Sigmaplot 13 0 Crack Cocaine
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Bars represent the means ( s.e.m.) over the last 3 stable testing sessions of: (A) total responses, (B) rewards earned and (C) breakpoints as a function of reward type [cocaine versus saccharin (sacc)]. *, different from sweet water [P
(A) Choice between water sweetened with saccharin and cocaine. The horizontal dashed line at 0 indicates the indifference level. Values above 0 indicate a preference for sweet water while values below 0 indicate a preference for intravenous cocaine. *, different from the first day (P
Bars represent the means ( s.e.m.) over the last 3 stable testing sessions of: (A) total responses and (B) breakpoints as a function of reward type (cocaine versus saccharin) and of post-reward delay (0 versus 10 min). *, different from saccharin (P
During extinction testing, the lever previously associated with cocaine was presented concurrently with the lever previously associated with saccharin during 45 min. Pressing on either lever was recorded but had no programmed consequence (no response-contingent reward delivery or light cue presentation). (A) Bars represent the mean total number of responses ( s.e.m.) on the cocaine- and saccharin-associated levers over the 45-min extinction period. *, different from the other reward (P
Curves represent (A) choice between cocaine and water sweetened with saccharin and (B) percent of completed trials as a function of the relative cost of saccharin. The cost of saccharin was gradually increased either between sessions (open circles) or within sessions (closed circles). In the former case, each cost level was tested at least 5 times consecutively until stabilization of behavior. Data points represent the means ( s.e.m.) of the last 3 stable testing sessions. For other details, see Materials and Methods, and legend of Figure 3. *, different from the indifference level (P
(A) Distribution of individual preferences regardless of past cocaine use. Only 16 individuals out of a total of 184 rats tested in the choice procedure preferred cocaine over water sweetened with saccharin (closed circles). (B) Histograms represent the frequency of cocaine-preferring individuals (i.e., cocaine choices >50% of completed trials over the last 3 stable testing sessions) as a function of past cocaine use (i.e., amount of self-administered cocaine prior to choice testing). (C) Bars represent mean ( s.e.m.) preference over the last 3 stable testing sessions as a function of past cocaine use. For other details, see Materials and Methods, and legend of Figure 3. #, different from the indifference level (P
Locomotion (i.e., mean number of cage crossings per min s.e.m.) was measured during 10 min after the first cocaine sampling (0.25 mg, i.v.) and was averaged across the last 3 stable choice sessions for each individual. The arrow indicates the intravenous injection of cocaine. The shaded area indicates the mean pre-injection level of locomotion ( s.e.m.). Note that the first cocaine sampling was followed 10 min later by the first saccharin sampling.
Overall and considering the above information, the present study shows that no matter how heavy was past cocaine self-administration, the large majority of rats readily and almost completely give up cocaine use to engage in another rewarding activity that is biologically inessential (i.e., drinking water sweetened with a non-caloric sweetener is not essential for growth, survival and/or reproduction). Only a small minority of rats, fewer than 15% at the highest degree of severity of past cocaine use, continue to take cocaine despite the opportunity of making a different choice. Importantly, these few rats continued to prefer cocaine, even when hungry and offered a natural sugar (i.e., sucrose) that could relieve their need of calories, a behavior that recalls drug addiction (i.e., continued drug use at the expense of other important activities or occupations). In contrast, the rapid, self-initiated abstinence from cocaine use in the large majority of rats strongly suggests that the value of intravenous cocaine is weaker than previously thought. In support of this interpretation, a systematic cost-effect analysis in these rats revealed that cocaine is low on their value ladder, near the lowest concentration of sweet water. This hedonic position can be visualized in a single graph that represents the distribution of the indifference points corresponding to the different alternatives to cocaine tested in the present series of experiments (Figure 11). The low value of cocaine explains why the conditioned incentive value of the lever associated with cocaine, as measured during extinction, remains relatively low, despite more than 1000 repeated cocaine self-administration from this lever. The weak relative value of intravenous cocaine may also explain why in a previous study, a 6-fold increase in cocaine dose (from 0.25 to a maximum of 1.5 mg) was apparently not sufficient to shift preference to cocaine, even following extended access to cocaine self-administration [21]. Finally, it may also contribute to explain why to study cocaine preference, it is often necessary to increase the cost of the alternative reward [57], [58]. For instance, in several recent studies in monkeys, the cost of cocaine (i.e., FR10) was much lower than the cost of food (i.e., FR100), thereby favoring cocaine preference [57], [58]. As shown here, when the cost of sweet water is much higher than the cost of cocaine, rats too prefer cocaine.
The present findings have several potential implications for future research in animal models of drug addiction. First, previous research on the neurobiology of drug addiction did not distinguish among animals with extensive cocaine use the minority that is vulnerable to addiction from the majority that is resilient [16]. As a result, brain changes associated with extensive cocaine use are difficult to interpret and their significance for the neurobiology of cocaine addiction is uncertain. In fact, since resilient animals appear to represent a large majority, it is likely that many of these brain changes do not represent neurobiological correlates of addiction but rather other, perhaps normal, neuroplastic adaptations to the novel, salient and unique experience of repeated cocaine use. One way to clarify this important issue in future neurobiological research would be to systematically compare and contrast the minority of vulnerable rats with the resilient majority. Such comparisons could indeed bring unprecedented insights into the neurobiological dysfunctions that are hypothesized to underlie cocaine addiction. Second, another related implication of the present findings is their relevance to preclinical models of cocaine self-administration for the development of medications to treat cocaine addiction. Despite many hopes and promises, experimental research on animal models of drug addiction has had so far only a modest translational impact. This research identified many potential pharmacological targets but no effective treatment for cocaine addiction [69]. Thus, more is clearly needed to improve the predictive validity of preclinical self-administration models in medication development for addiction. In this context, screening medications for their ability to decrease cocaine choice in the small subset of rats that prefer cocaine may better predict their therapeutic efficacy in cocaine-addicted humans. 153554b96e
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