Chemical Neuroanatomy Laboratory

Lab head: Vladimir Balcar
Location: Anderson Stuart Building

Research conducted by this laboratory is concerned with investigating neurochemical, pharmacological and anatomical aspects of central synaptic transmission. Of particular interest is the transport and metabolism of glutamate, as impaired transport of this excitatory transmitter is implicated in a number of disease states, including: Alzheimer's disease, neurodegeneration following head injury and stroke, and tissue damage accompanying the growth of brain tumours. By studying the effects of glutamate transport modulators on in vitro brain preparations, this group has revealed metabolic deficiencies arising from glutamate transport impairment that may be involved in the development of some of the disease states described above.

Lab members: V Balcar (head)

Metabolomics of mental disease: effects of clozapine on brain metabolome

Primary supervisor: 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 GABAB 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

Discipline: Anatomy & Histology