|Paul Albert, PhD
Telephone: 613-562-5800 ext. 8307
Senior Scientist, Neuroscience, Ottawa Hospital Research Institute
Professor Albert is working in the area of molecular mechanisms of autoreceptor desensitization. Successful therapy of major depression (as well as generalized anxiety, obsessive-compulsive, and other mental disorders) using a variety of antidepressant compounds (e.g., serotonin-specific reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, and 5-HT1A receptor agonists) is associated with a three-week time course before clinical improvement may be observed. Antidepressants appear to act by directly modifying the serotonergic system which originates in the raphe nuclei of the brain. Desensitization of inhibitory 5-HT1A autoreceptors occurs following chronic (but not acute) antidepressant treatment, and allows for enhanced firing of serotonergic raphe neurons in the presence of antidepressant. The enhanced firing results in increased serotonergic neurotransmission as the post-synaptic 5-HT receptors do not desensitize to the same extent. Receptor desensitization involves several sequential steps: uncoupling (min), mediated by phosphorylation, receptor sequestration (min-hr), and down-regulation (hr-days), involving receptor degradation and/or decreased receptor synthesis.
The importance of receptor phosphorylation, G proteins, and effectors in 5-HT1A and dopamine-D2 receptor signalling and desensitization is being probed in model cellular systems using a variety of molecular approaches, including: sense and antisense transfections, mutagenesis, cDNA cloning of novel receptors/kinases, immunoblotting/epitope tagging, and functional (cAMP, CA, secretion) assays.
The importance of transcriptional and post-transcriptional events is being probed using 5-HT1A receptor promoter constructs, DNAase protection assays, RNAase protection assays, etc., with the ultimate aim of identifying genetic sequences that may confer susceptibility to mental disorders or responsiveness to anti-depressant treatment.
Professor Albert has established a research collaboration with the Royal Ottawa Hospital (Royal Ottawa Health Care Group) to apply this work in the area of schizophrenia.