Background: Alcohol abuse is common in patients with schizophrenia (SCZ);although alcohol consumption in SCZ tends to be moderate, it worsens the progression of SCZ. The overarching goals of this proposal are: (A) to begin to understand the factors underlying alcohol consumption in the Syrian golden hamster, an animal model with strong predictive validity for the ability of drugs to decrease alcohol abuse in patients with SCZ and (B) to characterize a potential screening tool for the ability of drugs to decrease alcohol consumption in patients with SCZ. The hamster consumes alcohol steadily in free access conditions, but the hamster's preference and motivation for alcohol have not been tested. In patients with SCZ and in the hamster, the atypical antipsychotic clozapine (CLOZ) dramatically decreases alcohol consumption but the typical antipsychotic haloperidol (HAL) does not. In the current proposal, we will differentiate between drug effects on preference (conditioned place preference;CPP) vs. motivation (operant self-administration;OSA) for rewards in the golden hamster.
Specific Aims :
The specific aims of this proposal are: (1) To explore whether alcohol produces dose-dependent CPP in the hamster;(2) to explore whether CLOZ , but not HAL, can block the preference for alcohol in the CPP paradigm;(3) to determine whether the hamster shows a higher motivation to consume alcohol and isocaloric sucrose, compared to saccharin, water, and food, in an OSA paradigm;and (4) to determine whether HAL, but not CLOZ, will decrease the motivation of the hamster to respond for rewards in the OSA paradigm. Experimental Protocols:
Aim 1 : CPP in response to alcohol or vehicle injections will be tested in the hamster.
Aim 2 : The effects of vehicle, clozapine, or haloperidol on alcohol CPP in the hamster will be tested.
Aim 3 : Hamsters will be trained to administer food and fluids by lever-pressing first on a fixed-ratio schedule, then tested for maximum responding (break point) for water, sucrose, saccharin, and alcohol on a progressive-ratio schedule.
Aim 4 : Once hamsters are trained to lever press for food and fluids, the effects of vehicle, clozapine, or haloperidol on break points for food, water, sucrose, saccharin, and alcohol will be tested. Significance: Although the golden hamster has been used as a model of alcohol abuse in SCZ, the factors underlying alcohol consumption in this animal have not been fully characterized, and Aims 1 and 3 will allow us to examine two of these factors - preference and motivation for alcohol. Studying the effects of CLOZ and HAL in these tasks will help us to determine whether CPP or OSA is a better screen for the ability of drugs to decrease alcohol intake, and to begin to understand in what manner CLOZ is acting to decrease alcohol abuse in patients with SCZ.
The proposed research will provide a foundation for the development of novel pharmacotherapies for co- occurring schizophrenia and drug abuse by elucidating the actions of clozapine, an effective but toxic medication used to treat these co-occurring disorders. This research will also provide new information about the behavior of the Syrian golden hamster, which has been used to test the ability of antipsychotic drugs and other medications to decrease alcohol consumption. Finally, this work will help to characterize a potential screening tool to test the ability of drugs to decrease alcohol consumption in patients with schizophrenia.
|Gamsby, J J; Templeton, E L; Bonvini, L A et al. (2013) The circadian Per1 and Per2 genes influence alcohol intake, reinforcement, and blood alcohol levels. Behav Brain Res 249:15-21|