Discovery of the antipsychotic efficacy of dopamine (DA) receptor antagonists in the early 1950's initiated several decades of research into the regulation and control of DA-mediated neural transmission in mammalian brain (1). Now, a considerable body of knowledge has accrued about CNS DA systems, including their circuitry, biochemistry, regional specificity, and receptor diversity, to suggest additional and perhaps more sophisticated approaches to their pharmacologic manipulation (2). The development of specific pharmaceutical agents to selectively affect particular components and distinct receptors of the dopaminergic system has been initiated (3,4). Hence, it is now possible to apply novel pharmacologic strategies involving the DA system to the treatment of neuropsychiatric illnesses, like schizophrenia. This grant will propose 1) the evaluation of several partial DA agonists in actively-psychotic drug-free schizophrenic patients to test their antipsychotic activity; 2) the evaluation of these drugs in deficit schizophrenia with low dose thioridazine, to test their activity in the negative symptoms of the illness; and 3) clarification of the relationship between the intrinsic activity of those different partial DA agonists and their clinical behavioral and biochemical characteristics in the human patient. Partial DA agonists are a putative novel antipsychotic strategy. Their full clinical activity in schizophrenia remains to be defined. There is evidence in the literature that partial agonists have antipsychotic properties. We have completed additional confirmatory studies with (-)-3PPP. As DA agonists, however, the drugs should lack any hypokinetic side effects, and lack the delayed-onset dyskinesias prominent with neuroleptics, because the drugs have a measure of agonist activity at the DA receptor. The theoretical rationale for antipsychotic action, and the preliminary data testing some of these partial agonists in schizophrenia, appear positive. However, since partial agonists can vary widely in their partial agonist activity (from 1% to 99% of the activity of dopamine itself; with apomorphines for example, having 63% intrinsic activity), there are a range of partial agonists to pick from. This application proposes the testing of three different partial agonists in schizophrenia (with and without concomitant neuroleptic and in different phenomenologic subtypes), each drug with varying levels of intrinsic activity; two, to be tested immediately and the third to be selected and tested in later years.
| Lahti, Adrienne C; Weiler, Martin A; Holcomb, Henry H et al. (2006) Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia. Neuropsychopharmacology 31:221-30 |
| Lahti, R A; Cochrane, E V; Roberts, R C et al. (1998) [3H]Neurotensin receptor densities in human postmortem brain tissue obtained from normal and schizophrenic persons. An autoradiographic study. J Neural Transm 105:507-16 |
| Lahti, R A; Roberts, R C; Conley, R R et al. (1996) D2-type dopamine receptors in postmortem human brain sections from normal and schizophrenic subjects. Neuroreport 7:1945-8 |
| Lahti, R A; Mutin, A; Cochrane, E V et al. (1996) Affinities and intrinsic activities of dopamine receptor agonists for the hD21 and hD4.4 receptors. Eur J Pharmacol 301:R11-3 |
| Lahti, R A; Roberts, R C; Tamminga, C A (1995) D2-family receptor distribution in human postmortem tissue: an autoradiographic study. Neuroreport 6:2505-12 |
