Learning that a cocaine reward is smaller than expected: A test of Redish's computational model of addiction.

The present experiment tested the prediction of Redish's (2004) computational model of addiction that drug reward expectation continues to grow even when the received drug reward is smaller than expected. Initially, rats were trained to press two levers, each associated with a large dose of cocaine. Then, the dose associated with one of the levers was substantially reduced. Thus, when rats first pressed the reduced-dose lever, they expected a large cocaine reward, but received a small one. On subsequent choice tests, preference for the reduced-dose lever was reduced, demonstrating that rats learned to devalue the reduced-dose lever. The finding that rats learned to lower reward expectation when they received a smaller-than-expected cocaine reward is in opposition to the hypothesis that drug reinforcers produce a perpetual and non-correctable positive prediction error that causes the learned value of drug rewards to continually grow. Instead, the present results suggest that standard error-correction learning rules apply even to drug reinforcers.

Demand for food and cocaine in Fischer and Lewis rats.

Fischer and Lewis rat strains often serve as animal vulnerability models for drug abuse and addiction. When these strains respond for drugs of abuse, several measures, including total drug intake, response rate and progressive-ratio breakpoints, have been reported to be strain-dependent, a result suggesting genetic differences in drug reactivity and vulnerability. The present study extends these strain comparisons to a previously untested measure--demand analysis. In Experiment 1, four Fischer and four Lewis rats earned their daily food ration by lever pressing under a fixed-ratio schedule, the size of which was increased every three sessions from 3 to 1,000 in logarithmic steps. Consumption was plotted as a function of ratio size, and modeled by the exponential-demand equation (Hursh & Silberberg, 2008). Experiment 2 replicated Experiment 1 except that different rats were used, and cocaine reinforced lever pressing. A between-experiment comparison showed a commodity-by-strain interaction: Fischer rats defended consumption with greater vigor when cocaine served as the reinforcer than did Lewis rats; for food, this relation was reversed. However, for both strains, defense of consumption of food exceeded that of cocaine.

Demand for cocaine and food over time.

When reinterpreted, data from Ahmed and Koob [Ahmed, S.H., Koob, G.F., Transition from moderate to excessive drug intake: Change in hedonic set point. Science 1998; 282:298-301.] show that the reinforcing strength of cocaine, an inessential good, increases with experience. However, no such effect obtains with a homeostatically regulated good such as food. The present study evaluated whether this difference could serve to distinguish abused drugs from biologically necessary goods. In Experiment 1, five rats from Christensen, Silberberg, Hursh, Huntsberry and Riley [Christensen, C.J., Silberberg, A., Hursh, S.R., Huntsberry, M.E., Riley, A.L., Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 2008;198(2):221-229.] earned cocaine under a Fixed-Ratio 3 schedule for 7 sessions. Thereafter, in a demand procedure identical to that in Christensen et al., demand was re-assessed by measuring consumption at Fixed Ratios between 3 and 560. In Experiment 2, five different rats from Christensen et al. had their food demand curves re-determined using an identical procedure as the first. When fit with the exponential model, the second determination of cocaine demand in Experiment 1 showed greater essential value than the first, indicating that strength increased with cocaine exposure. In Experiment 2, the re-determined food demand curves showed no change from their initial determination. These results show that the strength of cocaine, but not food, increases with increased experience. Measures of time-based changes in essential value may serve as a basis for distinguishing addictive from non-addictive reinforcers.

Essential value of cocaine and food in rats: tests of the exponential model of demand.

