Parsing the addiction phenomenon: Self-administration procedures modeling enhanced motivation for drug and escalation of drug intake

Abstract

Investigators who study drug addiction are fortunate to have access to excellent animal models. Such models will be invaluable in the assessment of factors involved in the progression of drug addiction. The relevance of these findings, however, will depend on the general understanding of how each model is related to drug addiction. The present review focuses on several procedures that were designed to model the addiction process and questions whether these models are tapping into the same underlying process or whether each is addressing a unique feature. Furthermore, various factors (e.g., rate of drug onset, dose magnitude, early drug history, periods of abstinence) influencing the progression of these addiction-like changes in behavior are discussed. KeywordsCocaine; Escalation; Motivation; Sensitization; Tolerance; Self Administration A better understanding of the neurobiology of drug addiction is beginning to emerge through the analysis of brain changes in individuals addicted to drugs. Recent advances in neuroimaging have shown activation of specific brain regions associated with drug craving (see reviews, [1,2]). Chronic drug abuse has also been shown to cause changes in brain structure and function (see reviews, [3,4,5]). Additional advancements in the application of molecular biology techniques has provided important post-mortem analyses of brain tissue from addicts (see reviews, [6,7]).There are, however, many limitations and challenges associated with studying drug addiction in human subjects. Various confounding factors exist within samples of drug addicts that may be difficult to parse apart, such as differences in environment, genetics, poly-drug use and route of administration. Attrition is also a concern due to the general social instability associated with drug addicts. Moreover, various ethical dilemmas may restrict the experimental design of longitudinal studies and the administration of pharmacological treatments to illicit drug users.*Corresponding Author: David C.S. Roberts, Ph.D., Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, Tel: (336) Fax: (336) 716-8501, dscrobts@wfubmc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Animal studies offer an opportunity to investigate specific aspects of the addiction process without the confounding factors associated with human studies. As this special issue of Drug Discovery Today attests, a variety of animal models have been developed which can be used to address fundamental issues related to drug abuse and de...

Modeling the development of drug addiction in male and female animals

“…The procedure used for extended access self-administration may also be critical. For example, as mentioned earlier, although an enhanced motivation for drug has been reported following escalation using the long access procedure, effects appear to be variable with some studies showing enhanced motivation (Ahmed et al 2000; Ducret et al 2016; Paterson and Markou 2003; Wade et al 2015; Wee et al 2008; Whitfield et al 2015), but others findings no change or decreased motivation for the drug (Allen 2014; Anker et al 2009; Crawford et al 2013; Larson et al 2007; Liu et al 2015; Oleson and Roberts 2007; 2008; Roberts et al 2007; Whitfield et al 2015), and evidence for tolerance to its reinforcing effects (Calipari et al 2013; 2014a; Oleson and Roberts 2009). Although many of the escalation studies have examined levels of motivation within a day or two of the extended access self-administration period, others have examined effects following protracted abstinence and have not observed enhancements (Oleson and Roberts 2009; Roberts et al 2007).…”

“…There have been several recent reviews on animal models of particular characteristics of addiction such as escalation of drug intake (Ahmed 2009; Edwards and Koob 2013), drug seeking (Mantsch et al 2016; Marchant et al 2013; Venniro et al 2016), incubation of drug seeking/relapse vulnerability (Li et al 2015; Wolf 2016), enhanced motivation for drug (Allain et al 2015; Oleson and Roberts 2008), as well as reviews on methods used to induce one or more features of addiction in certain populations of animals (Ahmed 2012; Belin-Rauscent et al 2016; Deroche-Gamonet and Piazza 2014; Waters et al 2014). There have also been several recent reviews detailing sex differences in the behavioral and neurobiological mechanisms of addiction as a function of stage of the addiction process (Becker et al 2017; Becker and Koob 2016; Bobzean et al 2014; Carroll and Lynch 2016).…”

On the early life origins of vulnerability to opioid addiction

“…Rats were trained on a previously described within-session economic thresholding procedure [17][18][19][20]. In order to avoid undesired effects of drug satiety on responding due to the long halflife of heroin, the short-acting opioid remifentanil, a fentanyl analog, was used for this task.…”

“…On each training day, presses on the active lever delivered remifentanil and cue presentations on an FR1 schedule. The duration of each self-administered cue/infusion was decreased every 10 min across the 110-min session, requiring rats to exert increasing effort over time to maintain the desired blood level of drug [19,20]. Drug intake was determined at the various response requirements (i.e., costs) and consumption data was then modeled with an exponential demand equation: lnQ = lnQo + k(e -αQoC -1) as previously described [17][18][19], yielding variables corresponding to hedonic set-point (Q0,reflecting extrapolated value of remifentanil at price 0) and motivation (α, reflecting demand elasticity).…”

The strength of aversive and appetitive associations and maladaptive behaviors

“…Notably, however, in these studies, the escalation of drug intake is rather modest, about 1.25‐ to 1.5‐fold increase in the number of drug infusion over a 2‐week period. Some studies questioned the significance of escalation in psychostimulant self‐administration because the final outcome of escalated and fixed drug self‐administration was not different .…”