The dopamine antagonist properties of antipsychotic drugs have been thoroughly studied in vitro and in vivo, and most, but not all, are potent antagonists of dopamine D-2 receptors. Antipsychotic drugs are also potent antagonists at alpha-1 noradrenergic receptors. However, the relative alpha-1 noradrenergic antagonist activity of antipsychotic drugs has rarely been determined in vivo, especially during extended treatment. Such treatment provides a better model of clinical drug effects than the more frequently determined potencies of drugs in vitro, such as in test tube assays of competition for binding sites. To test the hypothesis that effective antipsychotic drugs are effective alpha- 1 noradrenergic antagonists at clinically relevant doses in vivo, rats will receive repeated antipsychotic drug treatment. Following treatment, the affinity and density of binding at dopamine D2 and alpha-1 noradrenergic receptor sites will be determined in striatum and brain exclusive of striatum, respectively. Effective antagonism should lead to an increase in density of the relevant receptors. Preliminary in vivo experiments suggest that all clinically proved antipsychotic drugs are effective antagonists at alpha-1 noradrenergic receptors, but not all are potent at dopamine D-2 receptors. The range of drugs tested will now be enlarged. Various typical and """"""""atypical"""""""" neuroleptics, as well as drugs representing the available chemical classes of antipsychotic agents will be studied. For comparison, agents which are not clinically effective antipsychotic drugs, in particular, antidepressant drugs, which are moderately potent alpha-1 an dopamine D-2 antagonists in vitro, will be studied. As effective alpha-1 noradrenergic antagonism may produce adrenergic supersensitivity, in addition to receptor upregulation, alterations in alpha-1 noradrenergic-mediated behavior will be monitored in test animals following ICV injections of the alpha-1 agonist phenylephrine. (Supersensitivity of dopaminergic systems after treatment with antipsychotic drugs has already been well studied.) These studies will help to clarify the relative roles of dopamine D-2 and alpha-1 noradrenergic antagonism in producing the therapeutic effects of antipsychotic drugs. The """"""""dopamine hypothesis"""""""" of antipsychotic drug actions has not led to breakthroughs in the understanding of psychosis or to more effective or safer treatments. Increased knowledge of the mechanisms of action of the antipsychotic drugs should aid in developing better drugs with a more favorable ratio of efficacy to unnecessary side effects. In addition, such knowledge may provide clues regarding the pathophysiology of the idiopathic psychoses.
| Nguyen, T V; Kosofsky, B E; Birnbaum, R et al. (1992) Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine. Proc Natl Acad Sci U S A 89:4270-4 |
