Developing an Animal Model for Prediction of Individual Vulnerability to Addiction-like Behavior for Heroin PDF Download

Author: Christopher Jenney
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Languages : en
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Drug addiction has become a social epidemic. Approximately 15% of humans who try alcohol or cocaine become addicted (J. C. W. Anthony, Lynn A.; Kessler, Ronald C., 1994), and 50% of those who try heroin become dependent (Substance Abuse and Mental Health Services Administration., 2012). The cost of substance abuse in the US is estimated to exceed $700 billion annually (National Institute on Drug Abuse, 2015). While the initial decision to take a drug is usually voluntary, with continued use, brain changes impair a persons ability to resist drugs. Use evolves to abuse, which evolves to compulsive use, often with multiple periods of abstention and relapse. Addiction is characterized as a chronic brain disease of relapse and use despite harmful consequences (Leshner, 1997; National Institute on Drug Abuse, 2012; Roberts, Morgan, & Liu, 2007; Volkow, Koob, & McLellan, 2016).Addiction can be studied in the laboratory using animal models designed to reproduce characteristics of the human addiction process including behaviors such as craving, loss of control, and relapse. To this end, drug self-administration models are very useful. Limited access models allow for 1-2 h access to drug/day. This model can be used to examine the initiation phase of drug-taking (i.e., acquisition), and is also useful in identifying factors that contribute to vulnerability to the reinforcing effects of drugs (Campbell & Carroll, 2000). Limited access to drug, however, fails to recapitulate a key feature of addiction, escalation. In humans, drug-taking is generally found to increase over time. An alternative model, the extended access model (allowing for 6 h or more access to drug/day) reproduces the transition from controlled to compulsive use known as escalation (Roberts et al., 2007). In this case, however, overall drug exposure differs between those who escalate and those who do not. A third model, the intermittent access model, supports identical drug-taking, but still allows for behavioral stratification of subjects into those exhibiting low and high addiction-like behaviors for drug. Specifically, the intermittent access model ranks animals by individual differences in drug-seeking behavior, willingness to work for drug, and persistence in responding for drug, all criteria for the diagnosis of substance use disorder from the then current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association, 2000).In a final model under consideration here, rats suppress intake of a palatable taste cue, such as saccharin, when paired with a drug of abuse, such as morphine or cocaine. Avoidance of the drug-paired cue was originally interpreted as a conditioned taste aversion (Nachman, 1970). In 1997, we proposed a new interpretation (Grigson, 1997), referred to as reward comparison. This interpretation posits that avoidance is due to devaluation of the otherwise palatable saccharin cue in anticipation of the availability of the rewarding properties of the drug of abuse. Additional studies revealed large individual differences whereby some rats, referred to as large suppressers, exhibited greater avoidance of the drug-paired cue than did others, referred to as small suppressers (Gomez, Leo, & Grigson, 2000).Published data show that greater avoidance of the drug-paired cue at test is associated with greater drug-seeking and drug-taking (Grigson & Twining, 2002b; Imperio & Grigson, 2015; Twining, Bolan, & Grigson, 2009). Moreover, these individual differences in avoidance of the drug-paired taste cue emerge very early in training, within 3-5 trials. It is not clear, however, whether addiction-like behaviors also occur early. In general, addiction is thought to take a long time (Deroche-Gamonet, Belin, & Piazza, 2004) and/or a great deal drug exposure (Ahmed & Koob, 1998) to develop. After the Introduction in Chapter 1, Chapter 2 tests whether addiction develops early over a short 5-day study where brief access to the saccharin cue predicts 6 h access to heroin. Chapter 3 describes a study testing whether early avoidance of the drug-paired cue will predict escalation of heroin self-administration using the extended access paradigm. Chapter 4 uses the intermittent access model to test whether early avoidance of the drug-paired cue will predict individual differences in the expression of addiction-like behaviors in the intermittent access model. Chapter 5 presents data from 3 taste-drug pairing trials to stratify rats into large and small suppresser groups, and then examines their neuronal tissue for differences which could help explain early individual vulnerability to addiction-like behavior for heroin. Chapter 6 will review and discuss the findings of the present chapters and summarize conclusions from the collected data.