mdl-100907 and Basal-Ganglia-Diseases

Explaining the underlying mechanisms of antipsychotic drug-induced movement disorders remains a substantial challenge. The association of atypical antipsychotic agents with fewer drug-induced movement disorders than conventional agents has engendered several pathophysiologic hypotheses: (1) the hypothesis that, unlike conventional antipsychotic agents, atypical antipsychotics have greater activity in blocking serotonin-2A (5-HT(2A)) receptors than dopamine-2 (D(2)) receptors, which mitigates extrapyramidal symptoms; (2) the hypothesis that atypical antipsychotics block D(2) receptors only long enough to cause an antipsychotic action, but not as long as conventional agents; (3) the hypothesis that, in tardive dyskinesia, the nigrostriatal dopamine receptor system might develop increased sensitivity to dopamine as a result of treatment with conventional antipsychotic drugs, but this may not occur with atypical antipsychotics; and (4) the hypothesis that there might be a genetic association in tardive dystonia relating to the dopamine D(3) allele. A number of factors contribute to the difficult task of gaining insight into the pathophysiologic processes of antipsychotic agents and why these agents may lead to drug-induced movement disorders.

Topics: Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Models, Biological; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Sex Factors

The low incidence of extrapyramidal side effects associated with the atypical antipsychotic iloperidone may be linked to its unique binding profile of high affinity antagonism of both α1 adrenergic receptors and serotonin 2A receptors.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Basal Ganglia Diseases; Corpus Striatum; Dopamine; Humans; Isoxazoles; Piperidines; Serotonin 5-HT2 Receptor Antagonists

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

Topics: Animals; Basal Ganglia Diseases; Behavior, Animal; Dopamine; Electrophysiology; Fluorobenzenes; Indoles; Male; Mice; Microdialysis; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Neurons; Piperidines; Quinolizines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists