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Neuropharmacology Laboratory

Mailman Research Center

Mailman Research Center

Since Since 1969 the Neuropharmacology Laboratory has conducted neurochemical, physiological, and histochemical studies of the effects of known and novel drugs on central monoaminergic neurotransmission systems, with special interest in the pharmacology of dopamine receptors and transporters in mammalian brain. Laboratory collaborations include development of novel ligands for dopamine receptors and transporters with medicinal and radiochemists. Collaborative clinical studies on the treatment of major mental illnesses involve members of McLean's Bipolar & Psychotic Disorders and Psychopharmacology Programs, also directed by Professor Baldessarini, as well as with colleagues in other centers.

Current laboratory projects include quantitative autoradiographic analysis of long-term effects of typical, atypical, and novel antipsychotic drugs on the level and distribution of dopaminergic, serotonergic, glutamatergic and other receptors in rat forebrain, following indications that cortical D2 and striatal D4 receptors are common sites of action of antipsychotics. Other projects include developing novel ligands, radioligands, and alkylating agents selective for D1, D3, and D4 dopamine receptors, dopamine and serotonin transporters, and serotonin receptors, as well as comparisons of the pharmacology of dopamine transporters defined with known and novel radioligands. Lesioning studies seek to refine the histolocation of dopamine and glutamate receptor subtypes, including recent identification of D4 heteroceptors with NMDA autoreceptors on glutamatergic corticostriatal projections, and NMDA and kainate autoreceptors on hippocampostriatal terminals.
Quantitative behavioral analyses have mapped behavioral responses throughout rat nucleus accumbens, and are used to evaluate actions of known and novel dopamine agonists and antagonists in normal and selectively lesioned and intact developing and mature rats. The laboratory has a long-standing interest in adaptive responses to long-term treatment with dopamine agonists and antagonists, and was first to quantitatively demonstrate supersensitivity of dopamine receptor functions and to suggest its role in neuropsychiatric disorders including tardive dyskinesia.

Collaborative clinical projects include quantitative assessment of the effects of discontinuing psychotropic drugs that include sharp, time-limited, increases in morbidity and mortality. Such effects complicate clinical management of patients and the ethical design and sound interpretation of studies involving drug discontinuation or drug-placebo comparisons. Other studies include analyses of the impact of shortening hospital length-of-stay on outcome in psychotic disorders, the course of first-episode bipolar and psychotic disorder patients, as well as defining factors that predict clinical response, outcome, and suicide risk in manic-depressive and psychotic patients.