| dc.description.abstract | The atypical antipsychotics are a group of second generation drugs used for the treatment of schizophrenia, schizoaffective disorder, as well as some forms of bipolar and major depressive disorder. First generation or the "typical antipsychotics" are an older group of drugs whose first member, chlorpromazine was developed in the early 1950's. The typical antipsychotics have a higher propensity to induce extrapyramidal side effects (EPS), and elevate prolactin levels. The introduction to this thesis begins with the history of the typical antipsychotics; particularly the introduction of chlorpromazine, up to the introduction of clozapine a compound which revolutionized the treatment of schizophrenia. Then the five subsequently approved atypical antipsychotic drugs are discussed. The introduction of clozapine soon revealed agranuocytosis as a relatively frequent side effect, and made it clear that a need remains for antipsychotics that are equally or more efficacious without deadly leukocytopenic side effects. While the atypical antipsychotics are often lumped into one category, they are diverse compounds with different EPS liabilities, side effects, and pharmacodynamic properties. Thus, the pharmacology of the atypical antipsychotics and the most interesting set of side effects, the extrapyramidal side effects are reviewed. Extrapyramidal side effects include akathisia, parkinsonism, dystonia, and tardive dyskinesia, and are complex motor side effects with mental components. This set of troublesome side effects often result in compliance issues particularly with the typical antipsychotics. Dopamine D2 receptor antagonism in the nigrostriatal pathways of the brain is believed to be the primary cause of extrapyramidal side effects. Dopamine D2 receptor antagonism in the mesolimbic dopamine pathway is thought to result in the antipsychotic affect, and compounds that target this pathway selectively are hypothesized to have lower EPS liabilities. Although the atypical antipsychotics are a diverse group of drugs they have some common features including lower extrapyramidal side effect liabilities, and minimal or no prolactin elevation. Within this context two major hypothesis' of atypicality will be reviewed, the fast-dissociation hypothesis and 5-HT2A/D2 affinity ratio hypothesis. Orolingual components of extrapyramidal side effects will be reviewed as well as neural control of the tongue by the hypoglossal nucleus, hypoglossal nucleus organization, and tongue anatomy, and physiology. Relevant preclinical behavioral research of both typical and atypical antipsychotics will be reviewed. The research presented here is concerned with both the acute and subchronic effects of the atypical antipsychotic on orolingual function in rats as a model of EPS. Licking behavior in rats is believed to be controlled by central pattern generators in the brainstem, and the rhythm (Hz) of licking, peak force, and the number of licks will be quantitatively analyzed and compared. Tolerance and sensitization will be assessed using a subchronic dosing regimen. These data will then be discussed in the context of past studies concerning licking dynamics with haloperidol and clozapine, and to a lesser extent risperidone. | |