RATIONALE: To provide a prospective test of the predictive adequacy of the exponential model of demand (Hursh and Silberberg, Psych Rev 115(1):186-198, 2008). OBJECTIVES: In Experiment 1, to measure the 'essential value' (the propensity to defend consumption with changes in price) of cocaine and food in a demand analysis (functional relation between price and consumption) by means of the exponential model; in Experiment 2, to test whether the model's systematic underestimation of cocaine consumption in Experiment 1 was due to weight loss; and in Experiment 3, to evaluate the effects of cocaine on the essential value of food. MATERIALS AND METHODS: In Experiment 1, demand curves for food and cocaine were determined by measuring consumption of these goods in a multiple schedule over a range of fixed ratios; in Experiment 2, a demand curve for only cocaine was determined; and in Experiment 3, demand for food was determined in the absence of cocaine. RESULTS: In Experiment 1, the exponential equation accommodated high portions of variance for both curves, but systematically underestimated cocaine demand; in Experiment 2, this predictive underestimation of the equation was eliminated; and in Experiment 3, the essential value of food was greater than in Experiment 1. CONCLUSIONS: The exponential model of demand accommodated the data variance for all cocaine and food demand curves. Compared to food, cocaine is a good of lower essential value.

Reduction of cocaine seeking by a food-based inhibitor in rats.

Environmental stimuli can exert a powerful influence over drug seeking and taking. For example, previous experiments found that combining multiple drug-related stimuli tripled drug seeking and doubled drug intake (L. V. Panlilio, S. J. Weiss, & C. W. Schindler, 1996, 2000), whereas a signal for the absence of cocaine (i.e., a drug-related inhibitor) dramatically reduced cocaine seeking in rats by over 90% (D. N. Kearns, S. J. Weiss, C. W. Schindler, & L. V. Panlilio, 2005). In the present experiment, a signal for the absence of food created through the A+/AB- conditioned inhibition paradigm also suppressed responding for cocaine by approximately 90%. Symmetrically, a signal for the absence of cocaine (i.e., a cocaine-based inhibitor) suppressed food seeking to a similar degree. These findings, consistent with the appetitive-aversive interaction theory of motivation, suggest that using inhibitors based on nondrug appetitive reinforcers might be a practical method of reducing drug seeking in human drug abusers and should be seriously considered for clinical test and application.

The strange case of the earliest silver extraction by European colonists in the New World.

La Isabela, the first European town in the New World, was established in 1494 by the second expedition of Christopher Columbus but was abandoned by 1498. The main motive for settlement was to find and exploit deposits of precious metals. Archaeological evidence of silver extraction at La Isabela seemed to indicate that the expedition had located and tested deposits of silver-bearing lead ore in the Caribbean. Lead isotope analysis refutes this hypothesis but provides new evidence of the desperation of the inhabitants of La Isabela just before its abandonment.

Mark tests for mirror self-recognition in capuchin monkeys (Cebus apella) trained to touch marks.

In Experiment 1, three capuchin monkeys (Cebus apella) were exposed to a mirror in their home cage for 3 days and then given food treats for touching orange marks located on the surface of an experimental chamber. Following training, a mirror was added to the chamber to see if the monkeys would use it to guide non-reinforced contacts with an orange mark on their foreheads that was only visible as a mirror reflection (mark test). Two monkeys touched the head-mark more often with the mirror present than absent, but no mark touches were emitted while looking at the mirror. In Experiment 2, the monkeys were rewarded for touching orange marks on their bodies that were directly visible, followed by another head-mark test. Again, two monkeys touched the mark more often with the mirror present than absent, but these contacts were not emitted while looking at the mirror. Since facing the mirror while mark touching was not required for reinforcement during training, Experiment 3 further tested the possibility that increased mark touching in the presence of the mirror during Experiments 1 and 2 was the result of a memorial process. For this, a final, novel mark test was conducted using an orange mark on the neck that was only visible as a reflection (Experiment 3). No monkeys passed this test. These are the first mark tests given to capuchin monkeys. The results are consistent with the finding that no monkey species is capable of spontaneous mirror self-recognition. The implications of sequential training and mark testing for comparative evaluations of mirror self-recognition capacity are discussed.

Samarium-neodymium direct dating of fluorite mineralization.

