Neurochemistry Laboratory - Honours in 2010
An Honours project undertaken in this lab would be administered by the Discipline of Anatomy & Histology.
Metabolomics of mental disease: effects of neuroleptics on brain metabolome.
Supervisor + contact details:
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Neuroleptics of the second generation (NSG's, e.g. clozapine, introduced c. 1980) promised more refined and subtler therapy for mental disorders. However, despite many successful applications, wider use of NSG's has been limited because of uncertainty about their mechanisms of action (Kuroki et al. 2008) and side effects (Simpson et al. 2001).
We plan to use 13C-NMR spectroscopy combined with state of the art data analysis to generate a novel view of how some of these compounds exert their effects on brain. We have been using such approach to study how specific glutamatergic and GABAergic agonists and antagonists influence the brain metabolome (Rae et al. 2009). The "metabolome" in our experiments is defined as a set of metabolic parameters (total levels and metabolic rates of key biochemicals) in brain tissue kept under controlled conditions in vitro. We have been finding that each agonist and antagonist produces a typical pattern of changes - usually related to increased/decreased excitatory or inhibitory activities or energy metabolism. We intend to exploit this approach to determine how NSG's and related drugs alter the metabolome. Do they produce patterns of changes analogous to those observed with GABAergic and glutamatergic drugs? Will such metabolic "fingerprints" correlate with desirable or adverse actions? Mechanisms of NSG's are commonly explained in terms of actions on serotoninergic and dopaminergic systems (Kuroki et al. 2008). However, the most consistently reported neurochemical changes and the most "hopeful" candidate genes in schizophrenia relate to glutamatergic and GABAergic neurotransmission. Can our results help to resolve this apparent discrepancy?
Kuroki T, Nagano N & Nakahara T (2008) Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis.
Prog Brain Res 172 199-212
Rae C, Nasrallah FA, Griffin JL, Balcar VJ & (2009) Now I know my ABC. A system neurochemistry and functional metabolomic approach to understanding the GABAergic system. J Neurochem 109 (S1) 109-116
Simpson MM, Goetz RR, Devlin NJ, Goetz SA & Walsh BT (2001) Weight gain and antipsychotic medication: differences between antipsychotic-free and treatment periods. J Clin Psych 62 694-700
