Research reportThe transition from controlled to compulsive drug use is associated with a loss of sensitization
Introduction
Drug addiction is a compulsive, uncontrolled drug-taking behavior that persists despite adverse consequences [4], [53]. While many Americans engage in cocaine-taking behavior at least once in their life, only 5–18% of these people become addicted to cocaine, and the transition from recreational use to compulsive use of cocaine usually involves an escalating pattern of drug-taking behavior that occurs after years of use [15], [16], [21], [48]. The “animal” literature presents two kinds of explanations for this transition from occasional to compulsive drug use. One emphasizes sensitization of different processes that render the drug and/or any cues related to it with much greater control on behavior. Thus, Robinson and Berridge [47] suggested that drugs of abuse activate the neuronal system that attributes incentive value to perceived stimuli, and that with continuous use, this system is sensitized. As a consequence, the drug and the cues associated with it acquire heightened/sensitized incentive value and become ever more salient to the drug user. Through this process, drugs of abuse gain disproportionate control over behavior. Everitt and Wolf [12] argue that drugs of abuse significantly strengthen the learning involved in classical and operant conditioning. Therefore, the learned habit of performing a certain behavior in order to receive a drug reinforcement is abnormally strong. Finally, Jentsch and Taylor [26] also hold the view that with repeated use, drugs of abuse acquire sensitized salience, but add that brain areas (i.e., prefrontal cortex) that usually inhibit inappropriate behaviors become dysfunctional and are much less able to suppress compulsive drug taking. In contrast, the second type of explanation emphasizes a reduced response to the drug with repeated exposure. For example, Markou and Koob [35] suggested that activity in brain reward centers desensitize as a result of chronic drug use. Koob and Le Moal [32], [33] proposed that the transition from controlled to compulsive drug use involves spiraling down an “addiction cycle” that includes “three components: preoccupation–anticipation, binge–intoxication, and withdrawal–negative affect.” Initial sensitization to the drug's effects may facilitate the preoccupation/anticipation stage. However, with more sessions of drug administration, drug administration turns to binge use, and the withdrawal/negative affect stage appears as opponent processes work to return the internal milieu to normal. The individual takes even more drug, and withdrawal symptoms become stronger, which in turn cause the preoccupation with the drug to become even stronger. This spiraling through the cycle of drug administration and addiction continues until it gets to the point where homeostatic mechanisms are not sufficient to oppose the continuous effects of drug administration. At this point, allostatic mechanisms are activated such that basal reward function or sensitivity is shifted downward, which means that more is needed in order to lift the user's mood up to the level of euphoria that the drug induced when it was first used. The result of this cycle is that the need for the drug, and the loss of control over drug consumption, is ever growing.
Animal models of drug self-administration have traditionally employed relatively short periods of daily access to the reinforcing drug. This protocol results in a stable controlled pattern of drug administration that is somewhat reminiscent of the recreational drug-taking behavior seen in humans [13], [39], [42], [52]. In contrast, unlimited daily access to a drug of abuse can result in escalating uncontrolled drug self-administration, reminiscent of the compulsive pattern of drug taking seen in human addicts [8], [27]. Any thorough understanding of the neurobiology of drug addiction would require animal models that examine differences in self-administration patterns, and the corresponding changes in the brain that occur as exposure to the drug reinforcer is increased from limited to much longer periods of time each day.
In the present study, we employed a recently established model of transition to drug addiction [2], in which rats provided with short periods of daily access to cocaine showed stable rates of self-administration, while those provided with prolonged daily access exhibited escalated self-administration rates over days. The purpose was to examine if the different patterns of cocaine self-administration results in different patterns of neuroadaptations. For this, we monitored c-Fos and locomotor activation in response to one infusion of cocaine in animals that had previously been provided short versus long daily access to cocaine or saline.
Section snippets
Subjects
The subjects were male albino Sprague–Dawley rats weighing 300–350 g at the beginning of the experiment and obtained from Charles River Laboratories (Hollister, CA). The animals were housed individually in wire hanging cages located within a temperature-controlled (22 °C), 12:12-h-light/dark-cycle (lights on at 0700 h) environment in the Psychology Department vivarium at UCSB. Subjects had ad libitum access to food and water, except during operant training for food reinforcement (see food
Self-administration patterns
The behavior of cocaine-reinforced rats was different depending on their access to cocaine. As can be seen in Fig. 1 Panel B, well-trained animals that have 1-h access to cocaine per session/day (Coc1h; n=22) did not change their cocaine self-administration (i.e., number of infusions) over the course of an 8-day testing regimen. In contrast, similarly trained animals switched to 6 h of daily cocaine access (Coc6h; n=17) significantly increased their average intake from the first to the eighth
Discussion
Our results confirm that animals well trained to self-administer cocaine behave differently when provided short periods of daily access (1 h) as opposed to longer periods of access (6 h). The Coc1h group exhibited constant stable levels of drug self-administration, while subjects in the Coc6h condition exhibited escalating levels of cocaine self-administration over days (see Ref. [2]). These differences in group performance were mirrored by additional changes in both c-Fos reactivity (a marker
Acknowledgements
This work was supported by National Institute of Drug Abuse Grant DA05041 awarded to AE and by National Institute of Drug Abuse Grant DA 04398 awarded to GFK. SHA is supported by CNRS and University of Bordeaux 2. The authors would like to thank Mike Arends for his editorial assistance.
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