Antipsychotics have been in clinical use for more than half a century. Actions at various receptor sites, notably dopamine D2, serotonin 5-HT2A, and/or 5-HT1A receptors, are critically important for the therapeutic effect of antipsychotic drugs. How these actions at the neurobiological level translate into improvement of psychotic symptoms remains unresolved. The Principal Investigator's long-term goal is to understand the behavioral and neurobiological mechanisms of action of antipsychotic drugs. The objective of this application is to identify the behavioral mechanisms of antipsychotic action through a preclinical approach. The project hypothesis is that antipsychotic drugs achieve their anti-""""""""psychotic"""""""" effect via a dual action: (a) selectively weakening the aberrant motivational salience of stimuli (e.g., psychotic thoughts or abnormal perceptions, internal and external cues) and (b) producing a drug interoceptive state that allows the weakening effect on motivational salience of stimuli to be maintained over time. A conditioned avoidance response (CAR) model and phencyclidine (PCP)-induced hyperlocomotion model based on repeated treatment regimens will be innovatively used to test this hypothesis.
Aim 1 is designed to examine the weakening of motivational salience action in the CAR model.
Aim 2 is to characterize the second proposed mechanism of antipsychotic action: the interoceptive drug state using the CAR model.
Aim 3 is structured to use the phencyclidine (PCP)-induced hyperlocomotion model to cross-validate findings from the first two aims and further test our hypothesis. This project is innovative because several novel experimental manipulation techniques will be employed to characterize the exact psychological processes affected by antipsychotics and tease apart the ones relevant to antipsychotic action from irrelevant ones. In addition, multiple behavioral models sensitive to antipsychotic action will be used to cross-validate findings and test alternative hypotheses. Because antipsychotics will be directly compared with non-antipsychotics (e.g. chlordiazepoxide, fluoxetine, and citalopram), the reliability of data and the specificity of drug action will be greatly enhanced. Finally, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical condition and ensure the mechanisms identified are applicable to clinics.

Public Health Relevance

How antipsychotic drugs work in the brain and change the psychological processing to achieve their therapeutic effects is unknown. This project is designed to reveal the psychological mechanisms of how antipsychotic drugs work. Successful project completion is expected to enhance our understanding of the behavioral and neurobiological mechanisms of antipsychotic action. Such knowledge will, in turn, enhance our understanding of the neurobiological basis of psychosis and help screen future novel antipsychotic drugs.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Winsky, Lois M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Lincoln
Schools of Arts and Sciences
United States
Zip Code
Feng, Min; Sparkman, Nathan L; Sui, Nan et al. (2017) A drug-drug conditioning paradigm reveals multiple antipsychotic-nicotine interactions. J Psychopharmacol 31:474-486
Swalve, Natashia; Mulholland, Michele M; Schulz, Tiffany D et al. (2016) Effects of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats. Behav Pharmacol 27:321-30
Li, Ming (2016) Antipsychotic-induced sensitization and tolerance: Behavioral characteristics, developmental impacts, and neurobiological mechanisms. J Psychopharmacol 30:749-70
Zhang, Mengjiao; Li, Ming (2016) Behavioral and pharmacological validation of an integrated fear-potentiated startle and prepulse inhibition paradigm. Behav Brain Res 307:176-85
Chou, Shinnyi; Jones, Sean; Li, Ming (2015) Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia. Brain Res 1618:122-35
Swalve, Natashia; Barrett, Scott T; Bevins, Rick A et al. (2015) Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus. Behav Brain Res 291:253-259
Chou, Shinnyi; Davis, Collin; Jones, Sean et al. (2015) Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: assessing for tolerance and cross-tolerance to clozapine. Pharmacol Biochem Behav 128:78-88
Gao, Jun; Feng, Min; Swalve, Natashia et al. (2015) Effects of repeated quetiapine treatment on conditioned avoidance responding in rats. Eur J Pharmacol 769:154-61
Swalve, Natashia; Pittenger, Steven T; Bevins, Rick A et al. (2015) Behavioral effects of phencyclidine on nicotine self-administration and reinstatement in the presence or absence of a visual stimulus in rats. Psychopharmacology (Berl) 232:2877-87
Gao, Jun; Qin, Rongyin; Li, Ming (2015) Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function. J Psychopharmacol 29:390-400

Showing the most recent 10 out of 30 publications