Self-administration - Significant Findings

Significant Findings

Self-Administration studies have long been considered the “standard” in addiction research using both animal and human models. Conducting self-administration studies in animal models provides a much greater level of experimental flexibility than in humans because investigating the effects of novel pharmacological drug treatments poses significantly fewer ethical and practical barriers. In 1999, Pilla and colleagues published in Nature a study documenting the efficacy of a partial D3-agonist (BP-897) in reducing environmental cue-induced cocaine craving and vulnerability to relapse. An interesting aspect of this study was the use of second-order reinforcement schedules to identify a dissociation in the effects of BP-897 in that the drug inhibits cue-induced cocaine seeking but has no primary reinforcement effect. This latter condition is important for any pharmacological agent to be used in the treatment of addiction—drugs used to treat addiction should be less reinforcing than the drug whose addiction they treat and optimally have no reinforcing effects.

A recent study published in Nature showed an upregulation of microRNA-212 in the dorsal striatum of rats previously exposed to cocaine for extended periods. Animals infected with a viral vector overexpressing miR-212 in the dorsal striatum produced the same initial levels of cocaine intake; however, drug consumption progressively decreased as net cocaine exposure increased. The authors of the study noted that viral-infected animals exhibited decreased operant responding during the post-infusion time-out period and proposed that this demonstrated a reduction in compulsive drug-seeking behavior.(Hollander et al.) miR-212 acts through Raf1 to enhance the CREB response; CREB-TORC is known to negatively regulate the reinforcing effects of cocaine. (Hollander et al.) This study provides one example (miR-212, owing to its amplification of CREB) of a self-administration study that may provide potential therapeutic targets for the treatment of cocaine addiction. One of the most important advances to emerge from self-administration studies comes from a behavioral model for addiction in animals. This model relies on observation of three separate phenomena to classify a rat as “addicted:” 1) Persistence in drug-seeking: Depends on the attempts of rats to obtain drug during time-out or no-periods in the self-administration apparatus. 2) Resistance to punishment: Measured by how much rats maintain rates of self-administration when cocaine infusion is paired with an electric shock. 3) Motivation for the drug: Measured by the breakpoint in progressive ratio reinforcement. (Deroche-Gamonet et al.)

The researchers used an additional test to further support classification of a rat as “addicted” by measuring relapse rates during reinstatement paradigms. Human drug addicts reportedly relapse at a rate of >90% as measured from the initial diagnosis. Rats that responded at high rates after some form of cue-induced reinstatement could be considered likely to relapse.(Deroche-Gamonet et al.) This model provided an important advancement for the method of self-administration because it allows animal models to better approximate the physiological and behavioral aspects of drug addiction in humans.

Self-administration experiments can also be paired with methods such as in vitro electrophysiology or molecular biology to understand the effects of addiction on neural circuitry. Self-administration studies have allowed researchers to locate a staggering number of changes in brain signaling that occur in addiction. One example of such a study involved examining synaptic plasticity in rats undergoing the behavioral shift to addiction. Using the criteria for classifying rats as “addicts” or “non-addicts” as put forth by Deroche-Gamonet et al., it was found that addicted rats display a prolonged and persistent impairment in mGluR2/3-dependent Long-Term Depression. Despite exposure to the same self-administration paradigm, control rats recovered this form of synaptic plasticity. The authors of the study propose an important explanation for their results in that this specific loss of plasticity over an extended period is responsible for the progressive loss of controlled drug use.(Kasanetz et al.) This represents a potential molecular mechanism by which addicts might differ from non-addicts and undergo pathological learning processes during the development of addiction.

Much like animal studies, human experiments that pair self-administration studies with additional neuroscientific techniques provide unique insight into the disease of addiction. Human self-administration studies have gained momentum with the widespread use of fMRI technology to measure BOLD signals. Brain imaging coupled with human self-administration studies with the laboratory have led to the development of a three-stage model of human neurocircuitry of addiction: Binge/Intoxication, Preoccupation/Anticipation, and Withdrawal/Negative Effect. Koob, Lloyd, and Mason reviewed the laboratory models approximating each stage of the model of human addiction.(Koob et al.) The binge-intoxication phase traditionally has been modeled by drug or alcohol self-administration; the psychological effects of addiction might be modeled by the increased motivation for self-administration observed in drug-dependent animals. Self-administration studies capably model the somatic effects of addiction, but many of the most deleterious effects related to drug addiction can be considered psychological in nature. (Koob et al.) Models like the one published by Deroche-Gamonet and colleagues in 2004 better approximate the effects of addiction on physiology and psychology, but animal models are inherently limited in their ability to reproduce human behavior.

The use of the self-administration methodology to model human drug addiction provides powerful insight into the physiological and behavioral effects of the disease. While self-administration experiments in humans or animals each pose unique barriers to complete understanding of addiction, the scientific community continues to invest a great deal of effort in both avenues of research in the hopes of improving understanding and treatment of addiction.