A stimulus-control account of regulated drug intake in rats

Abstract

Rationale-Patterns of drug self-administration are often highly regular, with a consistent pause following each self-injection. This pausing might occur because the animal has learned that additional injections are not reinforcing once the drug effect has reached a certain level, possibly due to the reinforcement system reaching full capacity. Thus, interoceptive effects of the drug might function as a discriminative stimulus, signaling when additional drug will be reinforcing and when it will not.Objective-To emulate this hypothetical stimulus-control aspect of drug self-administration using a schedule of food reinforcement.Methods-Rats' nose-poke responses produced food only when a cue light was present. No drug was administered at any time. However, the state of the light stimulus was determined by calculating what the whole-body drug level would have been if each response in the session had produced a drug injection (delivered during a 5-s timeout). The light was only presented while this virtual drug level was below a specific threshold. A range of doses of cocaine and remifentanil were emulated, using parameters based on previous self-administration experiments.Results-Response patterns were highly regular, dose-dependent, and remarkably similar to actual drug self-administration.Conclusion-These results support a stimulus control account of regulated drug intake, in which rats learn to discriminate when the level of drug effect has fallen to a point where another self-injection will be reinforcing. KeywordsSelf-administration; Incentive Learning; Titration; Cocaine; Remifentanil; Food A prominent characteristic of intravenous drug self-administration is that it tends to occur in highly regular patterns. When each response delivers a fixed dose of a reinforcing drug, there tends to be a consistent pause following each injection. This phenomenon of regulated drug intake has been observed numerous times with a variety of drugs of abuse in rodents, nonhuman primates, and humans (Sughondhabirom et al. 2005), but the question of why it occurs continues to be the subject of debate (Lynch and Carroll, 2001;Panlilio et al. 2003;Tsibulsky and Norman 1999).There is evidence that animals tend to self-administer an injection whenever the level of drug effect drops below a certain point (Yokel and Pickens 1974), termed the "satiety threshold" (Tsibulsky and Norman 1999), "trigger point" (Ranaldi et al. 1999), or "set point" (Ahmed and Koob 1998, 1999. For example, Tsibusky and Norman (1999) showed that the durations of post-injection pauses are well described by a pharmacokinetic/ pharmacodynamic model in which the rat self-administers the next injection whenever its whole-body level of cocaine drops below a certain point. The terms "satiety" and "satiation," which have been used to describe this process, imply that it might involve drive reduction, in which the motivation to receive the drug is satisfied as long as the drug level is above the threshold (Wise 1987). In this state of satiety, the need state ha...

Cocaine self-administration on a hold-down schedule of reinforcement in rats

“…That is, under conditions with no time-out following a reinforcer delivery, the animals could make two responses in quick succession (resulting in delivery of a larger total unit dose); however, the typical finding is that the distribution of inter-response intervals simply shifts to the left (i.e., smaller intervals). Regardless of the reason this happens (see Panlilio et al 2007 for a stimulus control account of this phenomenon, and below for reference to other accounts), responding under the present schedule conditions seems to represent an extreme example of this phenomenon. Animals respond with a relatively short hold-down duration (followed by a relatively small reinforcer), and the inter-response interval gets shorter in a proportionately appropriate manner.…”

Neural Responses to BEGIN- and END-Stimuli of the Smoking Ritual in Nonsmokers, Nondeprived Smokers, and Deprived Smokers

“…Previous studies showed increased subjective, behavioral, physiological, and neuronal responses to smoking cues when smoking seems available (Carter and Tiffany, 2001;Wertz and Sayette, 2001;Wilson et al, 2004;McBride et al, 2006). Other studies showed that the end of drug consumption and stimuli predicting the nonoccurrence of the drug reduce drug seeking and wanting (Kearns et al, 2005; see also Panlilio et al, 2008). In sum, these results point to an inhibitory nature of END-stimuli.…”

An early attentional bias to BEGIN-stimuli of the smoking ritual is accompanied with mesocorticolimbic deactivations in smokers

“…Importantly, one should not prematurely assume ENDsmoking-stimuli to be simply weak cues because Mucha et al (2008) demonstrated that these stimuli are able to reduce the effects of BEGIN-smoking-stimuli when both are presented together. Similarly, other studies suggest that the end of drug consumption and stimuli predicting the nonoccurrence of the drug may reduce drug seeking and wanting (Kearns et al 2005; see also Panlilio et al 2008). Thus, END-smoking-stimuli seem to trigger a unique reactivity, which may even oppose responses triggered by BEGINsmoking-stimuli (Mucha et al 2008;Stippekohl et al 2010).…”