The direct dating of many styles of hydrothermal mineralization has proved difficult, limiting understanding of the geological processes that lead to crustal fluid flow and the formation of major ore deposits. The hydrothermal mineral fluorite (CaF(2)) displays large variations in rare earth element (REE) abundance and samarium/neodymium ratios within a single vein. Samarium-neodymium dating of fluorite from the classic granite-hosted tin deposits of southwest England demonstrates its use as a precise chronometer of mineralization. The concentrations of light rare earth elements (LREEs) in the fluorites are highly variable and suggest the coeval precipitation of an LREE-rich phase as the most likely cause of the extreme variation in samarium/neodymium ratios.

Sm-Nd evidence for the age and origin of a Mississippi Valley Type ore deposit.

MISSISSIPPI Valley Type (MVT) ore deposits represent the relatively common product of large-scale fluid transport in the continental lithosphere, yet the models for their genesis have been more controversial and unconstrained than those of any other class of giant ore deposit(1,2). Here we show that Sm-Nd isotope data can be used to determine the age and origin of an MVT deposit. Sm-Nd data for fluorites from the North Pennine orefield are difficult to explain unless some of the mineralization is of Mesozoic rather than the traditionally accepted Palaeozoic age. Furthermore, the Nd and Sr isotopie compositions of the fluorites do not support a variety of recent models that include derivation of the components from the mantle, the Lower Palaeozoic basement or the underlying buried granite which served to focus the flow of hydrothermal fluids.

Modified 1-2 Test™ System as a Rapid Screening Method for Detection of Salmonella in Foods and Feeds.

Modifications made to the procedure for the 1-2 Test™ System (BioControl Systems, Inc., 19805 North Creek Parkway, Bothell, WA 98011) resulted in reducing the time required for analysis by 24 h, while maintaining a high level of agreement with the standard culture procedure. Of 283 samples tested, 73 (25.8%) were found to be naturally contaminated with Salmonella by all analytical conditions combined. The standard culture procedure detected 73 of the contaminated samples, whereas the 1-2 Test™ system, as utilized in this study, found 70 samples to be positive for Salmonella . The modified 1-2 Test™ System procedure yielded a presumptive positive result after 48 h, compared to the 96 h required with the standard culture method, and 72 h with the 1-2 Test™ System as previously evaluated in this laboratory (8).

Evaluation of Enrichment Protocols for the 1-2Test™ for Salmonella Detection in Naturally Contaminated Foods & Feeds.

The 1-2 test™ system was used to detect Salmonella in naturally contaminated foods and feeds. The results were compared with the official Canadian Wet Culture Method. In Phase I, the analytical procedure used for the 1-2 test™ was that suggested by the manufacturer. For both methods, 196 food and feed samples were analyzed. Thirty-four samples were found positive by the Wet Culture Method but only 26 were found positive by the 1-2 test™. In Phase II, the procedure for the 1-2 test™ was modified to include an enrichment stage using tetrathionate brilliant green broth. Of the 314 samples analyzed, 84 samples were found to be positive. There were 79 samples found positive by both methods. In the remaining positives, 3 tested positive only by the 1-2 test™, and 2 tested positive only by the Wet Culture Method. The majority of positive samples in Phase II were animal feeds. The selective enrichment modification to the 1-2 Test™ procedure has enhanced its reliability for Salmonella detection in foods and feeds. The manufacturer's current procedure specifies a selective enrichment step.

Nitroblue tetrazolium reduction test in pregnancy.

The use of the nitroblue tetrozolium (NRT) dye reduction test as a screening method for bacterial and fungal infections is now widely recognized. Levels have been reported to be falsely elevated in the pregnant state. This report includes a prospective study which showed that the results of this test in 124 pregnant women were indistinguishable from those of a normal control population. Seven of 8 elevated levels were attributable to infection or allergy. With this data, it is concluded that the NBT test can be used to screen for bacterial and fungal illnesses in a febrile pregnant patient as well as in the general population.