63 research outputs found
Resurgence of Cocaine-Seeking in Rats Following Long Access and Punishment
No full textStrategies that provide access to alternative non-drug rewards are among the most effective at reducing substance use in individuals with substance use disorders, but relapse often occurs when alternative rewards are removed. Relapse induced by the loss of alternative rewards is called resurgence, and represents a challenge to otherwise effective strategies for reducing drug use. An animal model has been useful for studying resurgence, but the extant model has two limitations. First, humans usually refer to the negative consequences of drug use as the reason they stop taking drugs, but the extant model uses drug unavailability to reduce drug seeking. Second, individuals with substance use disorders display behaviors that can be summarized as uncontrolled drug seeking, but the extant model does not simulate uncontrolled drug seeking. Chapter 2 addressed the first concern by studying resurgence of previously-punished cocaine seeking. Chapter 3 addressed the second concern by using procedures shown to simulate uncontrolled drug seeking in rats to study resurgence of previously-punished cocaine seeking. Chapter 2 showed that resurgence of cocaine seeking can occur following suppression by punishment, and Chapter 3 showed that resurgence may be unaffected following procedures shown to increase relapse in other models. The models developed herein should contribute to future research into resurgence by better simulating the conditions under which individuals with substance use disorders experience relapse
Novelty-induced locomotor behavior predicts heroin addiction vulnerability in male, but not female, rats
No full textRationaleThe ongoing rise in opioid use disorder (OUD) has made it imperative to better model the individual variation within the human population that contributes to OUD vulnerability. Using animal models that capture such variation can be a useful tool. Individual variation in novelty-induced locomotion is predictive of substance use disorder (SUD) propensity. In this model, rats are characterized as high-responders (HR) or low-responders (LR) using a median split based on distance travelled during a locomotor test, and HR rats are generally found to exhibit a more SUD vulnerable behavioral phenotype.ObjectivesThe HR/LR model has commonly been used to assess behaviors in male rats using psychostimulants, with limited knowledge of the predictive efficacy of this model in females or the use of an opioid as the reward. In the current study, we assessed several behaviors across the different phases of drug addiction (heroin taking, refraining, and seeking) in over 500 male and female heterogeneous stock rats run at two geographically separate locations. Rats were characterized as HRs or LRs within each sex for analysis.ResultsOverall, females exhibit a more OUD vulnerable phenotype relative to males. Additionally, the HR/LR model was predictive of OUD-like behaviors in male, but not female rats. Furthermore, phenotypes did not differ in anxiety-related behaviors, reacquisition of heroin-taking, or punished heroin-taking behavior in either sex.ConclusionsThese results emphasize the importance of assessing females in models of individual variation in SUD and highlight limitations in using the HR/LR model to assess OUD propensity
J Neurochem
No full textSubstance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.I01 BX004727/BX/BLRD VAUnited States/P20GM121310/University of Wyoming/DA012513/DA/NIDA NIH HHSUnited States/DP5 OD026407/OD/NIH HHSUnited States/DA003906/DA/NIDA NIH HHSUnited States/BX004727/U.S. Department of Veterans Affairs/DA046373/DA/NIDA NIH HHSUnited States/U01 DA045300/DA/NIDA NIH HHSUnited States/P20 GM121310/GM/NIGMS NIH HHSUnited States/R00 DA046522/DA/NIDA NIH HHSUnited States/R37 DA003906/DA/NIDA NIH HHSUnited States/P50 DA046373/DA/NIDA NIH HHSUnited States/R01 DA012513/DA/NIDA NIH HHSUnited States/K99 DA046522/DA/NIDA NIH HHSUnited States/R01 DA003906/DA/NIDA NIH HHSUnited States/DP5 OD026407/CD/ODCDC CDC HHSUnited States/DA046522/DA/NIDA NIH HHSUnited States
Resurgence as Choice in Context: Treatment duration and on/off alternative reinforcement
No full textDistinct Behavioral Profiles and Neuronal Correlates of Heroin Vulnerability Versus Resiliency in a Multi-Symptomatic Model of Heroin Use Disorder in Rats
