Comparing the Discriminative Stimulus Properties of the Atypical Antipsychotic Drug Clozapine with the Typical Antipsychotic Drug Haloperidol in C57BL/6 Mice
First discovered in the early 1950s, antipsychotic drugs revolutionized the treatment of patients with psychotic disorders, mainly schizophrenia. Drugs such as haloperidol, chlorpromazine, and thioridazine are known as typical or first generation neuroleptics (antipsychotic medications). Their mechanism of action is chiefly as antagonists of dopamine D2 and D3 receptors in the brain. While these typical neuroleptics drugs work well in treating positive symptoms of schizophrenia, such as hallucinations, they are relatively ineffective in treating negative symptoms such as flat affect and anhedonia. Additionally, typicals often produce serious side effects such as tardive dyskinesia, Parkinsonian like tremors. Later, “atypical” or second generation antipsychotics like clozapine and amisulpride were developed. Like their predecessors, atypical antipsychotic drugs antagonize D2 and D3 receptors, but they also antagonize 5-HT serotonergic receptors. This mechanism appears to be responsible in treating the negative symptoms of schizophrenia. In addition, these newer drugs display a greater effect on D2 receptors in the limbic system as compared to D2 receptors in the mesostriatal system making them less likely to produce extrapyramidal motor side effects.
In the current study C57/BL6 mice will be trained to discriminate either amisulpride or haloperidol from vehicle in a two-lever drug discrimination task. This preclinical behavioral assay helps us to understand the similarities and differences among the various drugs that have been and are currently being developed for the treatment of schizophrenia. Once dose-response curves have been established for each training drug, haloperidol and amisulpride will be tested for cross-generalization to each other. This will provide insight to the importance of 5-HT antagonism in the discriminative cue of atypical antipsychotics as both of these drugs antagonize dopamine receptors, only amisulpride antagonizes serotonin receptors. We also plan to test selective ligands, specifically serotonergic and dopaminergic antagonists, to investigate the importance of specific receptor subtypes for the discriminative stimulus properties for both haloperidol and amisulpride.
Specific courses completed:
Prefer basic Biology and Physiological Psychology (not required however)
Student must be comfortable working with mice. Computer skills are very useful.
Student eligibility requirements: Prefer Psychology or Biology, but no restrictions.