the hirsh lab


Cocaine self-administration studies in animals such as mice and rats are helping to clarify the mechanisms and controls of cocaine reward and abuse. Self-administration studies are commonly done in rats using a catheter which is placed into a vein or directly into the brain. Researchers who choose to study the genetics of addiction and self-administration find mice are considerably more useful than rats. This is because their entire genome is sequenced and because we have the ability to mutate or knock out specific genes and then determine the changes in the mice without functional use of these genes. The problem with trying to do cocaine experiments on mice is that due to their small size, it is difficult to properly place and maintain the catheters.

Animals normally respond more severely to repeated doses of cocaine, indicating they are sensitized to subsequent doses of the same concentration. Sensitization can be measured by an increase in repeated behaviors, referred to as stereotypies, that are seen following a dose of cocaine. These behaviors can include excessive grooming, circling, and increased rearing, seizures or death. Along with showing behavioral changes following cocaine administration, animals will frequently pair physical space or visual cues with the reward of the drug. This conditioned place preference is observed in mice continually exposed to cocaine in a specific location.

Circadian rhythms are known to regulate numerous biological processes, such as heart rate, feeding, and locomotor behavior. There is preliminary evidence that the circadian system in fruit flies, rats and mice may play a role in regulating the cocaine reward pathway. Animals with mutations in their circadian clocks do not respond normally to cocaine self-administration. The differences include lacking conditioned place preference, not showing sensitization or showing hypersensitization, and altered stereotypies commonly seen in wild type, whether the cocaine was self-administered or injected.

I propose to define a novel method for cocaine self-administration in mice, where the mouse nose-pokes and receives a spray of aerosol cocaine. Utilizing this method, I can then look at numerous circadian mutant animals to characterize any difference in self-administration or reward learning to a food reward. The link between the circadian system and the cocaine reward pathway will be examined using these mutant mice as well as by altering a clock of wild type animals and determining any difference in cocaine self-administration and sterotypies. I then will attempt to further identify a connection in these processes by looking at putative cocaine mutant animals for defects in their circadian rhythms.