The strategy of using partial dopamine (DA) agonists as antidopaminergic antipsychotic agents is based on two sets of observations: first, that DA neurons have autoreceptors which function to decrease DA synthesis, release and neuronal firing and hence are antidopaminergic; and, second, that partial agonists have full affinity but reduced DA receptors, consequently they exert relatively lower receptor stimulation in competition with the natural neurotransmitter, dopamine. We have suggested that antipsychotic treatment with partial DA agonist, compared with full receptor antagonists may have clinical advantages, if these drugs can be shown to be effective. Efficacy and side effects of partial DA agonist will depend on the level of intrinsic of the partial agonist, a range which can extend from less than 10% to over 90%. Our work to date (see Progress Report) suggest that a partial agonist activity somewhat below 35% may be optimal to test in schizophrenia. Our most useful partial DA agonist at present is (-) -3PPP. The strategy of combining a small proportion of a full antagonist (eg. haloperidol) with the partial agonist (-) -3PPP, to produce a functionally lower intrinsic activity of (-)-3PPP, adds flexibility to our clinical testing of the partial agonist strategy. Since the respective roles of the D2, D3 and D4 receptors in mediating the antipsychotic action of neuroleptics is still unknown, we remain interested in discriminating actions at these receptors in psychosis and in agonist action. Our clinical studies will focus on testing the antipsychotic action of two different levels of (-)- 3PPP functional intrinsic activities, each evaluated in the three primary symptom clusters of schizophrenia: 1) hallucinations/delusions; 2) thought disorder; and 3) negative symptoms. Also, since dopamine agonists have different levels of intrinsic activity at each D2-family receptor, we need to determine which (or perhaps all) of the receptors to target for antipsychotic effect with a given intrinsic activity. Therefore, we propose to test the antipsychotic action full antagonists of the D3 and D4 receptors in schizophrenia on the three primary symptom clusters depressions (hallucinations/delusions; thought disorder; negative symptoms), to identify the role, if any, of these receptors inn the control of psychosis. In the laboratory, we propose to use the D2,l, D3, and D4.4 cloned receptors in cultured CHO or HB-108 cells to examine the intrinsic activity and the desensitization potential of different DA agonists at the human receptors, in vitro. These data will predict and later help us to select optimal agonist intrinsic activity a depression family receptor for clinical testing with respect to antipsychotic activity, duration of therapeutic action, and side effects. Lastly, in the laboratories, we propose to determine the functional consequences of selective D2, D3, and D4 receptors types in rat and human brain (see Progress Report) we will explore the distribution activation following selective receptor blockade as measured by IEG expression.
|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; 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; 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; Roberts, R C; Tamminga, C A (1995) D2-family receptor distribution in human postmortem tissue: an autoradiographic study. Neuroreport 6:2505-12|