Drug addiction remains among the most costly neuropsychiatric disorders in terms of personal tragedy and overall societal economic burden. Drug self-administration paradigms in preclinical animal models for the evaluation of stimulant and opiate drugs have relied primarily on intravenous drug administration in tethered animals. The extent to which tethering reshapes 'normal'behavior in these paradigms is likely substantial. What has become abundantly clear is that, as in the human population, the relative reinforcing strength of self- administered drugs is highly sensitive to environmental manipulations, many of which are difficult to model using tethered animals. Tethering is practical only in the study of behaviors of animals in isolation and is limited to a subset of behaviors, which present a low risk of entanglement of the animal with its cable. Because of the sensitivity of drug self-administration to stress and environmental factors, more 'naturalistic'settings are needed to study addictive behavior. This is particularly relevant in understanding the role played by genes in addiction and the importance of gene x environment interactions in current transgenic mouse models. Our interdisciplinary team seeks: (1) to develop an implantable minipump to allow tetherless, repeated drug delivery for drug self-administration mice. Currently, no such device is available commercially. In the pump, drug is administered by the displacement of a diaphragm driven by gas generated from electrolysis and powered by inductive power transfer, (2) to design and fabricate a behavioral cage interface for the pump to facilitate the use of the pump in preclinical studies of drug self-administration. In this cage, self-administration is initiated by a specific animal behavior (lever press) which triggers inductive power transfer to the electrolytic pump, (3) to test the tetherless infusion system in mice during the intravenous self-administration of cocaine. On-demand, tetherless drug delivery (a) promises to open new avenues for the study of addictive behavior in current transgenic mouse models, (b) reduces stress and eliminates the risk of catheter entanglement, thereby facilitating examination of the effects drug self-administration has on social, maternal and mating behaviors, as well as the effects enriched environments have on drug use, (c) allows 24 hour access to intravenous drug self-administration for drugs of lower addictive potential, where overnight exposure of an animal is needed to establish drug self-administration, (d) can be easily adapted to provide intracerebral administration for testing of the role of specific brain areas in addiction behavior, or scaled to other animal models of drug addiction such as nonhuman primates, (e) provides a unique experimental tool whose applications extend beyond the field of drug addiction for applications in the fields of pharmacology, animal behavior, and physiology.
The relative reinforcing strength of self-administered drugs of abuse is highly sensitive to environmental manipulations, yet current preclinical models involve animals tethered to external mechanical infusion pumps and do not allow significant exploration of the effects of environmental factors on addictive behavior. We propose the fabrication and validation of an implantable, self-contained minipump for on-demand, tetherless drug-delivery in mouse models of drug self-administration. This experimental tool will allow examination of the effects of complex behaviors (e.g. social behavior, maternal behavior) and complex environments on addiction. Its application in transgenic mouse models will allow examination of gene x environment interactions, which are crucial to the interpretation of the range and limits of genetic influences on addictive behaviors in human subjects.
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