No full textObjective: The behavioral , diagnostic heterogeneity within the opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting the translational relevance of the mechanistic research that is conducted in experimental animals. The authors hypothesized that a nonlinear clustering of OUD-like behavioral traits would capture population het- erogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles. Methods: Over 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors. A nonlinear stochastic block model clustering analysis was used to assign rats to OUD vulnerable, inter- mediate , resilient clusters. Additional behavioral tests and circuit analyses using c-fos protein activation were conducted on the vulnerable and resilient subpopulations. Results: OUD vulnerable rats exhibited greater heroin taking and seeking behaviors relative to those in the intermediate , resilient clusters. Akin to human OUD diagnosis, further vulnerable rat subclustering revealed subpopulations with different combinations of behavioral traits, including sex differences. Lastly, heroin cue-induced neuronal patterns of circuit activation differed between resilient and vul- nerable phenotypes. Behavioral sex differences were re- capitulated in patterns of circuitry activation, including preferential engagement of extended amygdala stress circuitry in males and cortico-striatal drug cue-seeking circuitry in females. Conclusion: Using a nonlinear clustering approach in rats, the analysis captured behavioral diagnostic heterogeneity reflective of human OUD diagnosis. OUD vulnerability and resiliency were associated with distinct neuronal activa- tion patterns, posing this approach as a translational tool in assessing neurobiological mechanisms underpinning OUD
Longer treatment with alternative non-drug reinforcement fails to reduce resurgence of cocaine or alcohol seeking in rats
No full textHigher rate alternative non-drug reinforcement produces faster suppression of cocaine seeking but more resurgence when removed
No full textRelapse following removal of an alternative source of reinforcement introduced during extinction of a target behavior is called resurgence. This form of relapse may be related to relapse of drug taking following loss of alternative non-drug reinforcement in human populations. Laboratory investigations of factors mediating resurgence with food-maintained behavior suggest higher rates of alternative reinforcement produce faster suppression of target behavior but paradoxically generate more relapse when alternative reinforcement is discontinued. At present, it is unknown if a similar effect occurs when target behavior is maintained by drug reinforcement and the alternative is a non-drug reinforcer. In the present experiment three groups of rats were trained to lever press for infusions of cocaine during baseline. Next, during treatment, cocaine reinforcement was suspended and an alternative response was reinforced with either high-rate, low-rate, or no alternative food reinforcement. Finally, all reinforcement was suspended to test for relapse of cocaine seeking. Higher rate alternative reinforcement produced faster elimination of cocaine seeking than lower rates or extinction alone, but when treatment was suspended resurgence of cocaine seeking occurred following only high-rate alternative reinforcement. Thus, although higher rate alternative reinforcement appears to more effectively suppress drug seeking, should it become unavailable, it can have the unfortunate effect of increasing relapse
Circuit selectivity in drug versus natural reward seeking behaviors
No full textSubstance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g. social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry necessary selectively for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate necessity of brain regions in drug- versus natural reward-associated behaviors
Beautiful Cleopatra Terrace, Mammoth Hot Springs, Yellowstone Nat. Park. Wyo.
No full textCLEOPATRA TERRACE, MAMMOTH HOT SPRINGS, YELLOWSTONE NAT. PARK. Following the pathway leading nearly N. across the incrustations from Hymen Terrace we come at a distance of about 750 ft. to the exquisite sculptures of Cleopatra Terrace, lifting pools of limpid blue water one above the other in shallow basins the semicircular sides of which seem carved in delicate fluting of alabaster and reddish brown stone. Over the lips of the basins the warm waters brim constantly, lending the sparkle of life to the hard surfaces beneath and steadily building the basins higher by the deposit of calcium carbonate, or travertine. What countless centuries have elapsed since the beginning of these activities of internal heat and percolating surface waters on Terrace Mountain may be imagined from the fact that the thickness of the beds of travertine beneath the springs is estimated at 300 ft. The brilliant and varied coloring which adds so much to the beauty of the terraces owes its existence to the presence of various species of thermal algae, low forms of minute plant life some of which are able to flourish at temperatures as high as 180° F. As the temperatures of the waters in the Mammoth Hot Springs are all below this, variously colored algae flourishing at different temperatures find dwelling places in different part of the same basins, lending infinite variety to the shadings, which run the gamut from rusty brown to pink, orange, yellow and green. On old terraces from which the water has withdrawn the colors quickly die out, leaving the mineral deposits themselves a dead, chalky white. (View looking N. Elev. 6,600 ft. Lat. 45° N.; Long. 111° W.
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