Chemical Neuroanatomy Laboratory - Honours in 2009

An Honours project undertaken in this lab would be administered by the Discipline of Anatomy & Histology.

Metabolomics of mental disease: effects of clozapine on brain metabolome

Supervisor + contact details:

• Associate Professor Vladimir Balcar

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 clozapine exerts its effects on brain. We have been using such approach to study how specific glutamatergic and GABAergic agonists and antagonists influence the brain metabolome (e.g. Nasrallah et al. 2007). 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 clozapine and other NSG's 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?

Relevant publications:

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

Nasrallah FA, Griffin JL, Balcar VJ & Rae C (2007) Understanding your inhibitions. Modulation of brain cortical metabolism by GABA_B receptors. J Cereb Blood Flow Metab 27 1510-1520

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