The investigator's main interests are in the molecular and behavioral physiology of central monoaminergic and related neurotransmission systems of mammalian brain, and the effects exerted on them by psychotropic agents, especially antipsychotic and mood-altering drugs.
His aims i nclude both increasing the scientific basis of rational clinical application of existing psychotropic agents which are crucial to the treatment of major mental illnesses, and developing principles and led examples of potential novel treatments. These interests lead to collaborations with medicinal chemists and are informed by close contact with clinical investigators as well as with basic neuroscientist in a comprehensive neuroscience research center environment within a lading university psychiatric center. This work also encourages limited collaborations on selected relevant clinical projects, as well as teaching of basic and clinical psychopharmacology and the training of many predoctoral and postdoctoral scientists and psychiatric investigators. The investigators's research interests are ina the basic neuropharmacology of postsynaptic and presynaptic dopamine (DA) receptors in maturing and adult mammalian brain. A major challenge is to develop molecular probes for proteins specific for DA neurons and cells with which they interact. Targets of interest include not only the well known D1 and D2 receptors, but also the several new DA receptors types, s well as heteroceptors and DA transporters. Agents of interest include ligands to serve as experimental molecular """"""""tools"""""""" and compounds which may lead to novel psychotropic gents or neuroradiological probes. Leads include hydroxyaminotetralins for limbic D3 receptors, phenyltropanes for DA transporters, alkylating phenylspiperones and phenylbenzazepines for D2-like and D1-like receptors and novel phenyl-aminotetralins for newly discovered sigma3 heteroceptors. Projects include analyses of receptor-mediated control of synthesis and release of DA by autoreceptors and heteroceptors, and changes in production of DA receptors during maturation. Encouraging findings with unique DA partial-agonists suggest principles which may lead to improved antipsychotic agents. Very promising leads include S(+) isomers of the dopamine agonist aporphines which not only are antagonistic to dopamine, but do so highly selectively in limbic forebrain: some are highly orally bioavailable. They induce neither immediate motor effects through the extrapyramidal basal ganglia nor long-term tolerance and supersensitivity - reactions which complicate most antipsychotic treatments in clinical use. Complementary studies with clinical collaborators seek to clarify the still uncertain rate of response to antipsychotic treatment, its modifiability by dose or time of application, and parallels with drug actions in animal brain. Efforts also continue to quantify early risks of interrupting long- term treatment of psychotic and manic-depressive patients. Mechanisms underlying this phenomenon may include receptor supersensitivity. It has profound clinical implications and may affect the design and interpretation of most research on long-term experimental therapeutics in psychiatry.
| Joffe, Hadine; Hall, Janet E; Cohen, Lee S et al. (2003) A putative relationship between valproic acid and polycystic ovarian syndrome: implications for treatment of women with seizure and bipolar disorders. Harv Rev Psychiatry 11:99-108 |
