transporters for dopamine and noradrenaline, most research into the effects of MPH on the brain has largely focused on these two monoamine neurotransmitter systems. Interestingly, recent studies have demonstrated metabolic changes in the brain of ADHD patients, but the impact of MPH on endogenous brain metabolites remains unclear. In this study, a proton nuclear magnetic resonance (1H NMR)-based metabolomics approach was employed to investigate the effects of MPH on brain biomolecules. Adolescent male Sprague Dawley rats were injected intraperitoneally with MPH (5.0 mg/kg) or saline (1.0 ml/kg), and cerebral extracts from the left and right hemispheres were analysed. A total of 22 variables (representing 13 distinct metabolites) were significantly increased in the MPH-treated samples relative to the saline-treated controls. The upregulated metabolites included: amino acid neurotransmitters such as GABA, glutamate and aspartate; large neutral amino acids (LNAA), including the aromatic amino acids (AAA) tyrosine and phenylalanine, both of which are involved in the metabolism of dopamine and noradrenaline; and metabolites associated with energy and cell membrane dynamics, such as creatine and myo-inositol. No significant differences in metabolite concentrations were found between the left and right cerebral hemispheres. These findings provide new insights into the mechanisms of action of the anti-ADHD drug MPH. 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 for Pharmacy and the Health Sciences
Pharmacology for Pharmacy and the Health Sciences Boarder, M. R.; Dixon, C. J.; Newby, D; Navti, P; Zetterstrom, T. S. C.
Tyrosine-free amino acid mixtures reduce physiologically-evoked release of dopamine in a selective and activity-dependent manner
Tyrosine-free amino acid mixtures reduce physiologically-evoked release of dopamine in a selective and activity-dependent manner Le Masurier, M.; Zetterstrom, T. S. C.; Cowen, P.; Sharp, T.
Effects of repeated 5-HT6 receptor stimulation on BDNF gene expression and cell survival
Effects of repeated 5-HT6 receptor stimulation on BDNF gene expression and cell survival de Foubert, G.; Khundakar, A. A.; Zetterstrom, T. S. C.
The role of 5-hydroxytryptamine receptor subtypes in the regulation of brain-derived neurotrophic factor gene expression
The role of 5-hydroxytryptamine receptor subtypes in the regulation of brain-derived neurotrophic factor gene expression Zetterstrom, T. S. C.; Coppell, A. A.; Khundakar, A. A.
Effects of GABAB ligands alone and in combination with paroxetine on hippocampal BDNF gene expression.
Effects of GABAB ligands alone and in combination with paroxetine on hippocampal BDNF gene expression. Khundakar, A. A.; Zetterstrom, T. S. C.
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.

Click here for a full listing of Tyra Zetterström‘s publications and outputs.

Key research outputs

Sharp, T. & Zetterström, T.S. (2007) What did we learn from microdialysis? In: Handbook of microdialysis. Handbook of behavioural sciences (EDS Westerink BHC and Cremers TIFH), Academic Press, pp. 5-16.

de Foubert, G., Carney, S.L., Robinson, C.S., Destexhe, E.J., Tomlinson, R., Hicks, C.A., Murray, T.K., Gaillard, J.P., DeVille, C., Xhenseval, V., Thomas, C.E., O’Neill, M.J. & Zetterström, T.S. (2004) Fluoxetine induced change in rat brain expression of brain derived neurotrophic factor varies depending on length of treatment. Neuroscience, 128, 597-604.

Coppell, A.L., Pei, Q. & Zetterström, T.S. (2003) Bi-Phasic BDNF gene expression following antidepressant drug treatment. Neuropharmacology, 22, 903-910.

Research interests/expertise

Pharmacology and physiology of monoamine neurotransmitters
Neuroadaptive processes associated with treatment of psychiatric conditions including depression and ADHD
Physiological and pharmacological regulation of brain derived neurotrophic factor (BDNF) expression.

Areas of teaching

Chemical transmission and drug action in the central nervous system
Therapeutics and Mental Health (anxiolytics, antidepressants, antipsychotics and hypnotics)
Antiepileptic drugs
Analgesic drugs
Drug addiction, dependence and abuse
CNS stimulants and treatment of ADHD
CNS drugs and neuronal adaptation
Physiology and Pharmacology of the Sympathetic nervous system
Lung disorders and drug treatment.

Membership of external committees

1989-present, Member of British Pharmacological Society
1995-present, Member of British Neuroscience Association, including Federation of European Neuroscience (FENS)
2005-present, Member of British Association of psychopharmacology.

Conference attendance

Recent lectures at conferences and meetings of international and national scientific societies include:

British Association for Psychopharmacology, Invited Speaker (2011)
British Association for Psychopharmacology Invited Speaker (2009)
ECNP, Istanbul, Invited Speaker Turkey (2009)

Consultancy work

Neuropharmacology: Molecular action of antidepressant drugs
Effects of Psychostimulants and its use in children.

Current research students

Ayah Komal Siddiqi 1 supervisor

Internally funded research project information

RIF Grant
Project Title: Chronic treatment with methylphenidate (Ritalin) during development and neuronal toxicity into adulthood: a proof of principle study.
Start Date: September 2010
End Date: August 2011.