Introduction
psychiatric illness, addiction-related behaviors, alcoholism
BLIND
Alcohol dependence as defined by ICD-10 is a frequent and costly psychiatric illness causing significant medical and social harm [GBD 2016 Alcohol Collaborators [In order to bridge the gap between preclinical research and the clinical treatment of alcoholism, several human laboratory models have been suggested [ASA experiments can be tailored to investigate specific aspects of alcohol consumption and addiction. Free-access paradigms, for example, measure alcohol “liking” [The standard method of ASA is oral ingestion; easy to perform and conforming best with the behavior to be altered. However, disadvantages with oral ASA are that (i) it is impossible to standardize the extent and time course of brain alcohol exposure, (ii) attempts to blind the taste and smell of alcohol, and the amount already consumed, have been largely unsatisfactory, (iii) due to the inevitable alcohol reservoir in the stomach, complying with safety limits is only possible by restricting the number and/or time course of possible drinks, limiting peak breath alcohol concentrations (BrACs) achieved, and thus narrowing bandwidth of the main outcome variable. Intravenous (i.v.) ethanol self-administration avoids these drawbacks and allows for faster, fully-controlled alcohol exposure dynamics, both when BrAC is ascending (during a reward) and descending (in between rewards) [Building on these insights, we devised a new laboratory paradigm, the Test system to Screen Medications for Alcoholism (TESMA). The TESMA paradigm covers several of the above-described aspects of addiction-related behaviors. Our approach was to investigate the willingness to perform voluntary work for “rewards” (VWR); either an incremental i.v. infused exposure ethanol that quickly increased BrAC by the same fixed amount within and across subjects, or of the infusate vehicle, i.e., saline. The latter served as a control condition, to check whether subjects worked specifically for alcohol or for nonspecific reasons such as boredom or curiosity. In between alcohol rewards, the infusion rate is designed to produce a steep linear decline of BrAC, faster than after oral ingestion, potentially increasing the contrast between the subjective perceptions of feeling vs. not feeling a reward and emphasizing the subjective effects of falling BrACs. A progressive-ratio work schedule was implemented; requiring an increasing number of iterations of a task for each successive work-set before a reward was delivered. In a pilot study, this method was able to detect medication effects on operant alcohol self-administration [As a result of this setup, the contingency of reinforcement changed over experimental time course within each session. The first few work-sets could be finished quickly, rendering the workload so low that it approximated free-access ASA and allowed for rapidly increasing BrACs. In this first experimental (“ascending”) phase, work for alcohol (WFA) was predominantly positively reinforced. However, if subjects continued steady WFA, the time required to complete each work-set exponentially increased, and—in between rewards—the BrAC continued its pre-determined descent. Towards the end of the experiment, work for the next reward took so long that, during work time, the BrAC dropped by more than the following reward increased it, marking the beginning of a phase of “futility”. In this second experimental (“plateau”) phase, BrAC inevitably decreased, but the rate of descent could still be slowed down by continuous WFA. We assume that an unintended drop of BrAC is perceived aversive, therefore WFA during the plateau phase can be seen as negatively rather than positively reinforced (See Fig. As a second consequence, the continuous transition from low- to high-demand operant ASA in subjects working continuously for alcohol also implies that the incentive components driving WFA might shift over experimental time. In the beginning, WFA is so easy that it comes very close to a free-access paradigm, where ASA is driven by both hedonic (“liking”) and motivational (“wanting”) aspects of alcohol consumption. However, with increasing work demand and decreasing positive reinforcement, the participant’s behavior towards the end of the experiment might be more determined by motivation.The aim of the present study was to validate the TESMA paradigm by detecting an effect of naltrexone, a drug which not only helps alcohol-dependent patients to drink less [